Clinical Review

The past year brought new information and guidance from the American College of Obstetricians and Gynecologists (ACOG) on many relevant obstetric topics, making it difficult to choose just a few for this Update. Opioid use in pregnancy was an obvious choice given the national media attention and the potential opportunity for intervention in pregnancy for both the mother and the fetus/newborn. Postpartum hemorrhage, an “oldie but goodie,” was chosen for several reasons: It got a new definition, a new focus on multidisciplinary care, and an exciting novel tool for the treatment toolbox. Finally, given the rapidly changing technology, new screening recommendations, and the complexity of counseling, carrier screening was chosen as a genetic hot topic for this year.

Opioids, obstetrics, and opportunities

Reddy UM, Davis JM, Ren Z, Greene MF; Opioid Use in Pregnancy, Neonatal Abstinence Syndrome, and Childhood Outcomes Workshop Invited Speakers. Opioid use in pregnancy, neonatal abstinence syndrome, and childhood outcomes: Executive summary of a joint workshop. Obstet Gynecol. 2017;130(1):10-28.

ACOG Committee on Obstetric Practice. ACOG committee opinion No. 711: Opioid use and opioid use disorder in pregnancy. Obstet Gynecol. 2017;130(2):e81-e94.

The term "opioid epidemic" is omnipresent in both the lay media and the medical literature. In the past decade, the United States has had a huge increase in the number of opioid prescriptions, the rate of admissions and deaths due to prescription opioid misuse and abuse, and an increased rate of heroin use attributed to prior prescription opioid use.

Obstetrics is unique in that opioid use and abuse disorders affect 2 patients simultaneously (the mother and fetus), and the treatment options are somewhat at odds in that they need to balance a stable maternal status and intrauterine environment with the risk of neonatal abstinence syndrome (NAS). Additionally, pregnancy is an opportunity for a woman with opioid use disorder to have access to medical care (possibly for the first time) leading to the diagnosis and treatment of her disease. As the clinicians on the front line, obstetricians therefore require education and guidance on best practice for management of opioid use in pregnancy.

In 2017, Reddy and colleagues, as part of a joint workshop on opioid use in pregnancy, and a committee opinion from ACOG provided the following recommendations.

Screening

Universally screen for substance use, starting at the first prenatal visit; this is recommended over risk factor-based screening.

Use a validated screening tool. A tool such as a questionnaire is recommended as the first-line screening test (for example, the 4Ps screen, the National Institute on Drug Abuse Quick Screen, and the CRAFFT Screening Interview).

Do not universally screen urine and hair for drugs. This type of screening has many limitations, such as the limited number of substances tested, false-positive results, and inaccurate determination of the frequency or timing of drug use. Information regarding the consequences of the test must be provided, and patient consent must be obtained prior to performing the test.

Treatment

Use medication-assisted treatment with buprenorphine or methadone, which is preferred to medically supervised withdrawal. Medication-assisted treatment prevents withdrawal symptoms and cravings, decreases the risk of relapse, improves compliance with prenatal care and addiction treatment programs, and leads to better obstetric outcomes (higher birth weight, lower rate of preterm birth, lower perinatal mortality).

Know that buprenorphine has several advantages over methadone, including the convenience of an outpatient prescription, a lower risk of overdose, and improved neonatal outcomes (higher birth weight, lower doses of morphine to treat NAS, shorter treatment duration).

Prioritize methadone as the preferred option for pregnant women who are already receiving methadone treatment (changing to buprenorphine may precipitate withdrawal), those with a long-standing history of or multi-substance abuse, and those who have failed other treatment programs.

Prenatal care

Screen for comorbid conditions such as sexually transmitted infections, other medications or substance use, social conditions, and mental health disorders.

Perform ultrasonography serially to monitor fetal growth because of the increased risk of fetal growth restriction.

Consult with anesthesiology for pain control recommendations for labor and delivery and with neonatalogy/pediatrics for NAS counseling.

Intrapartum/postpartum care

Recognize heightened pain. Women with opioid use disorder have increased sensitivity to painful stimuli.

Continue the maintenance dose of methadone or buprenorphine throughout hospitalization, with short-acting opioids added for a brief period for postoperative pain.

Prioritize regional anesthesia for pain control in labor or for cesarean delivery.

Consider alternative therapies such as regional blocks, nonopioid medications (nonsteroidal anti-inflammatory drugs, acetaminophen), or relaxation/mindfulness training.

Avoid mixed antagonist and agonist narcotics (butorphanol, nalbuphine, pentazocine) as they may cause acute withdrawal.

Encourage breastfeeding to decrease the severity of NAS and maternal stress and increase maternal-child bonding and maternal confidence.

Offer contraceptive counseling and services immediately postpartum in the hospital, with strong consideration for long-acting reversible contraception.

Opioid prescribing practices

Opioids are prescribed in excess post–cesarean delivery. Several recent studies have demonstrated that most women are prescribed opioids post–cesarean delivery in excess of the amount they use (median 30–40 tablets prescribed, median 20 tablets used).^1,2 The leftover opioid medication usually is not discarded and therefore is at risk for diversion or misuse. A small subset of patients will use all the opioids prescribed and feel as though they have not received enough medication.

Prescribe post–cesarean delivery opioids more appropriately by considering individual inpatient opioid requirements or a shared decision-making model.³

Prioritize acetaminophen and ibuprofen during breastfeeding. In a recent editorial in OBG Management, Robert L. Barbieri, MD, recommended that whenever possible, acetaminophen and ibuprofen should be the first-line treatment for breastfeeding women, and narcotics that are metabolized by CYP2D6 should be avoided to reduce the risk to the newborn.⁴

Read about new strategies for postpartum hemorrhage.

Postpartum hemorrhage: New definitions and new strategies for stemming the flow

ACOG Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin No. 183: Postpartum hemorrhage. Obstet Gynecol. 2017;130(4):e168-e186.

From the very first sentence of the new ACOG practice bulletin, postpartum hemorrhage (PPH) is redefined as "cumulative blood loss greater than or equal to 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process (includes intrapartum loss) regardless of route of delivery." Although this does not seem to be a huge change from the traditional teaching of a 500-mL blood loss at vaginal delivery and a 1,000-mL loss at cesarean delivery, it reflects a shift in focus from simply responding to a certain amount of bleeding to using a multidisciplinary action plan for treating this leading cause of maternal mortality worldwide.

Focus on developing a PPH action plan

As part of the shift toward a multidisciplinary action plan for PPH, all obstetric team members should be aware of the following:  

• For most postpartum women, by the time they begin to show signs of hemodynamic compromise, the amount of blood loss approaches 25% of their total blood volume (1,500 mL). Lactic acidosis, systemic inflammation, and a consumptive coagulopathy result.  
• Risk stratification prior to delivery, recognition and identification of the source of bleeding, and aggressive early resuscitation to prevent hypovolemia are paramount. Experience gleaned from trauma massive transfusion protocols suggests that judicious transfusion of packed red blood cells, fresh frozen plasma, and platelets in a 1:1:1 ratio is appropriate for obstetric patients. Additionally, patients with low fibrinogen levels should be treated with cryoprecipitate.  
• The use of fixed transfusion ratios and standardized protocols for recognition and management of PPH has been demonstrated to increase earlier intervention and resolution of hemorrhage at an earlier stage, although the maternal outcomes results have been mixed.  
• Multidisciplinary team drills and simulation exercises also should be considered to help solidify training of an institution's teams responsible for PPH response.

Novel management option: Tranexamic acid

In addition to these strategies, there is a new recommendation for managing refractory PPH: tranexamic acid, which works by binding to lysine receptors on plasminogen and plasmin, inhibiting plasmin-mediated fibrin degradation.5 Previously, tranexamic acid was known to be effective in trauma, heart surgery, and in patients with thrombophilias. Pacheco and colleagues recently demonstrated reduced mortality from obstetric bleeding if tranexamic acid was given within 3 hours of delivery, without increased thrombotic complications.⁵ ACOG recommends its use if initial medical therapy fails, while the World Health Organization strongly recommends that tranexamic acid be part of a standard PPH package for all cases of PPH (TABLE).⁶

Read about new ACOG guidance on prepregnancy and prenatal screening.

ACOG Committee on Genetics. Committee opinion No. 690: Carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129(3):e35-e40.

ACOG Committee on Genetics. Committee opinion No. 691: Carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41-e55.

Ideally, carrier screening should be offered prior to pregnancy to fully inform couples of their reproductive risks and options for pregnancy. If not performed in the preconception period, carrier screening should be offered to all pregnant women. If a patient chooses screening and screens positive for a particular disorder, her reproductive partner should then be offered screening so that the risk of having an affected child can be determined.

New ACOG guidance on prepregnancy and prenatal screening

Carrier screening recommendations have evolved as the technology available has expanded. All 3 of the following strategies now are considered "acceptable" according to 2 recently published ACOG committee opinions.

Traditional ethnic-specific carrier screening, previously ACOG's sole recommendation, involves offering specific genetic screening to patients from populations with a high prevalence for certain conditions. One such example is Tay-Sachs disease screening in Ashkenazi Jewish patients.

Panethnic screening, which takes into account mixed or uncertain backgrounds, involves screening for a certain panel of disorders and is available to all patients regardless of their background (for example, cystic fibrosis screening offered to all pregnant patients).

Expanded carrier screening is when a large number of disorders can be screened for simultaneously for a lower cost than previous testing strategies. Expanded carrier screening panels vary in number and which conditions are tested by the laboratory. An ideal expanded carrier screening panel has been debated in the literature but not agreed on.⁷

ObGyns and practices therefore are encouraged to develop a standard counseling and screening protocol to offer to all their patients while being flexible to make available any patient-requested screening that is outside their protocol. Pretest and posttest counseling, including a thorough family history, is essential (as with any genetic testing) and should include residual risk after testing, potential need for specific familial mutation testing instead of general carrier screening, and issues with consanguinity.

Three essential screens

Regardless of the screening strategy chosen from the above options, 3 screening tests should be offered to all pregnant women or couples considering pregnancy (either individually or in the context of an expanded screening panel):

• Cystic fibrosis. At the least, a panel of the 23 most common mutations should be used. More expanded panels, which include hundreds of mutations, increase detection in non-Caucasian populations and for milder forms of the disease or infertility-related mutations.
• Hemoglobinopathies (sickle cell, α- and β-thalassemia). Complete blood count and red blood indices are recommended for all, with hemoglobin electrophoresis recommended for patients of African, Middle Eastern, Mediterranean, or West Indian descent or if mean corpuscular volume is low.
• Spinal muscular atrophy (SMA). The most recent addition to ACOG's recommendations for general carrier screening due to the relatively high carrier frequency (1-in-40 to 1-in-60) and the severity of the disease, SMA causes degeneration of the spinal cord neurons, skeletal muscular atrophy, and overall weakness. Screening is via polymerase chain reaction for SMN1 copy number: 2 copies are normal, and 1 copy indicates a carrier of the SMN1 deletion. About 3% to 4% of patients will screen negative but still will be "carriers" due to having 2 copies of the SMN1 gene on 1 chromosome and no copies on the other chromosome.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The past year brought new information and guidance from the American College of Obstetricians and Gynecologists (ACOG) on many relevant obstetric topics, making it difficult to choose just a few for this Update. Opioid use in pregnancy was an obvious choice given the national media attention and the potential opportunity for intervention in pregnancy for both the mother and the fetus/newborn. Postpartum hemorrhage, an “oldie but goodie,” was chosen for several reasons: It got a new definition, a new focus on multidisciplinary care, and an exciting novel tool for the treatment toolbox. Finally, given the rapidly changing technology, new screening recommendations, and the complexity of counseling, carrier screening was chosen as a genetic hot topic for this year.

Opioids, obstetrics, and opportunities

Reddy UM, Davis JM, Ren Z, Greene MF; Opioid Use in Pregnancy, Neonatal Abstinence Syndrome, and Childhood Outcomes Workshop Invited Speakers. Opioid use in pregnancy, neonatal abstinence syndrome, and childhood outcomes: Executive summary of a joint workshop. Obstet Gynecol. 2017;130(1):10-28.

ACOG Committee on Obstetric Practice. ACOG committee opinion No. 711: Opioid use and opioid use disorder in pregnancy. Obstet Gynecol. 2017;130(2):e81-e94.

The term "opioid epidemic" is omnipresent in both the lay media and the medical literature. In the past decade, the United States has had a huge increase in the number of opioid prescriptions, the rate of admissions and deaths due to prescription opioid misuse and abuse, and an increased rate of heroin use attributed to prior prescription opioid use.

Obstetrics is unique in that opioid use and abuse disorders affect 2 patients simultaneously (the mother and fetus), and the treatment options are somewhat at odds in that they need to balance a stable maternal status and intrauterine environment with the risk of neonatal abstinence syndrome (NAS). Additionally, pregnancy is an opportunity for a woman with opioid use disorder to have access to medical care (possibly for the first time) leading to the diagnosis and treatment of her disease. As the clinicians on the front line, obstetricians therefore require education and guidance on best practice for management of opioid use in pregnancy.

In 2017, Reddy and colleagues, as part of a joint workshop on opioid use in pregnancy, and a committee opinion from ACOG provided the following recommendations.

Screening

Universally screen for substance use, starting at the first prenatal visit; this is recommended over risk factor-based screening.

Use a validated screening tool. A tool such as a questionnaire is recommended as the first-line screening test (for example, the 4Ps screen, the National Institute on Drug Abuse Quick Screen, and the CRAFFT Screening Interview).

Do not universally screen urine and hair for drugs. This type of screening has many limitations, such as the limited number of substances tested, false-positive results, and inaccurate determination of the frequency or timing of drug use. Information regarding the consequences of the test must be provided, and patient consent must be obtained prior to performing the test.

Treatment

Use medication-assisted treatment with buprenorphine or methadone, which is preferred to medically supervised withdrawal. Medication-assisted treatment prevents withdrawal symptoms and cravings, decreases the risk of relapse, improves compliance with prenatal care and addiction treatment programs, and leads to better obstetric outcomes (higher birth weight, lower rate of preterm birth, lower perinatal mortality).

Know that buprenorphine has several advantages over methadone, including the convenience of an outpatient prescription, a lower risk of overdose, and improved neonatal outcomes (higher birth weight, lower doses of morphine to treat NAS, shorter treatment duration).

Prioritize methadone as the preferred option for pregnant women who are already receiving methadone treatment (changing to buprenorphine may precipitate withdrawal), those with a long-standing history of or multi-substance abuse, and those who have failed other treatment programs.

Prenatal care

Screen for comorbid conditions such as sexually transmitted infections, other medications or substance use, social conditions, and mental health disorders.

Perform ultrasonography serially to monitor fetal growth because of the increased risk of fetal growth restriction.

Consult with anesthesiology for pain control recommendations for labor and delivery and with neonatalogy/pediatrics for NAS counseling.

Intrapartum/postpartum care

Recognize heightened pain. Women with opioid use disorder have increased sensitivity to painful stimuli.

Continue the maintenance dose of methadone or buprenorphine throughout hospitalization, with short-acting opioids added for a brief period for postoperative pain.

Prioritize regional anesthesia for pain control in labor or for cesarean delivery.

Consider alternative therapies such as regional blocks, nonopioid medications (nonsteroidal anti-inflammatory drugs, acetaminophen), or relaxation/mindfulness training.

Avoid mixed antagonist and agonist narcotics (butorphanol, nalbuphine, pentazocine) as they may cause acute withdrawal.

Encourage breastfeeding to decrease the severity of NAS and maternal stress and increase maternal-child bonding and maternal confidence.

Offer contraceptive counseling and services immediately postpartum in the hospital, with strong consideration for long-acting reversible contraception.

Opioid prescribing practices

Opioids are prescribed in excess post–cesarean delivery. Several recent studies have demonstrated that most women are prescribed opioids post–cesarean delivery in excess of the amount they use (median 30–40 tablets prescribed, median 20 tablets used).^1,2 The leftover opioid medication usually is not discarded and therefore is at risk for diversion or misuse. A small subset of patients will use all the opioids prescribed and feel as though they have not received enough medication.

Prescribe post–cesarean delivery opioids more appropriately by considering individual inpatient opioid requirements or a shared decision-making model.³

Prioritize acetaminophen and ibuprofen during breastfeeding. In a recent editorial in OBG Management, Robert L. Barbieri, MD, recommended that whenever possible, acetaminophen and ibuprofen should be the first-line treatment for breastfeeding women, and narcotics that are metabolized by CYP2D6 should be avoided to reduce the risk to the newborn.⁴

Read about new strategies for postpartum hemorrhage.

Postpartum hemorrhage: New definitions and new strategies for stemming the flow

ACOG Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin No. 183: Postpartum hemorrhage. Obstet Gynecol. 2017;130(4):e168-e186.

From the very first sentence of the new ACOG practice bulletin, postpartum hemorrhage (PPH) is redefined as "cumulative blood loss greater than or equal to 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process (includes intrapartum loss) regardless of route of delivery." Although this does not seem to be a huge change from the traditional teaching of a 500-mL blood loss at vaginal delivery and a 1,000-mL loss at cesarean delivery, it reflects a shift in focus from simply responding to a certain amount of bleeding to using a multidisciplinary action plan for treating this leading cause of maternal mortality worldwide.

Focus on developing a PPH action plan

As part of the shift toward a multidisciplinary action plan for PPH, all obstetric team members should be aware of the following:  

• For most postpartum women, by the time they begin to show signs of hemodynamic compromise, the amount of blood loss approaches 25% of their total blood volume (1,500 mL). Lactic acidosis, systemic inflammation, and a consumptive coagulopathy result.  
• Risk stratification prior to delivery, recognition and identification of the source of bleeding, and aggressive early resuscitation to prevent hypovolemia are paramount. Experience gleaned from trauma massive transfusion protocols suggests that judicious transfusion of packed red blood cells, fresh frozen plasma, and platelets in a 1:1:1 ratio is appropriate for obstetric patients. Additionally, patients with low fibrinogen levels should be treated with cryoprecipitate.  
• The use of fixed transfusion ratios and standardized protocols for recognition and management of PPH has been demonstrated to increase earlier intervention and resolution of hemorrhage at an earlier stage, although the maternal outcomes results have been mixed.  
• Multidisciplinary team drills and simulation exercises also should be considered to help solidify training of an institution's teams responsible for PPH response.

Novel management option: Tranexamic acid

In addition to these strategies, there is a new recommendation for managing refractory PPH: tranexamic acid, which works by binding to lysine receptors on plasminogen and plasmin, inhibiting plasmin-mediated fibrin degradation.5 Previously, tranexamic acid was known to be effective in trauma, heart surgery, and in patients with thrombophilias. Pacheco and colleagues recently demonstrated reduced mortality from obstetric bleeding if tranexamic acid was given within 3 hours of delivery, without increased thrombotic complications.⁵ ACOG recommends its use if initial medical therapy fails, while the World Health Organization strongly recommends that tranexamic acid be part of a standard PPH package for all cases of PPH (TABLE).⁶

Read about new ACOG guidance on prepregnancy and prenatal screening.

ACOG Committee on Genetics. Committee opinion No. 690: Carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129(3):e35-e40.

ACOG Committee on Genetics. Committee opinion No. 691: Carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41-e55.

Ideally, carrier screening should be offered prior to pregnancy to fully inform couples of their reproductive risks and options for pregnancy. If not performed in the preconception period, carrier screening should be offered to all pregnant women. If a patient chooses screening and screens positive for a particular disorder, her reproductive partner should then be offered screening so that the risk of having an affected child can be determined.

New ACOG guidance on prepregnancy and prenatal screening

Carrier screening recommendations have evolved as the technology available has expanded. All 3 of the following strategies now are considered "acceptable" according to 2 recently published ACOG committee opinions.

Traditional ethnic-specific carrier screening, previously ACOG's sole recommendation, involves offering specific genetic screening to patients from populations with a high prevalence for certain conditions. One such example is Tay-Sachs disease screening in Ashkenazi Jewish patients.

Panethnic screening, which takes into account mixed or uncertain backgrounds, involves screening for a certain panel of disorders and is available to all patients regardless of their background (for example, cystic fibrosis screening offered to all pregnant patients).

Expanded carrier screening is when a large number of disorders can be screened for simultaneously for a lower cost than previous testing strategies. Expanded carrier screening panels vary in number and which conditions are tested by the laboratory. An ideal expanded carrier screening panel has been debated in the literature but not agreed on.⁷

ObGyns and practices therefore are encouraged to develop a standard counseling and screening protocol to offer to all their patients while being flexible to make available any patient-requested screening that is outside their protocol. Pretest and posttest counseling, including a thorough family history, is essential (as with any genetic testing) and should include residual risk after testing, potential need for specific familial mutation testing instead of general carrier screening, and issues with consanguinity.

Three essential screens

Regardless of the screening strategy chosen from the above options, 3 screening tests should be offered to all pregnant women or couples considering pregnancy (either individually or in the context of an expanded screening panel):

• Cystic fibrosis. At the least, a panel of the 23 most common mutations should be used. More expanded panels, which include hundreds of mutations, increase detection in non-Caucasian populations and for milder forms of the disease or infertility-related mutations.
• Hemoglobinopathies (sickle cell, α- and β-thalassemia). Complete blood count and red blood indices are recommended for all, with hemoglobin electrophoresis recommended for patients of African, Middle Eastern, Mediterranean, or West Indian descent or if mean corpuscular volume is low.
• Spinal muscular atrophy (SMA). The most recent addition to ACOG's recommendations for general carrier screening due to the relatively high carrier frequency (1-in-40 to 1-in-60) and the severity of the disease, SMA causes degeneration of the spinal cord neurons, skeletal muscular atrophy, and overall weakness. Screening is via polymerase chain reaction for SMN1 copy number: 2 copies are normal, and 1 copy indicates a carrier of the SMN1 deletion. About 3% to 4% of patients will screen negative but still will be "carriers" due to having 2 copies of the SMN1 gene on 1 chromosome and no copies on the other chromosome.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The past year brought new information and guidance from the American College of Obstetricians and Gynecologists (ACOG) on many relevant obstetric topics, making it difficult to choose just a few for this Update. Opioid use in pregnancy was an obvious choice given the national media attention and the potential opportunity for intervention in pregnancy for both the mother and the fetus/newborn. Postpartum hemorrhage, an “oldie but goodie,” was chosen for several reasons: It got a new definition, a new focus on multidisciplinary care, and an exciting novel tool for the treatment toolbox. Finally, given the rapidly changing technology, new screening recommendations, and the complexity of counseling, carrier screening was chosen as a genetic hot topic for this year.

Opioids, obstetrics, and opportunities

Reddy UM, Davis JM, Ren Z, Greene MF; Opioid Use in Pregnancy, Neonatal Abstinence Syndrome, and Childhood Outcomes Workshop Invited Speakers. Opioid use in pregnancy, neonatal abstinence syndrome, and childhood outcomes: Executive summary of a joint workshop. Obstet Gynecol. 2017;130(1):10-28.

ACOG Committee on Obstetric Practice. ACOG committee opinion No. 711: Opioid use and opioid use disorder in pregnancy. Obstet Gynecol. 2017;130(2):e81-e94.

The term "opioid epidemic" is omnipresent in both the lay media and the medical literature. In the past decade, the United States has had a huge increase in the number of opioid prescriptions, the rate of admissions and deaths due to prescription opioid misuse and abuse, and an increased rate of heroin use attributed to prior prescription opioid use.

Obstetrics is unique in that opioid use and abuse disorders affect 2 patients simultaneously (the mother and fetus), and the treatment options are somewhat at odds in that they need to balance a stable maternal status and intrauterine environment with the risk of neonatal abstinence syndrome (NAS). Additionally, pregnancy is an opportunity for a woman with opioid use disorder to have access to medical care (possibly for the first time) leading to the diagnosis and treatment of her disease. As the clinicians on the front line, obstetricians therefore require education and guidance on best practice for management of opioid use in pregnancy.

In 2017, Reddy and colleagues, as part of a joint workshop on opioid use in pregnancy, and a committee opinion from ACOG provided the following recommendations.

Screening

Universally screen for substance use, starting at the first prenatal visit; this is recommended over risk factor-based screening.

Use a validated screening tool. A tool such as a questionnaire is recommended as the first-line screening test (for example, the 4Ps screen, the National Institute on Drug Abuse Quick Screen, and the CRAFFT Screening Interview).

Do not universally screen urine and hair for drugs. This type of screening has many limitations, such as the limited number of substances tested, false-positive results, and inaccurate determination of the frequency or timing of drug use. Information regarding the consequences of the test must be provided, and patient consent must be obtained prior to performing the test.

Treatment

Use medication-assisted treatment with buprenorphine or methadone, which is preferred to medically supervised withdrawal. Medication-assisted treatment prevents withdrawal symptoms and cravings, decreases the risk of relapse, improves compliance with prenatal care and addiction treatment programs, and leads to better obstetric outcomes (higher birth weight, lower rate of preterm birth, lower perinatal mortality).

Know that buprenorphine has several advantages over methadone, including the convenience of an outpatient prescription, a lower risk of overdose, and improved neonatal outcomes (higher birth weight, lower doses of morphine to treat NAS, shorter treatment duration).

Prioritize methadone as the preferred option for pregnant women who are already receiving methadone treatment (changing to buprenorphine may precipitate withdrawal), those with a long-standing history of or multi-substance abuse, and those who have failed other treatment programs.

Prenatal care

Screen for comorbid conditions such as sexually transmitted infections, other medications or substance use, social conditions, and mental health disorders.

Perform ultrasonography serially to monitor fetal growth because of the increased risk of fetal growth restriction.

Consult with anesthesiology for pain control recommendations for labor and delivery and with neonatalogy/pediatrics for NAS counseling.

Intrapartum/postpartum care

Recognize heightened pain. Women with opioid use disorder have increased sensitivity to painful stimuli.

Continue the maintenance dose of methadone or buprenorphine throughout hospitalization, with short-acting opioids added for a brief period for postoperative pain.

Prioritize regional anesthesia for pain control in labor or for cesarean delivery.

Consider alternative therapies such as regional blocks, nonopioid medications (nonsteroidal anti-inflammatory drugs, acetaminophen), or relaxation/mindfulness training.

Avoid mixed antagonist and agonist narcotics (butorphanol, nalbuphine, pentazocine) as they may cause acute withdrawal.

Encourage breastfeeding to decrease the severity of NAS and maternal stress and increase maternal-child bonding and maternal confidence.

Offer contraceptive counseling and services immediately postpartum in the hospital, with strong consideration for long-acting reversible contraception.

Opioid prescribing practices

Opioids are prescribed in excess post–cesarean delivery. Several recent studies have demonstrated that most women are prescribed opioids post–cesarean delivery in excess of the amount they use (median 30–40 tablets prescribed, median 20 tablets used).^1,2 The leftover opioid medication usually is not discarded and therefore is at risk for diversion or misuse. A small subset of patients will use all the opioids prescribed and feel as though they have not received enough medication.

Prescribe post–cesarean delivery opioids more appropriately by considering individual inpatient opioid requirements or a shared decision-making model.³

Prioritize acetaminophen and ibuprofen during breastfeeding. In a recent editorial in OBG Management, Robert L. Barbieri, MD, recommended that whenever possible, acetaminophen and ibuprofen should be the first-line treatment for breastfeeding women, and narcotics that are metabolized by CYP2D6 should be avoided to reduce the risk to the newborn.⁴

Read about new strategies for postpartum hemorrhage.

Postpartum hemorrhage: New definitions and new strategies for stemming the flow

ACOG Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin No. 183: Postpartum hemorrhage. Obstet Gynecol. 2017;130(4):e168-e186.

From the very first sentence of the new ACOG practice bulletin, postpartum hemorrhage (PPH) is redefined as "cumulative blood loss greater than or equal to 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process (includes intrapartum loss) regardless of route of delivery." Although this does not seem to be a huge change from the traditional teaching of a 500-mL blood loss at vaginal delivery and a 1,000-mL loss at cesarean delivery, it reflects a shift in focus from simply responding to a certain amount of bleeding to using a multidisciplinary action plan for treating this leading cause of maternal mortality worldwide.

Focus on developing a PPH action plan

As part of the shift toward a multidisciplinary action plan for PPH, all obstetric team members should be aware of the following:  

• For most postpartum women, by the time they begin to show signs of hemodynamic compromise, the amount of blood loss approaches 25% of their total blood volume (1,500 mL). Lactic acidosis, systemic inflammation, and a consumptive coagulopathy result.  
• Risk stratification prior to delivery, recognition and identification of the source of bleeding, and aggressive early resuscitation to prevent hypovolemia are paramount. Experience gleaned from trauma massive transfusion protocols suggests that judicious transfusion of packed red blood cells, fresh frozen plasma, and platelets in a 1:1:1 ratio is appropriate for obstetric patients. Additionally, patients with low fibrinogen levels should be treated with cryoprecipitate.  
• The use of fixed transfusion ratios and standardized protocols for recognition and management of PPH has been demonstrated to increase earlier intervention and resolution of hemorrhage at an earlier stage, although the maternal outcomes results have been mixed.  
• Multidisciplinary team drills and simulation exercises also should be considered to help solidify training of an institution's teams responsible for PPH response.

Novel management option: Tranexamic acid

In addition to these strategies, there is a new recommendation for managing refractory PPH: tranexamic acid, which works by binding to lysine receptors on plasminogen and plasmin, inhibiting plasmin-mediated fibrin degradation.5 Previously, tranexamic acid was known to be effective in trauma, heart surgery, and in patients with thrombophilias. Pacheco and colleagues recently demonstrated reduced mortality from obstetric bleeding if tranexamic acid was given within 3 hours of delivery, without increased thrombotic complications.⁵ ACOG recommends its use if initial medical therapy fails, while the World Health Organization strongly recommends that tranexamic acid be part of a standard PPH package for all cases of PPH (TABLE).⁶

Read about new ACOG guidance on prepregnancy and prenatal screening.

ACOG Committee on Genetics. Committee opinion No. 690: Carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129(3):e35-e40.

ACOG Committee on Genetics. Committee opinion No. 691: Carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41-e55.

Ideally, carrier screening should be offered prior to pregnancy to fully inform couples of their reproductive risks and options for pregnancy. If not performed in the preconception period, carrier screening should be offered to all pregnant women. If a patient chooses screening and screens positive for a particular disorder, her reproductive partner should then be offered screening so that the risk of having an affected child can be determined.

New ACOG guidance on prepregnancy and prenatal screening

Carrier screening recommendations have evolved as the technology available has expanded. All 3 of the following strategies now are considered "acceptable" according to 2 recently published ACOG committee opinions.

Traditional ethnic-specific carrier screening, previously ACOG's sole recommendation, involves offering specific genetic screening to patients from populations with a high prevalence for certain conditions. One such example is Tay-Sachs disease screening in Ashkenazi Jewish patients.

Panethnic screening, which takes into account mixed or uncertain backgrounds, involves screening for a certain panel of disorders and is available to all patients regardless of their background (for example, cystic fibrosis screening offered to all pregnant patients).

Expanded carrier screening is when a large number of disorders can be screened for simultaneously for a lower cost than previous testing strategies. Expanded carrier screening panels vary in number and which conditions are tested by the laboratory. An ideal expanded carrier screening panel has been debated in the literature but not agreed on.⁷

ObGyns and practices therefore are encouraged to develop a standard counseling and screening protocol to offer to all their patients while being flexible to make available any patient-requested screening that is outside their protocol. Pretest and posttest counseling, including a thorough family history, is essential (as with any genetic testing) and should include residual risk after testing, potential need for specific familial mutation testing instead of general carrier screening, and issues with consanguinity.

Three essential screens

Regardless of the screening strategy chosen from the above options, 3 screening tests should be offered to all pregnant women or couples considering pregnancy (either individually or in the context of an expanded screening panel):

• Cystic fibrosis. At the least, a panel of the 23 most common mutations should be used. More expanded panels, which include hundreds of mutations, increase detection in non-Caucasian populations and for milder forms of the disease or infertility-related mutations.
• Hemoglobinopathies (sickle cell, α- and β-thalassemia). Complete blood count and red blood indices are recommended for all, with hemoglobin electrophoresis recommended for patients of African, Middle Eastern, Mediterranean, or West Indian descent or if mean corpuscular volume is low.
• Spinal muscular atrophy (SMA). The most recent addition to ACOG's recommendations for general carrier screening due to the relatively high carrier frequency (1-in-40 to 1-in-60) and the severity of the disease, SMA causes degeneration of the spinal cord neurons, skeletal muscular atrophy, and overall weakness. Screening is via polymerase chain reaction for SMN1 copy number: 2 copies are normal, and 1 copy indicates a carrier of the SMN1 deletion. About 3% to 4% of patients will screen negative but still will be "carriers" due to having 2 copies of the SMN1 gene on 1 chromosome and no copies on the other chromosome.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In the United States, circumcision is the fourth most common surgical procedure—behind cataract removal, cesarean delivery, and joint replacement.¹ This operation, which dates to ancient times, is chosen for medical, personal, or religious reasons. It is performed on 77% of males born in the United States and on 42% of those born elsewhere who are living in this country.² Whether it is performed depends not only on the parents’ race, ethnic background, and religion but also on region: US circumcision rates range from 74% in the Midwest to 30% in the West, and in between are the Northeast (67%) and the South (61%).³

Circumcision is not without controversy. Some claim that it is unnecessary cosmetic surgery, that it is genital mutilation, that the patient cannot choose it or object to it, or that it decreases sexual satisfaction.

In this article, I review 8 common questions about circumcision and provide data-based answers to them.

1. Should a newborn be circumcised?

For many years, the medical benefits of circumcision were scientifically ambiguous. With no clear answers, some thought that parents should base their decision for or against circumcision not on any potential medical benefit but rather on their family or religious tradition, or on a social standard, that is, what the majority of families in their community do.

Over the past 20 years, a growing body of evidence has demonstrated real medical benefits of circumcision. In 2012, the American Academy of Pediatrics (AAP), which previously had been neutral on the subject, issued a task force report concluding that the health benefits of circumcision outweigh its risks and justify access to the procedure.^3,4 However, the report stopped short of recommending circumcision.

Opponents have expressed several concerns about circumcision. First, they say, it is painful and unnecessary, and performing it when life has just begun takes the decision away from the adult-to-be, who may want to be uncircumcised as an adult but will have no recourse. Second, they say circumcision will diminish the adult’s sexual pleasure. However, there is no proof this occurs, and it is unclear how the claim could be adequately verified.⁵

2. What is the best analgesia for circumcision?

Although in decades past circumcision was often performed without any analgesia, in the United States analgesia is now standard of care. The AAP Task Force on Circumcision formalized this standard in a 2012 policy statement.⁴ For newborn circumcision, analgesia can be given in the form of analgesic cream, penile ring block, or dorsal nerve block.

Analgesic EMLA cream (a mixture of local anesthetics such as lidocaine 2.5%/prilocaine 2.5%) is easy to use but is minimally effective in relieving circumcision pain,⁶ although some investigators have reported it is efficacious compared with placebo.⁷ When used, the analgesic cream is applied 30 to 60 minutes before circumcision.

Both penile ring block and dorsal nerve block with 1% lidocaine are easy to administer and are very effective.^8,9 They are best used with buffered lidocaine, which partially relieves the burning that occurs with injection. With both methods, the smaller the needle used (preferably 30 gauge), the better.

These 2 block methods have different injection sites. For the ring block, small amounts of lidocaine (1 to 1.5 mL) are given in a series of injections around the entire circumference of the base of the penis. The dorsal block targets the 2 dorsal nerves located at 10 o’clock and 2 o’clock at the base of the penis. Epinephrine, given its vasoconstrictive properties and the potential for necrosis, should never be used with local analgesia for penile infiltration.

Analgesia can be supplemented with comfort measures, such as a pacifier, sugar water, gentle rubbing on the forehead, and soothing speech.¹⁰

Related article:
Circumcision impedes viral disease. Will opposition fade?

3. What conditions are required for safe circumcision?

As circumcision is not medically required and need not occur in the days immediately after birth, it should be performed only when conditions are optimal:

• A pediatrician or other practitioner must first examine the newborn.
• The newborn must be full-term, healthy, and stable.
  • The best time to circumcise a baby born prematurely is right before discharge from the intensive care nursery.
• The penis must be of normal size and without anatomical defect—no micropenis, hypospadias, or penoscrotal webbing.
• The lower abdominal fat pad must not be so large that it will cause the shaft’s skin to cover the exposed penile head.
• If there is a family history of a bleeding disorder, the newborn must be evaluated for the disorder before the circumcision.
• The newborn must have received his vitamin K shot.

4. What is the best circumcision method?

Circumcision can be performed with the Gomco circumcision clamp, the Mogen circumcision clamp, or the PlastiBell circumcision device. Each device works well, provides excellent results, and has its pluses and minuses. Practitioners should use the device with which they are most familiar and comfortable, which likely will be the device they used in training.

In the United States, the Gomco clamp is perhaps the most commonly used device. It provides good cosmetic results, and its metal “bell” protects the entire head of the penis. Of the 3 methods, however, it is the most difficult—the partially cut foreskin must be threaded between the bell and the clamp frame before the clamp is tightened. In many cases, too, there is bleeding at the penile frenulum.

The Mogen clamp, another commonly used device, also is used in traditional Jewish circumcisions. Of the 3 methods, it is the quickest, produces the best hemostasis, and is associated with the least discomfort.¹⁰ To those unfamiliar with the method, there may seem to be a potential for amputation of the head of the penis, but actually there virtually is no risk, as an indentation on the penile side of the clamp protects the penile head.

The PlastiBell device is very easy to use but must stay on until the foreskin becomes necrotic and the bell and foreskin fall off on their own—a process that takes 7 to 10 days. Many parents dislike this method because its final result is not immediate and they have to contend with a medical implement during their newborn’s first week home.

Electrocautery is not recommended. Some clinicians, especially urologists, use electrocautery as the cutting mechanism for circumcision. A review of the literature, however, reveals that electrocautery has not been studied head-to-head against traditional techniques, and that various significant complications—transected penile head, severe burns, meatal stenosis—have been reported.^11,12 It is certainly not a mainstream procedure for neonatal circumcision.

Evaluate penile anatomy for abnormalities

Before performing any circumcision, the head of the penis should be examined to rule out hypospadias or other penile abnormalities. This is because the foreskin is utilized in certain penile repair procedures. The pediatrician should perform an initial examination of the penis at the formal newborn physical within 24 hours of delivery. The clinician performing the circumcision should re-examine the penis just before the procedure is begun—by pushing back the foreskin as much as possible—as well as during the procedure, once the foreskin is lifted off the penile head but before the foreskin is excised.

Read about how to ensure the best outcome of circumcision.

5. When is the best time to perform a circumcision?

The medical literature provides no firm answer to this question. The younger the baby, the easier it is to perform a circumcision as a simple procedure with local anesthesia. The older the baby, the larger the penis and the more aware the baby will be of his surroundings. Both these factors will make the procedure more difficult.

Most clinicians would be reluctant to perform a circumcision in the office or clinic after the baby is 6 to 8 weeks old. If a family desires their son to be circumcised after that time—or a medical condition precludes earlier circumcision—the procedure is best performed by a pediatric urologist in the operating room.

Related article:
Circumcision accident: $1.3M verdict

6. What are the potential complications of circumcision?

The rate of circumcision complications is very low: 0.2%.¹³ That being said, the 3 most common types of complications are postoperative bleeding, infection, and damage to the penis.

Far and away the most common complication is postoperative bleeding , usually at the frenulum of the head of the penis (the 6 o’clock position). In most cases, the bleeding is light to moderate. It is controlled with direct pressure applied for several minutes, the use of processed gelatin (Gelfoam) or cellulose (Surgicel), sparing use of silver nitrate, or placement of a polyglycolic acid (Vicryl) 5-0 suture.

Infection, an unusual occurrence, is seen within 24 to 72 hours after circumcision. It is marked by swelling, redness, and a foul-smelling mucus discharge. This discharge must be differentiated from dried fibrin, which is commonly seen on the head of the penis in the days after circumcision but has no odor or association with erythema, fever, or infant fussiness. True infection should be treated, in collaboration with the child’s pediatrician, with a staphylococcal-sensitive penicillin (such as dicloxacillin).

More serious is damage to the penis, which ranges from accidental dilation of the meatus to partial amputation of the penile glans. Any such injury should immediately prompt a consultation with a pediatric urologist.

More of a nuisance than a complication is the sliding of the penile shaft’s skin up and over the glans. This is a relatively frequent occurrence after normal, successful circumcisions. Parents of an affected newborn should be instructed to gently slide the skin back until the head of the penis is completely exposed again. After several days, the skin will adhere to its proper position on the shaft.

7. What is a Jewish ritual circumcision?

For their newborn’s circumcision, Jewish parents may choose a bris ceremony, formally called a brit milah, in fulfillment of religious tradition. The ceremony involves a brief religious service, circumcision with the traditional Mogen clamp, a special blessing, and an official religious naming rite. The bris traditionally is performed by a mohel, a rabbi or other religious official trained in circumcision. Many parents have the bris done by a mohel who is a medical doctor. In the United States, the availability of both types of mohels varies.

8. Who should perform circumcisions—obstetricians or pediatricians?

The answer to this question depends on where you practice. In some communities or hospitals, the obstetrician performs newborn circumcision, while in other places the pediatrician does. In addition, depending on local circumstances or the specific population involved, circumcisions may be performed by a pediatric urologist, nurse practitioner, or even out of hospital by a trained religiously affiliated practitioner.

Obstetricians began doing circumcisions for 2 reasons. First, obstetricians are surgically trained whereas pediatricians are not. It was therefore thought to be more appropriate for obstetricians to do this minor surgical procedure. Second, circumcisions used to be done right in the delivery room shortly after delivery. It was thought that the crying induced by performing the circumcision helped clear the baby’s lungs and invigorated sluggish babies. Now, however, in-hospital circumcisions are usually done in the days following delivery, after the baby has had the opportunity to undergo his first physical examination to make sure that all is well and that the penile anatomy is normal.

Clinician experience, proper protocol contribute to a safe procedure

In the United States, a large percentage of male infants are circumcised. Although circumcision has known medical benefits, the procedure generally is performed for family, religious, or cultural reasons. Circumcision is a safe and straightforward procedure but has its risks and potential complications. As with most surgeries, the best outcomes are achieved by practitioners who are well trained, who perform the procedure under supervision until their experience is sufficient, and who follow correct protocol during the entire operation.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In the United States, circumcision is the fourth most common surgical procedure—behind cataract removal, cesarean delivery, and joint replacement.¹ This operation, which dates to ancient times, is chosen for medical, personal, or religious reasons. It is performed on 77% of males born in the United States and on 42% of those born elsewhere who are living in this country.² Whether it is performed depends not only on the parents’ race, ethnic background, and religion but also on region: US circumcision rates range from 74% in the Midwest to 30% in the West, and in between are the Northeast (67%) and the South (61%).³

Circumcision is not without controversy. Some claim that it is unnecessary cosmetic surgery, that it is genital mutilation, that the patient cannot choose it or object to it, or that it decreases sexual satisfaction.

In this article, I review 8 common questions about circumcision and provide data-based answers to them.

1. Should a newborn be circumcised?

For many years, the medical benefits of circumcision were scientifically ambiguous. With no clear answers, some thought that parents should base their decision for or against circumcision not on any potential medical benefit but rather on their family or religious tradition, or on a social standard, that is, what the majority of families in their community do.

Over the past 20 years, a growing body of evidence has demonstrated real medical benefits of circumcision. In 2012, the American Academy of Pediatrics (AAP), which previously had been neutral on the subject, issued a task force report concluding that the health benefits of circumcision outweigh its risks and justify access to the procedure.^3,4 However, the report stopped short of recommending circumcision.

Opponents have expressed several concerns about circumcision. First, they say, it is painful and unnecessary, and performing it when life has just begun takes the decision away from the adult-to-be, who may want to be uncircumcised as an adult but will have no recourse. Second, they say circumcision will diminish the adult’s sexual pleasure. However, there is no proof this occurs, and it is unclear how the claim could be adequately verified.⁵

2. What is the best analgesia for circumcision?

Although in decades past circumcision was often performed without any analgesia, in the United States analgesia is now standard of care. The AAP Task Force on Circumcision formalized this standard in a 2012 policy statement.⁴ For newborn circumcision, analgesia can be given in the form of analgesic cream, penile ring block, or dorsal nerve block.

Analgesic EMLA cream (a mixture of local anesthetics such as lidocaine 2.5%/prilocaine 2.5%) is easy to use but is minimally effective in relieving circumcision pain,⁶ although some investigators have reported it is efficacious compared with placebo.⁷ When used, the analgesic cream is applied 30 to 60 minutes before circumcision.

Both penile ring block and dorsal nerve block with 1% lidocaine are easy to administer and are very effective.^8,9 They are best used with buffered lidocaine, which partially relieves the burning that occurs with injection. With both methods, the smaller the needle used (preferably 30 gauge), the better.

These 2 block methods have different injection sites. For the ring block, small amounts of lidocaine (1 to 1.5 mL) are given in a series of injections around the entire circumference of the base of the penis. The dorsal block targets the 2 dorsal nerves located at 10 o’clock and 2 o’clock at the base of the penis. Epinephrine, given its vasoconstrictive properties and the potential for necrosis, should never be used with local analgesia for penile infiltration.

Analgesia can be supplemented with comfort measures, such as a pacifier, sugar water, gentle rubbing on the forehead, and soothing speech.¹⁰

Related article:
Circumcision impedes viral disease. Will opposition fade?

3. What conditions are required for safe circumcision?

As circumcision is not medically required and need not occur in the days immediately after birth, it should be performed only when conditions are optimal:

• A pediatrician or other practitioner must first examine the newborn.
• The newborn must be full-term, healthy, and stable.
  • The best time to circumcise a baby born prematurely is right before discharge from the intensive care nursery.
• The penis must be of normal size and without anatomical defect—no micropenis, hypospadias, or penoscrotal webbing.
• The lower abdominal fat pad must not be so large that it will cause the shaft’s skin to cover the exposed penile head.
• If there is a family history of a bleeding disorder, the newborn must be evaluated for the disorder before the circumcision.
• The newborn must have received his vitamin K shot.

4. What is the best circumcision method?

Circumcision can be performed with the Gomco circumcision clamp, the Mogen circumcision clamp, or the PlastiBell circumcision device. Each device works well, provides excellent results, and has its pluses and minuses. Practitioners should use the device with which they are most familiar and comfortable, which likely will be the device they used in training.

In the United States, the Gomco clamp is perhaps the most commonly used device. It provides good cosmetic results, and its metal “bell” protects the entire head of the penis. Of the 3 methods, however, it is the most difficult—the partially cut foreskin must be threaded between the bell and the clamp frame before the clamp is tightened. In many cases, too, there is bleeding at the penile frenulum.

The Mogen clamp, another commonly used device, also is used in traditional Jewish circumcisions. Of the 3 methods, it is the quickest, produces the best hemostasis, and is associated with the least discomfort.¹⁰ To those unfamiliar with the method, there may seem to be a potential for amputation of the head of the penis, but actually there virtually is no risk, as an indentation on the penile side of the clamp protects the penile head.

The PlastiBell device is very easy to use but must stay on until the foreskin becomes necrotic and the bell and foreskin fall off on their own—a process that takes 7 to 10 days. Many parents dislike this method because its final result is not immediate and they have to contend with a medical implement during their newborn’s first week home.

Electrocautery is not recommended. Some clinicians, especially urologists, use electrocautery as the cutting mechanism for circumcision. A review of the literature, however, reveals that electrocautery has not been studied head-to-head against traditional techniques, and that various significant complications—transected penile head, severe burns, meatal stenosis—have been reported.^11,12 It is certainly not a mainstream procedure for neonatal circumcision.

Evaluate penile anatomy for abnormalities

Before performing any circumcision, the head of the penis should be examined to rule out hypospadias or other penile abnormalities. This is because the foreskin is utilized in certain penile repair procedures. The pediatrician should perform an initial examination of the penis at the formal newborn physical within 24 hours of delivery. The clinician performing the circumcision should re-examine the penis just before the procedure is begun—by pushing back the foreskin as much as possible—as well as during the procedure, once the foreskin is lifted off the penile head but before the foreskin is excised.

Read about how to ensure the best outcome of circumcision.

5. When is the best time to perform a circumcision?

The medical literature provides no firm answer to this question. The younger the baby, the easier it is to perform a circumcision as a simple procedure with local anesthesia. The older the baby, the larger the penis and the more aware the baby will be of his surroundings. Both these factors will make the procedure more difficult.

Most clinicians would be reluctant to perform a circumcision in the office or clinic after the baby is 6 to 8 weeks old. If a family desires their son to be circumcised after that time—or a medical condition precludes earlier circumcision—the procedure is best performed by a pediatric urologist in the operating room.

Related article:
Circumcision accident: $1.3M verdict

6. What are the potential complications of circumcision?

The rate of circumcision complications is very low: 0.2%.¹³ That being said, the 3 most common types of complications are postoperative bleeding, infection, and damage to the penis.

Far and away the most common complication is postoperative bleeding , usually at the frenulum of the head of the penis (the 6 o’clock position). In most cases, the bleeding is light to moderate. It is controlled with direct pressure applied for several minutes, the use of processed gelatin (Gelfoam) or cellulose (Surgicel), sparing use of silver nitrate, or placement of a polyglycolic acid (Vicryl) 5-0 suture.

Infection, an unusual occurrence, is seen within 24 to 72 hours after circumcision. It is marked by swelling, redness, and a foul-smelling mucus discharge. This discharge must be differentiated from dried fibrin, which is commonly seen on the head of the penis in the days after circumcision but has no odor or association with erythema, fever, or infant fussiness. True infection should be treated, in collaboration with the child’s pediatrician, with a staphylococcal-sensitive penicillin (such as dicloxacillin).

More serious is damage to the penis, which ranges from accidental dilation of the meatus to partial amputation of the penile glans. Any such injury should immediately prompt a consultation with a pediatric urologist.

More of a nuisance than a complication is the sliding of the penile shaft’s skin up and over the glans. This is a relatively frequent occurrence after normal, successful circumcisions. Parents of an affected newborn should be instructed to gently slide the skin back until the head of the penis is completely exposed again. After several days, the skin will adhere to its proper position on the shaft.

7. What is a Jewish ritual circumcision?

For their newborn’s circumcision, Jewish parents may choose a bris ceremony, formally called a brit milah, in fulfillment of religious tradition. The ceremony involves a brief religious service, circumcision with the traditional Mogen clamp, a special blessing, and an official religious naming rite. The bris traditionally is performed by a mohel, a rabbi or other religious official trained in circumcision. Many parents have the bris done by a mohel who is a medical doctor. In the United States, the availability of both types of mohels varies.

8. Who should perform circumcisions—obstetricians or pediatricians?

The answer to this question depends on where you practice. In some communities or hospitals, the obstetrician performs newborn circumcision, while in other places the pediatrician does. In addition, depending on local circumstances or the specific population involved, circumcisions may be performed by a pediatric urologist, nurse practitioner, or even out of hospital by a trained religiously affiliated practitioner.

Obstetricians began doing circumcisions for 2 reasons. First, obstetricians are surgically trained whereas pediatricians are not. It was therefore thought to be more appropriate for obstetricians to do this minor surgical procedure. Second, circumcisions used to be done right in the delivery room shortly after delivery. It was thought that the crying induced by performing the circumcision helped clear the baby’s lungs and invigorated sluggish babies. Now, however, in-hospital circumcisions are usually done in the days following delivery, after the baby has had the opportunity to undergo his first physical examination to make sure that all is well and that the penile anatomy is normal.

Clinician experience, proper protocol contribute to a safe procedure

In the United States, a large percentage of male infants are circumcised. Although circumcision has known medical benefits, the procedure generally is performed for family, religious, or cultural reasons. Circumcision is a safe and straightforward procedure but has its risks and potential complications. As with most surgeries, the best outcomes are achieved by practitioners who are well trained, who perform the procedure under supervision until their experience is sufficient, and who follow correct protocol during the entire operation.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In the United States, circumcision is the fourth most common surgical procedure—behind cataract removal, cesarean delivery, and joint replacement.¹ This operation, which dates to ancient times, is chosen for medical, personal, or religious reasons. It is performed on 77% of males born in the United States and on 42% of those born elsewhere who are living in this country.² Whether it is performed depends not only on the parents’ race, ethnic background, and religion but also on region: US circumcision rates range from 74% in the Midwest to 30% in the West, and in between are the Northeast (67%) and the South (61%).³

Circumcision is not without controversy. Some claim that it is unnecessary cosmetic surgery, that it is genital mutilation, that the patient cannot choose it or object to it, or that it decreases sexual satisfaction.

In this article, I review 8 common questions about circumcision and provide data-based answers to them.

1. Should a newborn be circumcised?

For many years, the medical benefits of circumcision were scientifically ambiguous. With no clear answers, some thought that parents should base their decision for or against circumcision not on any potential medical benefit but rather on their family or religious tradition, or on a social standard, that is, what the majority of families in their community do.

Over the past 20 years, a growing body of evidence has demonstrated real medical benefits of circumcision. In 2012, the American Academy of Pediatrics (AAP), which previously had been neutral on the subject, issued a task force report concluding that the health benefits of circumcision outweigh its risks and justify access to the procedure.^3,4 However, the report stopped short of recommending circumcision.

Opponents have expressed several concerns about circumcision. First, they say, it is painful and unnecessary, and performing it when life has just begun takes the decision away from the adult-to-be, who may want to be uncircumcised as an adult but will have no recourse. Second, they say circumcision will diminish the adult’s sexual pleasure. However, there is no proof this occurs, and it is unclear how the claim could be adequately verified.⁵

2. What is the best analgesia for circumcision?

Although in decades past circumcision was often performed without any analgesia, in the United States analgesia is now standard of care. The AAP Task Force on Circumcision formalized this standard in a 2012 policy statement.⁴ For newborn circumcision, analgesia can be given in the form of analgesic cream, penile ring block, or dorsal nerve block.

Analgesic EMLA cream (a mixture of local anesthetics such as lidocaine 2.5%/prilocaine 2.5%) is easy to use but is minimally effective in relieving circumcision pain,⁶ although some investigators have reported it is efficacious compared with placebo.⁷ When used, the analgesic cream is applied 30 to 60 minutes before circumcision.

Both penile ring block and dorsal nerve block with 1% lidocaine are easy to administer and are very effective.^8,9 They are best used with buffered lidocaine, which partially relieves the burning that occurs with injection. With both methods, the smaller the needle used (preferably 30 gauge), the better.

These 2 block methods have different injection sites. For the ring block, small amounts of lidocaine (1 to 1.5 mL) are given in a series of injections around the entire circumference of the base of the penis. The dorsal block targets the 2 dorsal nerves located at 10 o’clock and 2 o’clock at the base of the penis. Epinephrine, given its vasoconstrictive properties and the potential for necrosis, should never be used with local analgesia for penile infiltration.

Analgesia can be supplemented with comfort measures, such as a pacifier, sugar water, gentle rubbing on the forehead, and soothing speech.¹⁰

Related article:
Circumcision impedes viral disease. Will opposition fade?

3. What conditions are required for safe circumcision?

As circumcision is not medically required and need not occur in the days immediately after birth, it should be performed only when conditions are optimal:

• A pediatrician or other practitioner must first examine the newborn.
• The newborn must be full-term, healthy, and stable.
  • The best time to circumcise a baby born prematurely is right before discharge from the intensive care nursery.
• The penis must be of normal size and without anatomical defect—no micropenis, hypospadias, or penoscrotal webbing.
• The lower abdominal fat pad must not be so large that it will cause the shaft’s skin to cover the exposed penile head.
• If there is a family history of a bleeding disorder, the newborn must be evaluated for the disorder before the circumcision.
• The newborn must have received his vitamin K shot.

4. What is the best circumcision method?

Circumcision can be performed with the Gomco circumcision clamp, the Mogen circumcision clamp, or the PlastiBell circumcision device. Each device works well, provides excellent results, and has its pluses and minuses. Practitioners should use the device with which they are most familiar and comfortable, which likely will be the device they used in training.

In the United States, the Gomco clamp is perhaps the most commonly used device. It provides good cosmetic results, and its metal “bell” protects the entire head of the penis. Of the 3 methods, however, it is the most difficult—the partially cut foreskin must be threaded between the bell and the clamp frame before the clamp is tightened. In many cases, too, there is bleeding at the penile frenulum.

The Mogen clamp, another commonly used device, also is used in traditional Jewish circumcisions. Of the 3 methods, it is the quickest, produces the best hemostasis, and is associated with the least discomfort.¹⁰ To those unfamiliar with the method, there may seem to be a potential for amputation of the head of the penis, but actually there virtually is no risk, as an indentation on the penile side of the clamp protects the penile head.

The PlastiBell device is very easy to use but must stay on until the foreskin becomes necrotic and the bell and foreskin fall off on their own—a process that takes 7 to 10 days. Many parents dislike this method because its final result is not immediate and they have to contend with a medical implement during their newborn’s first week home.

Electrocautery is not recommended. Some clinicians, especially urologists, use electrocautery as the cutting mechanism for circumcision. A review of the literature, however, reveals that electrocautery has not been studied head-to-head against traditional techniques, and that various significant complications—transected penile head, severe burns, meatal stenosis—have been reported.^11,12 It is certainly not a mainstream procedure for neonatal circumcision.

Evaluate penile anatomy for abnormalities

Before performing any circumcision, the head of the penis should be examined to rule out hypospadias or other penile abnormalities. This is because the foreskin is utilized in certain penile repair procedures. The pediatrician should perform an initial examination of the penis at the formal newborn physical within 24 hours of delivery. The clinician performing the circumcision should re-examine the penis just before the procedure is begun—by pushing back the foreskin as much as possible—as well as during the procedure, once the foreskin is lifted off the penile head but before the foreskin is excised.

Read about how to ensure the best outcome of circumcision.

5. When is the best time to perform a circumcision?

The medical literature provides no firm answer to this question. The younger the baby, the easier it is to perform a circumcision as a simple procedure with local anesthesia. The older the baby, the larger the penis and the more aware the baby will be of his surroundings. Both these factors will make the procedure more difficult.

Most clinicians would be reluctant to perform a circumcision in the office or clinic after the baby is 6 to 8 weeks old. If a family desires their son to be circumcised after that time—or a medical condition precludes earlier circumcision—the procedure is best performed by a pediatric urologist in the operating room.

Related article:
Circumcision accident: $1.3M verdict

6. What are the potential complications of circumcision?

The rate of circumcision complications is very low: 0.2%.¹³ That being said, the 3 most common types of complications are postoperative bleeding, infection, and damage to the penis.

Far and away the most common complication is postoperative bleeding , usually at the frenulum of the head of the penis (the 6 o’clock position). In most cases, the bleeding is light to moderate. It is controlled with direct pressure applied for several minutes, the use of processed gelatin (Gelfoam) or cellulose (Surgicel), sparing use of silver nitrate, or placement of a polyglycolic acid (Vicryl) 5-0 suture.

Infection, an unusual occurrence, is seen within 24 to 72 hours after circumcision. It is marked by swelling, redness, and a foul-smelling mucus discharge. This discharge must be differentiated from dried fibrin, which is commonly seen on the head of the penis in the days after circumcision but has no odor or association with erythema, fever, or infant fussiness. True infection should be treated, in collaboration with the child’s pediatrician, with a staphylococcal-sensitive penicillin (such as dicloxacillin).

More serious is damage to the penis, which ranges from accidental dilation of the meatus to partial amputation of the penile glans. Any such injury should immediately prompt a consultation with a pediatric urologist.

More of a nuisance than a complication is the sliding of the penile shaft’s skin up and over the glans. This is a relatively frequent occurrence after normal, successful circumcisions. Parents of an affected newborn should be instructed to gently slide the skin back until the head of the penis is completely exposed again. After several days, the skin will adhere to its proper position on the shaft.

7. What is a Jewish ritual circumcision?

For their newborn’s circumcision, Jewish parents may choose a bris ceremony, formally called a brit milah, in fulfillment of religious tradition. The ceremony involves a brief religious service, circumcision with the traditional Mogen clamp, a special blessing, and an official religious naming rite. The bris traditionally is performed by a mohel, a rabbi or other religious official trained in circumcision. Many parents have the bris done by a mohel who is a medical doctor. In the United States, the availability of both types of mohels varies.

8. Who should perform circumcisions—obstetricians or pediatricians?

The answer to this question depends on where you practice. In some communities or hospitals, the obstetrician performs newborn circumcision, while in other places the pediatrician does. In addition, depending on local circumstances or the specific population involved, circumcisions may be performed by a pediatric urologist, nurse practitioner, or even out of hospital by a trained religiously affiliated practitioner.

Obstetricians began doing circumcisions for 2 reasons. First, obstetricians are surgically trained whereas pediatricians are not. It was therefore thought to be more appropriate for obstetricians to do this minor surgical procedure. Second, circumcisions used to be done right in the delivery room shortly after delivery. It was thought that the crying induced by performing the circumcision helped clear the baby’s lungs and invigorated sluggish babies. Now, however, in-hospital circumcisions are usually done in the days following delivery, after the baby has had the opportunity to undergo his first physical examination to make sure that all is well and that the penile anatomy is normal.

Clinician experience, proper protocol contribute to a safe procedure

In the United States, a large percentage of male infants are circumcised. Although circumcision has known medical benefits, the procedure generally is performed for family, religious, or cultural reasons. Circumcision is a safe and straightforward procedure but has its risks and potential complications. As with most surgeries, the best outcomes are achieved by practitioners who are well trained, who perform the procedure under supervision until their experience is sufficient, and who follow correct protocol during the entire operation.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

More than 39.5 million people in the U.S. have been diagnosed with asthma, and about 3,400 deaths occur annually due to asthma complications.¹ Although the prevalence of atopy and asthma have increased over the past few decades in western countries, control and outcomes are improving.² Use of asthma protocols and early recognition by the primary care provider (PCP) are among the main reasons for trends toward decreased hospitalization and fewer asthma-related deaths.^3,4

In addition to the mainstay of treatments, including trigger avoidance, inhaled corticosteroids (ICS), and rescue bronchodilators, new therapies have been developed to supplement the treatment of severe persistent asthma, which constitutes about 5% to 10% of asthma cases. Severe asthma is defined as asthma that is unresponsive to baseline therapy.⁵

Three sets of guidelines and recommendations exist to provide structure to asthma treatment decision making. The Expert Panel Report-3 (EPR-3) was created by the National Education and Prevention Program (NAEPP) and was last published in 2007. The NAEPP favors a stepwise approach, based on asthma severity and age group.³ The International European Respiratory Society (ERS) and American Thoracic Society (ATS) task force report was updated in 2014.⁵ The Global Initiative for Asthma (GINA) report, updated in 2016, now includes several of the advances in asthma care for those patients refractory to standard treatments.

Asthma Therapies

In this review, the authors cover therapies for severe asthma that are becoming more important for PCPs to consider, including exhaled nitric oxide (NO) levels, the use of tiotropium for asthma, the applicability of biologic agents, the use of allergen immunotherapy, and the usefulness of roflumilast. This review also covers antileukotriene therapy, bronchial thermoplasty, and a discussion of long-acting beta-agonist (LABA) therapy.

Fractional Exhaled Nitric Oxide

Nitric oxide is present in the exhaled breath and is elevated in those with eosinophilic asthma.⁶ The role of NO in asthma pathology is complex, involving proinflammatory qualities that contribute to airway hyperresponsiveness (AHR) and as a weak mediator of smooth muscle relaxation. In exhaled air, NO correlates with up-regulation of NO synthase (NOS), which occurs with inflammation, therefore, quantifying airway inflammation.^6-8

There has been some variability in the evidence supporting the use of fractional exhaled NO (FeNO) levels as a diagnostic tool. Some studies have suggested that FeNO is also elevated in other nonasthma conditions, such as eosinophilic bronchitis, atopy, and allergic rhinitis. Also, FeNO levels have been shown to be variably influenced by smoking, bronchoconstriction, and viral respiratory infections.⁹ However, FeNO levels > 50 ppb correlated most strongly with eosinophilic asthma and steroid responsiveness.⁹

Fractional exhaled NO tests now can be performed in the PCP office with NIOX VERO (Chicago, IL), a small, relatively inexpensive device. Although the 2016 GINA guidelines and the 2015 ERS/ATS guidelines do not offer specific recommendations for use and do not support withholding ICS based on FeNO test results, guidelines for FeNO use do exist. In 2011, ATS published a specific set of FeNO interpretive guidelines for office-based use.⁹ When performed in conjunction with standard testing, FeNO levels can provide valuable clinically relevant information, such as (1) detection of eosinophilic airway inflammation; (2) determining the likelihood of corticosteroid responsiveness; (3) monitoring of airway inflammation to determine the need for steroids; and (4) unmasking of otherwise unsuspected nonadherence to corticosteroid therapy (Table 1).

Tiotropium as an Adjunct Treatment

Tiotropium is a long-acting inhaled anticholinergic. A sentinel 1984 study by Gross and Skorodin demonstrated that parasympathetic activity is the dominant reversible component in patients with chronic obstructive pulmonary disease (COPD), including emphysema.¹⁰ In addition, all achievable bronchodilation was obtained with an inhaled anticholinergic compared with that of separate or simultaneous administration of adrenergics. Sympathetic neural pathways are sparse in human lungs and have their endings on the cells of the cholinergic postganglionic fibers, because sympathetic terminals on airway smooth muscle cells are rare or nonexistent.¹¹ Therefore, sympathetic modulation or activation of beta cells could change the parasympathetic tone.¹¹

The FDA approved the addition of tiotropium for treating asthma in September 2015 for patients aged ≥ 12 years. The use of tiotropium is supported by both the ERS/ASTS and GINA 2016 guidelines. The recommended and approved dose of tiotropium for asthma is 2.5 µg daily (the recommended dose for COPD treatment is 5 µg).¹² A recent phase 3 study compared 2.5 µg vs 5 µg dosing with ICS but no LABA in adolescents, noting significant improvement with the 2.5 µg dose.¹³ Adding tiotropium to ICS + LABA in patients with severe symptomatic asthma has been associated with positive results in initial studies by Kersjens and colleagues.¹⁴ Even as early as 2010, the use of tiotropium was shown to produce statistically significant improvement in morning peak expiratory flow (PEF), with a mean difference of 25.8 L/min (n = 210, P < .001).¹⁵

Tiotropium also has been shown to provide a sustained reduction in lung hyperinflation for those with COPD, thus providing an improvement in exertional dyspnea and exercise tolerance. On day 42 of a randomized, double-blinded, placebo-controlled, parallel-group study of 187 patients, vital capacity and inspiratory capacity were noted to be increased with decreases in residual volume and functional residual capacity. Exercise endurance times increased by 105 ± 40 sec (21%).¹⁶ This effect has not been studied yet in a population of patients with asthma; however, the same principles may hold true.

Biologic Agents

Recent asthma research has been focused on disrupting the inflammatory cascade. Both GINA and ERS/ATS divide asthma into allergic vs nonallergic endotypes. Allergic asthma usually is manifested by sputum eosinophilia and high serum eosinophil counts, whereas other endotypes include aspirin-sensitive and exercise-induced asthmas that present with a neutrophilic predominance. Nonallergic asthma is more severe typically and has been linked to steroid resistance.¹⁷ Many differentphenotypes have been identified, but the main categories include eosinophilic, neutrophilic, mixed, and paucigranulocytic.¹⁸

Mast cells, bronchial epithelium, and macrophages are involved in asthma progression. Targeting the cytokines produced by these pathways can be achieved through direct and indirect modulation. Interleukin (IL)-13 is central to development of AHR, and its effect is mediated through binding to its receptor and IL-4 receptor α complexes.¹⁹ Patients with severe asthma with an eosinophilic phenotype can benefit with the use of the new biologics, which decrease the amount of eosinophilia in lung tissue by blocking specific receptors for IL-5.

Omalizumab

Omalizumab, an anti-immunoglobulin E (IgE) antibody, has been shown to be helpful in treating patients with allergic asthma. Omalizumab is a 95% humanized IgE monoclonal antibody (MAB) that binds to the IgE molecule at the fc region and prevents IgE from binding to cell-surface receptors. In a humanized MAB, only the hypervariable regions are from mouse origin vs the newer completely human MABs. Omalizumab forms small, biologically inert IgE+ anti-IgE complexes that cannot activate the complement cascade. The serum free IgE level is decreased.²⁰ Approved in 2003 for those aged ≤ 12 years, its use is restricted to patients with severe asthma, allergic sensitization (positive allergen skin testing), and an elevated serum IgE level (30-700 IU/mL). It is administered subcutaneously every 2 to 4 weeks, based on body weight and serum IgE levels.

For those with baseline eosinophil counts > 300 µL, addition of omalizumab most likely has been shown to improve quality of life (QOL) and reduce exacerbations, the use of rescue medications, ICS dosages, and ED visits.^21-26 The most dangerous adverse effect (AE) was found to be an anaphylaxis rate of 0.09%, most frequently occurring in the first 2 hours after the first dose. Therefore, the patient must be monitored for 2 hours after the first dose and 30 minutes after subsequent doses. Epinephrine injection also should be prescribed. Although a 5-year prospective cohort study and retrospective pooled analysis of more than 10,000 patients did not support any relationship with malignancy.^27,28 A higher incidence of cardiovascular and cerebrovascular AEs has been observed, and the FDA issued a safety announcement regarding this finding.²⁹

Both ERS/ATS and GINA 2016 recommended that a therapeutic trial of omalizumab should be performed in all patients with severe confirmed IgE dependent allergic asthma.^4,5 If there is no response in 4 months, it is unlikely that further administration would be beneficial.

Mepolizumab

Interleukin-5 is a key cytokine in the eosinophil life pathway. There are receptors for IL-5 on eosinophils, basophils, and β cells.³⁰ Mepolizumab is an anti-IL-5 antibody for those with refractory eosinophilic asthma and a history of continued exacerbations. It has beneficial effects in the management of persistent airways eosinophilia among corticosteroid-resistant subjects. In a 2009 study, rates of exacerbations at 50 weeks were significantly lower than with placebo (2.0 vs 3.4 mean exacerbations per subject, 95% confidence interval [CI], 0.32-0.92; P = .002) as were eosinophil counts in blood and sputum (P < .001 and P = .002 respectively.³¹ A 2014 randomized, double-blind trial by Ortega and colleagues demonstrated reduction in rate of asthma exacerbations (primary outcome) to 47% (95% CI, 29-61) among patients receiving IV dosing and 53% (95% CI, 37-65) in the oral mepolizumab group (P < .001 for both groups, n = 576).³²

In addition, there is significant data to show that even if the patient did not respond to omalizumab, he or she might still respond to mepolizumab. Data were collected from 2 randomized, double-blind, placebo-controlled studies with rate of exacerbation and percentage reduction in oral corticosteroid dose as the primary outcomes. In one of the studies (n = 576), the subjects were noted to have prior omalizumab use but still decreased exacerbation rate by 57%.³³

Reslizumab

Reslizumab also is an FDA-approved anti-IL-5 antibody. It binds directly to IL-5 and prevents it from binding to eosinophils.³⁴ For adults with severe eosinophilic asthma and refractory exacerbations, the goal of reslizumab therapy is to reduce eosinophil maturation, recruitment, and activation. Reslizumab is delivered in a weight-based IV dose (3 mg/kg) every 4 weeks. The FDA has issued a boxed warning for a 0.3% anaphylaxis rate.³⁵ The most common AEs are elevated creatinine kinase, musculoskeletal pain, and oropharyngeal pain. Use of reslizumab resulted in greater reduction in sputum eosinophils, improvements in airway function, and a trend toward greater asthma control compared with that of placebo.³⁴

Other Biologic Therapies

Many biologics are being developed as medical researchers continue to understand more of the mechanisms and pathways that contribute to allergic disease (Table 2). Dupilumab is an IL-4 inhibitor designated as a “breakthrough therapy” in 2014 by the FDA. This biologic blocks the downstream signaling events induced by IL-4 and IL-13 by binding to a subunit of the IL-4 receptor in the complexes. It has been found beneficial for those with high blood eosinophil counts and moderate-to-severe asthma and decreased asthma exacerbations when LABA and ICS were withdrawn.^36,37

Fevipiprant is a prostaglandin D2 inhibitor that blocks T-helper type 2 (Th2) cell migration and subsequent bronchoconstriction and cytokine effects with decreased IL-4, IL-5, and IL-13. Although sputum eosinophil percentage was noted to be decreased in a study involving 61 patients randomized to treatment for 12 weeks, asthma QOL questionnaires and prebronchodilator spirometry did not change.^38,39

Benralizumab is an anti-IL-5 receptor antibody that has been more effective in reduction of airway and blood eosinophils levels compared with that of mepolizumab (undetectable vs 52% reduction), within 24 hours of IV dosing. In contrast, the anti-IL-5 antibodies take about 4 weeks to decrease eosinophil levels in blood and sputum.³⁴ There have been no documented AEs aside from nasopharyngitis and injection site reactions and no safety concerns to date. It is currently undergoing phase 3 trials.⁴⁰

Immunotherapies

Allergen immunotherapy is recommended for mild-to-moderate asthma. A 2010 Cochrane Review found that subcutaneous immunotherapy compared with placebo demonstrated improvements in bronchial hyperresponsiveness and decreased medication use.⁴¹ Expert Panel Report-3 guidelines recommend consideration of immunotherapy for mild-to-moderate asthma.⁵ While ERS/ATS guidelines for severe asthma do not address allergen immunotherapy, GINA guidelines incorporate it as Evidence A for treating modifiable risk factors to reduce exacerbations, although the efficacy is limited.⁶

Roflumilast

Roflumilast is a selective PDE4 inhibitor that has shown an anti-inflammatory effect in COPD. Studies evaluating the reversibility and prevention of airway remodeling showed good promise in mouse models.⁴² Data from 8 placebo-controlled, double-blind, phase 1, 2, and 3 studies conducted at 14 sites in Europe, North America, and South Africa from 1997 to 2005 showed reduced sputum eosinophil and neutrophil counts, consistent with findings during COPD treatment. However, forced expiratory volume in one second (FEV₁) and PEF values were unchanged, suggesting that there was no acute bronchodilatory effect with roflumilast therapy.⁴³ Roflumilast is not addressed in the 2016 GINA guidelines and at this time does not have a role in the treatment of severe asthma.

Antileukotrienes

After the activation of mast cells and eosinophils, leukotrienes are generated by 5-lipoxygenase from arachidonic acid and create bronchoconstriction, vasodilation, increased mucus production, increased recruitment of eosinophils, and decreased ciliary motility. Some studies have encouraged addingleukotriene receptor blockers (both montelukast and zafirlukast) to ICS therapy^44,45 and to therapy for patients with aspirin-intolerant asthma or allergic asthma.^46,47 However, other studies have shown them to be of limited benefit.^48,49 A recent Cochrane Reviewof 18 randomized-controlled trials with 7,208 adults and children compared ICS + leukotriene receptor antagonist (LTRA) vs ICS + LABA.⁵⁰ The ICS + LABA resulted in greater improvements in lung function, symptoms score, and rates of exacerbations.⁵⁰

Most recommendations recognize the limitations of antileukotriene medications and agree that they are an adjunct rather than primary therapy. The GINA 2016 guidelines support the use of LTRAs in mild asthma, stating that although LTRAs are less effective than ICS (Evidence A), they may be appropriate for initial controller treatment for some patients who are unable or unwilling to use ICS or for patients with concurrent allergic rhinitis (Evidence B).^51,52

Zileuton is a different type of antileukotriene. It inhibits leukotrienes B4, C4, D4, and E4 by inhibition of 5-lipoxygenase, interfering with leukotriene formation. It is approved for patients aged ≥ 12 years and is more expensive than montelukast or zafirlukast. Most studies supporting its use were conducted in patients with mild-to-moderate asthma on β-agonist therapy only. A 1988 study showed that zileuton therapy improved FEV₁, reduced nasal symptoms, and decreased bronchial responsiveness to inhaled aspirin and histamine.⁵³ All but 1 study patient were on ICS or oral corticosteroids. Zileuton was noted to be effective for patients with aspirin-intolerant asthma.

Some earlier studies reported that a small number of subjects had an increase in transaminases that resolved when they discontinued the medication. Therefore, it is recommended to check baseline laboratory results every 2 to 3 months.^54,55 Neither GINA nor ERS/ATS guidelines address the use of zileuton.

Bronchial Thermoplasty

With asthma there is marked hypertrophy and hyperplasia that occurs in the airway smooth muscle. The airway of the patient with asthma also is lined with cells that promote inflammation. Thermal energy is used to perform controlled destruction of the inflammatory lining and pathologic hyperplasia. Three sequential bronchoscopies are performed 3 weeks apart to treat the right lower lobe, left lower lobe, and bilateral upper lobes. The right middle lobe is not treated due to its smaller diameter. Each bronchoscopy takes about 30 to 60 minutes. Patients are given perioperative steroids.⁵⁶

Three large phase 3 clinical trials have evaluated the efficacy of bronchial thermoplasty (BT). The AIR (Asthma Intervention Research) trial in 2007 was a randomized controlled study of 112 patients with moderate or severe asthma that showed improved exacerbation rates, symptom-free days and QOL scores (1.3 ± 1.0 vs 0.6 ± 1.1; P = .003), but no difference in prebronchodilator FEV₁ or AHR.⁵⁷ There was a significant reduction in the rate of mild exacerbations and increase in morning PEF rates.⁵⁷ Findings at 5 years showed improved AHR but no difference in frequency of need for oral corticosteroids and frequency of hospital or emergency department (ED) visits.⁵⁸

The Research in Severe Asthma (RISA) clinical trial was a randomized controlled study (n = 32, 15 randomly assigned to BT) that showed improved prebronchodilator FEV₁ in patients with severe, symptomatic asthma and baseline FEV₁ of 62% to 66% with half the patients requiring oral corticosteroids (percentage predicted; 14.9 ± 17.4 vs -0.9 ± 22.3; P =.04).⁵⁷ Quality of life scores were also significantly improved. At 5 years (14 BT patients were followed), the frequency of hospitalizations and ED visits decreased.⁵⁹

The 2010 AIR2 study was a randomized, double blind, sham-controlled study (n = 288) developed to address the limitations of the 2 previous studies. It excluded the severest asthma cases, and its blinded nature was created with sham bronchoscopy to eliminate possible placebo effect. The study questionnaires showed improved QOL overall (79% vs 64%); however, there was a definite placebo effect noted.⁶⁰ Decreased frequency of severe exacerbations as well as ED visits and days lost from work or school also were documented as secondary endpoints. At 5 years, decreased frequency of severe exacerbations and ED visits continued in the control group (85% consented to follow-up).⁶¹ Importantly, despite the placebo effect in QOL scores, there were no improvements in exacerbation rates or hospitalizations in those receiving sham bronchoscopy at the 1-year mark.⁶¹

Although more longitudinal studies need to be planned, including evaluation of those with the most severe asthma, there seems to be a sustained improvement in patients. Those who have received BT generally are found to have reduced airway smooth muscle with lower concentration of key inflammatory cytokines on follow-up bronchoscopy. However, variability in response has been documented.⁵⁶ There has been no documented deterioration in pulmonary function with BT, and no significant structural abnormalities have been seen on high-resolution computed tomography.^56,58 Both GINA 2016 and ERS/ATS support the use of BT in the context of adults with severe asthma, calling for more long-term studies to address delayed benefits and safety.

LABA Inhalers

A multicenter, double-blind, 26-week study of 11,693 patients randomized to ICS + LABA (budesonide/formoterol) vs ICS (budesonide) alone has shown no increased AEs in either arm. The study found that treatment with budesonide/formoterol was associated with lower risk of asthma exacerbations than using budesonide alone (16.5%; P = .002).⁶²

The safety of adding a LABA to fluticasone also has been evaluated recently. A 2016 study of almost 12,000 patients (aged > 12 years) compared fluticasone proprionate alone vs fluticasone with salmeterol.⁶³ There were no asthma-related deaths, but 2 patients in the fluticasone-only group were intubated with asthma complications. The risk of a severe asthma exacerbation seemed to be lower in the combination group (8% vs 10%; P < .001).⁶³

A 2014 Cochrane Review supported the view that LABAs in adults seem to be safe when used concurrently with an ICS with a A-level recommendation, based on consistent good-quality, patient-oriented evidence.⁶⁴ Multiple organizations have issued guidelines to this effect in the past, but previous results of studies showed that asthma deaths and a small increase in nonfatal serious AEs were noted in those using LABA monotherapy alone.⁶⁴

NAEPP (EPR-3) and ERS/ATS recommend stepwise increases in the dose of ICS in combination with a LABA. The GINA guidelines recommend controller therapy to include combination IHS and LABA but with the consideration of higher doses of ICS than are routinely recommended for general use.

Inhaler and Inhaler Combinations

Many different inhalers of ICS alone and ICS/LABA combinations exist on the market today. There are differences in delivery that affect patient preference but these differences have not been found to improve delivery. Small particle ICS therapy could possibly correlate with improved delivery to the small airways.⁶⁵ There are 3 preparations of inhaled steroids that fit in to this group, including beclomethasone, ciclesonide, and flunisolide. Other inhaled steroid formulations include budesonide, fluticasone propionate, fluticasone furoate, and mometasone.

Combination therapy (ICS + LABA) inhalers also are widely available. They include budesonide/formoterol, fluticasone proprionate/salmeterol, mometasone/formoterol, and the newer fluticasone furoate/vilanterol, a once-daily combination approved for those aged ≥ 18 years.

Conclusion

The treatment of severe asthma has progressed from simple manipulation of avoidance, bronchodilators, and corticosteroids to include many other treatments that have improved QOL for patients with refractory asthma. Although many of these options are delivered in coordination with an allergy and pulmonary specialist, it is important for the PCP to have a good knowledge base and awareness of additional treatments that are currently available.

More than 39.5 million people in the U.S. have been diagnosed with asthma, and about 3,400 deaths occur annually due to asthma complications.¹ Although the prevalence of atopy and asthma have increased over the past few decades in western countries, control and outcomes are improving.² Use of asthma protocols and early recognition by the primary care provider (PCP) are among the main reasons for trends toward decreased hospitalization and fewer asthma-related deaths.^3,4

In addition to the mainstay of treatments, including trigger avoidance, inhaled corticosteroids (ICS), and rescue bronchodilators, new therapies have been developed to supplement the treatment of severe persistent asthma, which constitutes about 5% to 10% of asthma cases. Severe asthma is defined as asthma that is unresponsive to baseline therapy.⁵

Three sets of guidelines and recommendations exist to provide structure to asthma treatment decision making. The Expert Panel Report-3 (EPR-3) was created by the National Education and Prevention Program (NAEPP) and was last published in 2007. The NAEPP favors a stepwise approach, based on asthma severity and age group.³ The International European Respiratory Society (ERS) and American Thoracic Society (ATS) task force report was updated in 2014.⁵ The Global Initiative for Asthma (GINA) report, updated in 2016, now includes several of the advances in asthma care for those patients refractory to standard treatments.

Asthma Therapies

In this review, the authors cover therapies for severe asthma that are becoming more important for PCPs to consider, including exhaled nitric oxide (NO) levels, the use of tiotropium for asthma, the applicability of biologic agents, the use of allergen immunotherapy, and the usefulness of roflumilast. This review also covers antileukotriene therapy, bronchial thermoplasty, and a discussion of long-acting beta-agonist (LABA) therapy.

Fractional Exhaled Nitric Oxide

Nitric oxide is present in the exhaled breath and is elevated in those with eosinophilic asthma.⁶ The role of NO in asthma pathology is complex, involving proinflammatory qualities that contribute to airway hyperresponsiveness (AHR) and as a weak mediator of smooth muscle relaxation. In exhaled air, NO correlates with up-regulation of NO synthase (NOS), which occurs with inflammation, therefore, quantifying airway inflammation.^6-8

There has been some variability in the evidence supporting the use of fractional exhaled NO (FeNO) levels as a diagnostic tool. Some studies have suggested that FeNO is also elevated in other nonasthma conditions, such as eosinophilic bronchitis, atopy, and allergic rhinitis. Also, FeNO levels have been shown to be variably influenced by smoking, bronchoconstriction, and viral respiratory infections.⁹ However, FeNO levels > 50 ppb correlated most strongly with eosinophilic asthma and steroid responsiveness.⁹

Fractional exhaled NO tests now can be performed in the PCP office with NIOX VERO (Chicago, IL), a small, relatively inexpensive device. Although the 2016 GINA guidelines and the 2015 ERS/ATS guidelines do not offer specific recommendations for use and do not support withholding ICS based on FeNO test results, guidelines for FeNO use do exist. In 2011, ATS published a specific set of FeNO interpretive guidelines for office-based use.⁹ When performed in conjunction with standard testing, FeNO levels can provide valuable clinically relevant information, such as (1) detection of eosinophilic airway inflammation; (2) determining the likelihood of corticosteroid responsiveness; (3) monitoring of airway inflammation to determine the need for steroids; and (4) unmasking of otherwise unsuspected nonadherence to corticosteroid therapy (Table 1).

Tiotropium as an Adjunct Treatment

Tiotropium is a long-acting inhaled anticholinergic. A sentinel 1984 study by Gross and Skorodin demonstrated that parasympathetic activity is the dominant reversible component in patients with chronic obstructive pulmonary disease (COPD), including emphysema.¹⁰ In addition, all achievable bronchodilation was obtained with an inhaled anticholinergic compared with that of separate or simultaneous administration of adrenergics. Sympathetic neural pathways are sparse in human lungs and have their endings on the cells of the cholinergic postganglionic fibers, because sympathetic terminals on airway smooth muscle cells are rare or nonexistent.¹¹ Therefore, sympathetic modulation or activation of beta cells could change the parasympathetic tone.¹¹

The FDA approved the addition of tiotropium for treating asthma in September 2015 for patients aged ≥ 12 years. The use of tiotropium is supported by both the ERS/ASTS and GINA 2016 guidelines. The recommended and approved dose of tiotropium for asthma is 2.5 µg daily (the recommended dose for COPD treatment is 5 µg).¹² A recent phase 3 study compared 2.5 µg vs 5 µg dosing with ICS but no LABA in adolescents, noting significant improvement with the 2.5 µg dose.¹³ Adding tiotropium to ICS + LABA in patients with severe symptomatic asthma has been associated with positive results in initial studies by Kersjens and colleagues.¹⁴ Even as early as 2010, the use of tiotropium was shown to produce statistically significant improvement in morning peak expiratory flow (PEF), with a mean difference of 25.8 L/min (n = 210, P < .001).¹⁵

Tiotropium also has been shown to provide a sustained reduction in lung hyperinflation for those with COPD, thus providing an improvement in exertional dyspnea and exercise tolerance. On day 42 of a randomized, double-blinded, placebo-controlled, parallel-group study of 187 patients, vital capacity and inspiratory capacity were noted to be increased with decreases in residual volume and functional residual capacity. Exercise endurance times increased by 105 ± 40 sec (21%).¹⁶ This effect has not been studied yet in a population of patients with asthma; however, the same principles may hold true.

Biologic Agents

Recent asthma research has been focused on disrupting the inflammatory cascade. Both GINA and ERS/ATS divide asthma into allergic vs nonallergic endotypes. Allergic asthma usually is manifested by sputum eosinophilia and high serum eosinophil counts, whereas other endotypes include aspirin-sensitive and exercise-induced asthmas that present with a neutrophilic predominance. Nonallergic asthma is more severe typically and has been linked to steroid resistance.¹⁷ Many differentphenotypes have been identified, but the main categories include eosinophilic, neutrophilic, mixed, and paucigranulocytic.¹⁸

Mast cells, bronchial epithelium, and macrophages are involved in asthma progression. Targeting the cytokines produced by these pathways can be achieved through direct and indirect modulation. Interleukin (IL)-13 is central to development of AHR, and its effect is mediated through binding to its receptor and IL-4 receptor α complexes.¹⁹ Patients with severe asthma with an eosinophilic phenotype can benefit with the use of the new biologics, which decrease the amount of eosinophilia in lung tissue by blocking specific receptors for IL-5.

Omalizumab

Omalizumab, an anti-immunoglobulin E (IgE) antibody, has been shown to be helpful in treating patients with allergic asthma. Omalizumab is a 95% humanized IgE monoclonal antibody (MAB) that binds to the IgE molecule at the fc region and prevents IgE from binding to cell-surface receptors. In a humanized MAB, only the hypervariable regions are from mouse origin vs the newer completely human MABs. Omalizumab forms small, biologically inert IgE+ anti-IgE complexes that cannot activate the complement cascade. The serum free IgE level is decreased.²⁰ Approved in 2003 for those aged ≤ 12 years, its use is restricted to patients with severe asthma, allergic sensitization (positive allergen skin testing), and an elevated serum IgE level (30-700 IU/mL). It is administered subcutaneously every 2 to 4 weeks, based on body weight and serum IgE levels.

For those with baseline eosinophil counts > 300 µL, addition of omalizumab most likely has been shown to improve quality of life (QOL) and reduce exacerbations, the use of rescue medications, ICS dosages, and ED visits.^21-26 The most dangerous adverse effect (AE) was found to be an anaphylaxis rate of 0.09%, most frequently occurring in the first 2 hours after the first dose. Therefore, the patient must be monitored for 2 hours after the first dose and 30 minutes after subsequent doses. Epinephrine injection also should be prescribed. Although a 5-year prospective cohort study and retrospective pooled analysis of more than 10,000 patients did not support any relationship with malignancy.^27,28 A higher incidence of cardiovascular and cerebrovascular AEs has been observed, and the FDA issued a safety announcement regarding this finding.²⁹

Both ERS/ATS and GINA 2016 recommended that a therapeutic trial of omalizumab should be performed in all patients with severe confirmed IgE dependent allergic asthma.^4,5 If there is no response in 4 months, it is unlikely that further administration would be beneficial.

Mepolizumab

Interleukin-5 is a key cytokine in the eosinophil life pathway. There are receptors for IL-5 on eosinophils, basophils, and β cells.³⁰ Mepolizumab is an anti-IL-5 antibody for those with refractory eosinophilic asthma and a history of continued exacerbations. It has beneficial effects in the management of persistent airways eosinophilia among corticosteroid-resistant subjects. In a 2009 study, rates of exacerbations at 50 weeks were significantly lower than with placebo (2.0 vs 3.4 mean exacerbations per subject, 95% confidence interval [CI], 0.32-0.92; P = .002) as were eosinophil counts in blood and sputum (P < .001 and P = .002 respectively.³¹ A 2014 randomized, double-blind trial by Ortega and colleagues demonstrated reduction in rate of asthma exacerbations (primary outcome) to 47% (95% CI, 29-61) among patients receiving IV dosing and 53% (95% CI, 37-65) in the oral mepolizumab group (P < .001 for both groups, n = 576).³²

In addition, there is significant data to show that even if the patient did not respond to omalizumab, he or she might still respond to mepolizumab. Data were collected from 2 randomized, double-blind, placebo-controlled studies with rate of exacerbation and percentage reduction in oral corticosteroid dose as the primary outcomes. In one of the studies (n = 576), the subjects were noted to have prior omalizumab use but still decreased exacerbation rate by 57%.³³

Reslizumab

Reslizumab also is an FDA-approved anti-IL-5 antibody. It binds directly to IL-5 and prevents it from binding to eosinophils.³⁴ For adults with severe eosinophilic asthma and refractory exacerbations, the goal of reslizumab therapy is to reduce eosinophil maturation, recruitment, and activation. Reslizumab is delivered in a weight-based IV dose (3 mg/kg) every 4 weeks. The FDA has issued a boxed warning for a 0.3% anaphylaxis rate.³⁵ The most common AEs are elevated creatinine kinase, musculoskeletal pain, and oropharyngeal pain. Use of reslizumab resulted in greater reduction in sputum eosinophils, improvements in airway function, and a trend toward greater asthma control compared with that of placebo.³⁴

Other Biologic Therapies

Many biologics are being developed as medical researchers continue to understand more of the mechanisms and pathways that contribute to allergic disease (Table 2). Dupilumab is an IL-4 inhibitor designated as a “breakthrough therapy” in 2014 by the FDA. This biologic blocks the downstream signaling events induced by IL-4 and IL-13 by binding to a subunit of the IL-4 receptor in the complexes. It has been found beneficial for those with high blood eosinophil counts and moderate-to-severe asthma and decreased asthma exacerbations when LABA and ICS were withdrawn.^36,37

Fevipiprant is a prostaglandin D2 inhibitor that blocks T-helper type 2 (Th2) cell migration and subsequent bronchoconstriction and cytokine effects with decreased IL-4, IL-5, and IL-13. Although sputum eosinophil percentage was noted to be decreased in a study involving 61 patients randomized to treatment for 12 weeks, asthma QOL questionnaires and prebronchodilator spirometry did not change.^38,39

Benralizumab is an anti-IL-5 receptor antibody that has been more effective in reduction of airway and blood eosinophils levels compared with that of mepolizumab (undetectable vs 52% reduction), within 24 hours of IV dosing. In contrast, the anti-IL-5 antibodies take about 4 weeks to decrease eosinophil levels in blood and sputum.³⁴ There have been no documented AEs aside from nasopharyngitis and injection site reactions and no safety concerns to date. It is currently undergoing phase 3 trials.⁴⁰

Immunotherapies

Allergen immunotherapy is recommended for mild-to-moderate asthma. A 2010 Cochrane Review found that subcutaneous immunotherapy compared with placebo demonstrated improvements in bronchial hyperresponsiveness and decreased medication use.⁴¹ Expert Panel Report-3 guidelines recommend consideration of immunotherapy for mild-to-moderate asthma.⁵ While ERS/ATS guidelines for severe asthma do not address allergen immunotherapy, GINA guidelines incorporate it as Evidence A for treating modifiable risk factors to reduce exacerbations, although the efficacy is limited.⁶

Roflumilast

Roflumilast is a selective PDE4 inhibitor that has shown an anti-inflammatory effect in COPD. Studies evaluating the reversibility and prevention of airway remodeling showed good promise in mouse models.⁴² Data from 8 placebo-controlled, double-blind, phase 1, 2, and 3 studies conducted at 14 sites in Europe, North America, and South Africa from 1997 to 2005 showed reduced sputum eosinophil and neutrophil counts, consistent with findings during COPD treatment. However, forced expiratory volume in one second (FEV₁) and PEF values were unchanged, suggesting that there was no acute bronchodilatory effect with roflumilast therapy.⁴³ Roflumilast is not addressed in the 2016 GINA guidelines and at this time does not have a role in the treatment of severe asthma.

Antileukotrienes

After the activation of mast cells and eosinophils, leukotrienes are generated by 5-lipoxygenase from arachidonic acid and create bronchoconstriction, vasodilation, increased mucus production, increased recruitment of eosinophils, and decreased ciliary motility. Some studies have encouraged addingleukotriene receptor blockers (both montelukast and zafirlukast) to ICS therapy^44,45 and to therapy for patients with aspirin-intolerant asthma or allergic asthma.^46,47 However, other studies have shown them to be of limited benefit.^48,49 A recent Cochrane Reviewof 18 randomized-controlled trials with 7,208 adults and children compared ICS + leukotriene receptor antagonist (LTRA) vs ICS + LABA.⁵⁰ The ICS + LABA resulted in greater improvements in lung function, symptoms score, and rates of exacerbations.⁵⁰

Most recommendations recognize the limitations of antileukotriene medications and agree that they are an adjunct rather than primary therapy. The GINA 2016 guidelines support the use of LTRAs in mild asthma, stating that although LTRAs are less effective than ICS (Evidence A), they may be appropriate for initial controller treatment for some patients who are unable or unwilling to use ICS or for patients with concurrent allergic rhinitis (Evidence B).^51,52

Zileuton is a different type of antileukotriene. It inhibits leukotrienes B4, C4, D4, and E4 by inhibition of 5-lipoxygenase, interfering with leukotriene formation. It is approved for patients aged ≥ 12 years and is more expensive than montelukast or zafirlukast. Most studies supporting its use were conducted in patients with mild-to-moderate asthma on β-agonist therapy only. A 1988 study showed that zileuton therapy improved FEV₁, reduced nasal symptoms, and decreased bronchial responsiveness to inhaled aspirin and histamine.⁵³ All but 1 study patient were on ICS or oral corticosteroids. Zileuton was noted to be effective for patients with aspirin-intolerant asthma.

Some earlier studies reported that a small number of subjects had an increase in transaminases that resolved when they discontinued the medication. Therefore, it is recommended to check baseline laboratory results every 2 to 3 months.^54,55 Neither GINA nor ERS/ATS guidelines address the use of zileuton.

Bronchial Thermoplasty

With asthma there is marked hypertrophy and hyperplasia that occurs in the airway smooth muscle. The airway of the patient with asthma also is lined with cells that promote inflammation. Thermal energy is used to perform controlled destruction of the inflammatory lining and pathologic hyperplasia. Three sequential bronchoscopies are performed 3 weeks apart to treat the right lower lobe, left lower lobe, and bilateral upper lobes. The right middle lobe is not treated due to its smaller diameter. Each bronchoscopy takes about 30 to 60 minutes. Patients are given perioperative steroids.⁵⁶

Three large phase 3 clinical trials have evaluated the efficacy of bronchial thermoplasty (BT). The AIR (Asthma Intervention Research) trial in 2007 was a randomized controlled study of 112 patients with moderate or severe asthma that showed improved exacerbation rates, symptom-free days and QOL scores (1.3 ± 1.0 vs 0.6 ± 1.1; P = .003), but no difference in prebronchodilator FEV₁ or AHR.⁵⁷ There was a significant reduction in the rate of mild exacerbations and increase in morning PEF rates.⁵⁷ Findings at 5 years showed improved AHR but no difference in frequency of need for oral corticosteroids and frequency of hospital or emergency department (ED) visits.⁵⁸

The Research in Severe Asthma (RISA) clinical trial was a randomized controlled study (n = 32, 15 randomly assigned to BT) that showed improved prebronchodilator FEV₁ in patients with severe, symptomatic asthma and baseline FEV₁ of 62% to 66% with half the patients requiring oral corticosteroids (percentage predicted; 14.9 ± 17.4 vs -0.9 ± 22.3; P =.04).⁵⁷ Quality of life scores were also significantly improved. At 5 years (14 BT patients were followed), the frequency of hospitalizations and ED visits decreased.⁵⁹

The 2010 AIR2 study was a randomized, double blind, sham-controlled study (n = 288) developed to address the limitations of the 2 previous studies. It excluded the severest asthma cases, and its blinded nature was created with sham bronchoscopy to eliminate possible placebo effect. The study questionnaires showed improved QOL overall (79% vs 64%); however, there was a definite placebo effect noted.⁶⁰ Decreased frequency of severe exacerbations as well as ED visits and days lost from work or school also were documented as secondary endpoints. At 5 years, decreased frequency of severe exacerbations and ED visits continued in the control group (85% consented to follow-up).⁶¹ Importantly, despite the placebo effect in QOL scores, there were no improvements in exacerbation rates or hospitalizations in those receiving sham bronchoscopy at the 1-year mark.⁶¹

Although more longitudinal studies need to be planned, including evaluation of those with the most severe asthma, there seems to be a sustained improvement in patients. Those who have received BT generally are found to have reduced airway smooth muscle with lower concentration of key inflammatory cytokines on follow-up bronchoscopy. However, variability in response has been documented.⁵⁶ There has been no documented deterioration in pulmonary function with BT, and no significant structural abnormalities have been seen on high-resolution computed tomography.^56,58 Both GINA 2016 and ERS/ATS support the use of BT in the context of adults with severe asthma, calling for more long-term studies to address delayed benefits and safety.

LABA Inhalers

A multicenter, double-blind, 26-week study of 11,693 patients randomized to ICS + LABA (budesonide/formoterol) vs ICS (budesonide) alone has shown no increased AEs in either arm. The study found that treatment with budesonide/formoterol was associated with lower risk of asthma exacerbations than using budesonide alone (16.5%; P = .002).⁶²

The safety of adding a LABA to fluticasone also has been evaluated recently. A 2016 study of almost 12,000 patients (aged > 12 years) compared fluticasone proprionate alone vs fluticasone with salmeterol.⁶³ There were no asthma-related deaths, but 2 patients in the fluticasone-only group were intubated with asthma complications. The risk of a severe asthma exacerbation seemed to be lower in the combination group (8% vs 10%; P < .001).⁶³

A 2014 Cochrane Review supported the view that LABAs in adults seem to be safe when used concurrently with an ICS with a A-level recommendation, based on consistent good-quality, patient-oriented evidence.⁶⁴ Multiple organizations have issued guidelines to this effect in the past, but previous results of studies showed that asthma deaths and a small increase in nonfatal serious AEs were noted in those using LABA monotherapy alone.⁶⁴

NAEPP (EPR-3) and ERS/ATS recommend stepwise increases in the dose of ICS in combination with a LABA. The GINA guidelines recommend controller therapy to include combination IHS and LABA but with the consideration of higher doses of ICS than are routinely recommended for general use.

Inhaler and Inhaler Combinations

Many different inhalers of ICS alone and ICS/LABA combinations exist on the market today. There are differences in delivery that affect patient preference but these differences have not been found to improve delivery. Small particle ICS therapy could possibly correlate with improved delivery to the small airways.⁶⁵ There are 3 preparations of inhaled steroids that fit in to this group, including beclomethasone, ciclesonide, and flunisolide. Other inhaled steroid formulations include budesonide, fluticasone propionate, fluticasone furoate, and mometasone.

Combination therapy (ICS + LABA) inhalers also are widely available. They include budesonide/formoterol, fluticasone proprionate/salmeterol, mometasone/formoterol, and the newer fluticasone furoate/vilanterol, a once-daily combination approved for those aged ≥ 18 years.

Conclusion

The treatment of severe asthma has progressed from simple manipulation of avoidance, bronchodilators, and corticosteroids to include many other treatments that have improved QOL for patients with refractory asthma. Although many of these options are delivered in coordination with an allergy and pulmonary specialist, it is important for the PCP to have a good knowledge base and awareness of additional treatments that are currently available.

More than 39.5 million people in the U.S. have been diagnosed with asthma, and about 3,400 deaths occur annually due to asthma complications.¹ Although the prevalence of atopy and asthma have increased over the past few decades in western countries, control and outcomes are improving.² Use of asthma protocols and early recognition by the primary care provider (PCP) are among the main reasons for trends toward decreased hospitalization and fewer asthma-related deaths.^3,4

In addition to the mainstay of treatments, including trigger avoidance, inhaled corticosteroids (ICS), and rescue bronchodilators, new therapies have been developed to supplement the treatment of severe persistent asthma, which constitutes about 5% to 10% of asthma cases. Severe asthma is defined as asthma that is unresponsive to baseline therapy.⁵

Three sets of guidelines and recommendations exist to provide structure to asthma treatment decision making. The Expert Panel Report-3 (EPR-3) was created by the National Education and Prevention Program (NAEPP) and was last published in 2007. The NAEPP favors a stepwise approach, based on asthma severity and age group.³ The International European Respiratory Society (ERS) and American Thoracic Society (ATS) task force report was updated in 2014.⁵ The Global Initiative for Asthma (GINA) report, updated in 2016, now includes several of the advances in asthma care for those patients refractory to standard treatments.

Asthma Therapies

In this review, the authors cover therapies for severe asthma that are becoming more important for PCPs to consider, including exhaled nitric oxide (NO) levels, the use of tiotropium for asthma, the applicability of biologic agents, the use of allergen immunotherapy, and the usefulness of roflumilast. This review also covers antileukotriene therapy, bronchial thermoplasty, and a discussion of long-acting beta-agonist (LABA) therapy.

Fractional Exhaled Nitric Oxide

Nitric oxide is present in the exhaled breath and is elevated in those with eosinophilic asthma.⁶ The role of NO in asthma pathology is complex, involving proinflammatory qualities that contribute to airway hyperresponsiveness (AHR) and as a weak mediator of smooth muscle relaxation. In exhaled air, NO correlates with up-regulation of NO synthase (NOS), which occurs with inflammation, therefore, quantifying airway inflammation.^6-8

There has been some variability in the evidence supporting the use of fractional exhaled NO (FeNO) levels as a diagnostic tool. Some studies have suggested that FeNO is also elevated in other nonasthma conditions, such as eosinophilic bronchitis, atopy, and allergic rhinitis. Also, FeNO levels have been shown to be variably influenced by smoking, bronchoconstriction, and viral respiratory infections.⁹ However, FeNO levels > 50 ppb correlated most strongly with eosinophilic asthma and steroid responsiveness.⁹

Fractional exhaled NO tests now can be performed in the PCP office with NIOX VERO (Chicago, IL), a small, relatively inexpensive device. Although the 2016 GINA guidelines and the 2015 ERS/ATS guidelines do not offer specific recommendations for use and do not support withholding ICS based on FeNO test results, guidelines for FeNO use do exist. In 2011, ATS published a specific set of FeNO interpretive guidelines for office-based use.⁹ When performed in conjunction with standard testing, FeNO levels can provide valuable clinically relevant information, such as (1) detection of eosinophilic airway inflammation; (2) determining the likelihood of corticosteroid responsiveness; (3) monitoring of airway inflammation to determine the need for steroids; and (4) unmasking of otherwise unsuspected nonadherence to corticosteroid therapy (Table 1).

Tiotropium as an Adjunct Treatment

Tiotropium is a long-acting inhaled anticholinergic. A sentinel 1984 study by Gross and Skorodin demonstrated that parasympathetic activity is the dominant reversible component in patients with chronic obstructive pulmonary disease (COPD), including emphysema.¹⁰ In addition, all achievable bronchodilation was obtained with an inhaled anticholinergic compared with that of separate or simultaneous administration of adrenergics. Sympathetic neural pathways are sparse in human lungs and have their endings on the cells of the cholinergic postganglionic fibers, because sympathetic terminals on airway smooth muscle cells are rare or nonexistent.¹¹ Therefore, sympathetic modulation or activation of beta cells could change the parasympathetic tone.¹¹

The FDA approved the addition of tiotropium for treating asthma in September 2015 for patients aged ≥ 12 years. The use of tiotropium is supported by both the ERS/ASTS and GINA 2016 guidelines. The recommended and approved dose of tiotropium for asthma is 2.5 µg daily (the recommended dose for COPD treatment is 5 µg).¹² A recent phase 3 study compared 2.5 µg vs 5 µg dosing with ICS but no LABA in adolescents, noting significant improvement with the 2.5 µg dose.¹³ Adding tiotropium to ICS + LABA in patients with severe symptomatic asthma has been associated with positive results in initial studies by Kersjens and colleagues.¹⁴ Even as early as 2010, the use of tiotropium was shown to produce statistically significant improvement in morning peak expiratory flow (PEF), with a mean difference of 25.8 L/min (n = 210, P < .001).¹⁵

Tiotropium also has been shown to provide a sustained reduction in lung hyperinflation for those with COPD, thus providing an improvement in exertional dyspnea and exercise tolerance. On day 42 of a randomized, double-blinded, placebo-controlled, parallel-group study of 187 patients, vital capacity and inspiratory capacity were noted to be increased with decreases in residual volume and functional residual capacity. Exercise endurance times increased by 105 ± 40 sec (21%).¹⁶ This effect has not been studied yet in a population of patients with asthma; however, the same principles may hold true.

Biologic Agents

Recent asthma research has been focused on disrupting the inflammatory cascade. Both GINA and ERS/ATS divide asthma into allergic vs nonallergic endotypes. Allergic asthma usually is manifested by sputum eosinophilia and high serum eosinophil counts, whereas other endotypes include aspirin-sensitive and exercise-induced asthmas that present with a neutrophilic predominance. Nonallergic asthma is more severe typically and has been linked to steroid resistance.¹⁷ Many differentphenotypes have been identified, but the main categories include eosinophilic, neutrophilic, mixed, and paucigranulocytic.¹⁸

Mast cells, bronchial epithelium, and macrophages are involved in asthma progression. Targeting the cytokines produced by these pathways can be achieved through direct and indirect modulation. Interleukin (IL)-13 is central to development of AHR, and its effect is mediated through binding to its receptor and IL-4 receptor α complexes.¹⁹ Patients with severe asthma with an eosinophilic phenotype can benefit with the use of the new biologics, which decrease the amount of eosinophilia in lung tissue by blocking specific receptors for IL-5.

Omalizumab

Omalizumab, an anti-immunoglobulin E (IgE) antibody, has been shown to be helpful in treating patients with allergic asthma. Omalizumab is a 95% humanized IgE monoclonal antibody (MAB) that binds to the IgE molecule at the fc region and prevents IgE from binding to cell-surface receptors. In a humanized MAB, only the hypervariable regions are from mouse origin vs the newer completely human MABs. Omalizumab forms small, biologically inert IgE+ anti-IgE complexes that cannot activate the complement cascade. The serum free IgE level is decreased.²⁰ Approved in 2003 for those aged ≤ 12 years, its use is restricted to patients with severe asthma, allergic sensitization (positive allergen skin testing), and an elevated serum IgE level (30-700 IU/mL). It is administered subcutaneously every 2 to 4 weeks, based on body weight and serum IgE levels.

For those with baseline eosinophil counts > 300 µL, addition of omalizumab most likely has been shown to improve quality of life (QOL) and reduce exacerbations, the use of rescue medications, ICS dosages, and ED visits.^21-26 The most dangerous adverse effect (AE) was found to be an anaphylaxis rate of 0.09%, most frequently occurring in the first 2 hours after the first dose. Therefore, the patient must be monitored for 2 hours after the first dose and 30 minutes after subsequent doses. Epinephrine injection also should be prescribed. Although a 5-year prospective cohort study and retrospective pooled analysis of more than 10,000 patients did not support any relationship with malignancy.^27,28 A higher incidence of cardiovascular and cerebrovascular AEs has been observed, and the FDA issued a safety announcement regarding this finding.²⁹

Both ERS/ATS and GINA 2016 recommended that a therapeutic trial of omalizumab should be performed in all patients with severe confirmed IgE dependent allergic asthma.^4,5 If there is no response in 4 months, it is unlikely that further administration would be beneficial.

Mepolizumab

Interleukin-5 is a key cytokine in the eosinophil life pathway. There are receptors for IL-5 on eosinophils, basophils, and β cells.³⁰ Mepolizumab is an anti-IL-5 antibody for those with refractory eosinophilic asthma and a history of continued exacerbations. It has beneficial effects in the management of persistent airways eosinophilia among corticosteroid-resistant subjects. In a 2009 study, rates of exacerbations at 50 weeks were significantly lower than with placebo (2.0 vs 3.4 mean exacerbations per subject, 95% confidence interval [CI], 0.32-0.92; P = .002) as were eosinophil counts in blood and sputum (P < .001 and P = .002 respectively.³¹ A 2014 randomized, double-blind trial by Ortega and colleagues demonstrated reduction in rate of asthma exacerbations (primary outcome) to 47% (95% CI, 29-61) among patients receiving IV dosing and 53% (95% CI, 37-65) in the oral mepolizumab group (P < .001 for both groups, n = 576).³²

In addition, there is significant data to show that even if the patient did not respond to omalizumab, he or she might still respond to mepolizumab. Data were collected from 2 randomized, double-blind, placebo-controlled studies with rate of exacerbation and percentage reduction in oral corticosteroid dose as the primary outcomes. In one of the studies (n = 576), the subjects were noted to have prior omalizumab use but still decreased exacerbation rate by 57%.³³

Reslizumab

Reslizumab also is an FDA-approved anti-IL-5 antibody. It binds directly to IL-5 and prevents it from binding to eosinophils.³⁴ For adults with severe eosinophilic asthma and refractory exacerbations, the goal of reslizumab therapy is to reduce eosinophil maturation, recruitment, and activation. Reslizumab is delivered in a weight-based IV dose (3 mg/kg) every 4 weeks. The FDA has issued a boxed warning for a 0.3% anaphylaxis rate.³⁵ The most common AEs are elevated creatinine kinase, musculoskeletal pain, and oropharyngeal pain. Use of reslizumab resulted in greater reduction in sputum eosinophils, improvements in airway function, and a trend toward greater asthma control compared with that of placebo.³⁴

Other Biologic Therapies

Many biologics are being developed as medical researchers continue to understand more of the mechanisms and pathways that contribute to allergic disease (Table 2). Dupilumab is an IL-4 inhibitor designated as a “breakthrough therapy” in 2014 by the FDA. This biologic blocks the downstream signaling events induced by IL-4 and IL-13 by binding to a subunit of the IL-4 receptor in the complexes. It has been found beneficial for those with high blood eosinophil counts and moderate-to-severe asthma and decreased asthma exacerbations when LABA and ICS were withdrawn.^36,37

Fevipiprant is a prostaglandin D2 inhibitor that blocks T-helper type 2 (Th2) cell migration and subsequent bronchoconstriction and cytokine effects with decreased IL-4, IL-5, and IL-13. Although sputum eosinophil percentage was noted to be decreased in a study involving 61 patients randomized to treatment for 12 weeks, asthma QOL questionnaires and prebronchodilator spirometry did not change.^38,39

Benralizumab is an anti-IL-5 receptor antibody that has been more effective in reduction of airway and blood eosinophils levels compared with that of mepolizumab (undetectable vs 52% reduction), within 24 hours of IV dosing. In contrast, the anti-IL-5 antibodies take about 4 weeks to decrease eosinophil levels in blood and sputum.³⁴ There have been no documented AEs aside from nasopharyngitis and injection site reactions and no safety concerns to date. It is currently undergoing phase 3 trials.⁴⁰

Immunotherapies

Allergen immunotherapy is recommended for mild-to-moderate asthma. A 2010 Cochrane Review found that subcutaneous immunotherapy compared with placebo demonstrated improvements in bronchial hyperresponsiveness and decreased medication use.⁴¹ Expert Panel Report-3 guidelines recommend consideration of immunotherapy for mild-to-moderate asthma.⁵ While ERS/ATS guidelines for severe asthma do not address allergen immunotherapy, GINA guidelines incorporate it as Evidence A for treating modifiable risk factors to reduce exacerbations, although the efficacy is limited.⁶

Roflumilast

Roflumilast is a selective PDE4 inhibitor that has shown an anti-inflammatory effect in COPD. Studies evaluating the reversibility and prevention of airway remodeling showed good promise in mouse models.⁴² Data from 8 placebo-controlled, double-blind, phase 1, 2, and 3 studies conducted at 14 sites in Europe, North America, and South Africa from 1997 to 2005 showed reduced sputum eosinophil and neutrophil counts, consistent with findings during COPD treatment. However, forced expiratory volume in one second (FEV₁) and PEF values were unchanged, suggesting that there was no acute bronchodilatory effect with roflumilast therapy.⁴³ Roflumilast is not addressed in the 2016 GINA guidelines and at this time does not have a role in the treatment of severe asthma.

Antileukotrienes

After the activation of mast cells and eosinophils, leukotrienes are generated by 5-lipoxygenase from arachidonic acid and create bronchoconstriction, vasodilation, increased mucus production, increased recruitment of eosinophils, and decreased ciliary motility. Some studies have encouraged addingleukotriene receptor blockers (both montelukast and zafirlukast) to ICS therapy^44,45 and to therapy for patients with aspirin-intolerant asthma or allergic asthma.^46,47 However, other studies have shown them to be of limited benefit.^48,49 A recent Cochrane Reviewof 18 randomized-controlled trials with 7,208 adults and children compared ICS + leukotriene receptor antagonist (LTRA) vs ICS + LABA.⁵⁰ The ICS + LABA resulted in greater improvements in lung function, symptoms score, and rates of exacerbations.⁵⁰

Most recommendations recognize the limitations of antileukotriene medications and agree that they are an adjunct rather than primary therapy. The GINA 2016 guidelines support the use of LTRAs in mild asthma, stating that although LTRAs are less effective than ICS (Evidence A), they may be appropriate for initial controller treatment for some patients who are unable or unwilling to use ICS or for patients with concurrent allergic rhinitis (Evidence B).^51,52

Zileuton is a different type of antileukotriene. It inhibits leukotrienes B4, C4, D4, and E4 by inhibition of 5-lipoxygenase, interfering with leukotriene formation. It is approved for patients aged ≥ 12 years and is more expensive than montelukast or zafirlukast. Most studies supporting its use were conducted in patients with mild-to-moderate asthma on β-agonist therapy only. A 1988 study showed that zileuton therapy improved FEV₁, reduced nasal symptoms, and decreased bronchial responsiveness to inhaled aspirin and histamine.⁵³ All but 1 study patient were on ICS or oral corticosteroids. Zileuton was noted to be effective for patients with aspirin-intolerant asthma.

Some earlier studies reported that a small number of subjects had an increase in transaminases that resolved when they discontinued the medication. Therefore, it is recommended to check baseline laboratory results every 2 to 3 months.^54,55 Neither GINA nor ERS/ATS guidelines address the use of zileuton.

Bronchial Thermoplasty

With asthma there is marked hypertrophy and hyperplasia that occurs in the airway smooth muscle. The airway of the patient with asthma also is lined with cells that promote inflammation. Thermal energy is used to perform controlled destruction of the inflammatory lining and pathologic hyperplasia. Three sequential bronchoscopies are performed 3 weeks apart to treat the right lower lobe, left lower lobe, and bilateral upper lobes. The right middle lobe is not treated due to its smaller diameter. Each bronchoscopy takes about 30 to 60 minutes. Patients are given perioperative steroids.⁵⁶

Three large phase 3 clinical trials have evaluated the efficacy of bronchial thermoplasty (BT). The AIR (Asthma Intervention Research) trial in 2007 was a randomized controlled study of 112 patients with moderate or severe asthma that showed improved exacerbation rates, symptom-free days and QOL scores (1.3 ± 1.0 vs 0.6 ± 1.1; P = .003), but no difference in prebronchodilator FEV₁ or AHR.⁵⁷ There was a significant reduction in the rate of mild exacerbations and increase in morning PEF rates.⁵⁷ Findings at 5 years showed improved AHR but no difference in frequency of need for oral corticosteroids and frequency of hospital or emergency department (ED) visits.⁵⁸

The Research in Severe Asthma (RISA) clinical trial was a randomized controlled study (n = 32, 15 randomly assigned to BT) that showed improved prebronchodilator FEV₁ in patients with severe, symptomatic asthma and baseline FEV₁ of 62% to 66% with half the patients requiring oral corticosteroids (percentage predicted; 14.9 ± 17.4 vs -0.9 ± 22.3; P =.04).⁵⁷ Quality of life scores were also significantly improved. At 5 years (14 BT patients were followed), the frequency of hospitalizations and ED visits decreased.⁵⁹

The 2010 AIR2 study was a randomized, double blind, sham-controlled study (n = 288) developed to address the limitations of the 2 previous studies. It excluded the severest asthma cases, and its blinded nature was created with sham bronchoscopy to eliminate possible placebo effect. The study questionnaires showed improved QOL overall (79% vs 64%); however, there was a definite placebo effect noted.⁶⁰ Decreased frequency of severe exacerbations as well as ED visits and days lost from work or school also were documented as secondary endpoints. At 5 years, decreased frequency of severe exacerbations and ED visits continued in the control group (85% consented to follow-up).⁶¹ Importantly, despite the placebo effect in QOL scores, there were no improvements in exacerbation rates or hospitalizations in those receiving sham bronchoscopy at the 1-year mark.⁶¹

Although more longitudinal studies need to be planned, including evaluation of those with the most severe asthma, there seems to be a sustained improvement in patients. Those who have received BT generally are found to have reduced airway smooth muscle with lower concentration of key inflammatory cytokines on follow-up bronchoscopy. However, variability in response has been documented.⁵⁶ There has been no documented deterioration in pulmonary function with BT, and no significant structural abnormalities have been seen on high-resolution computed tomography.^56,58 Both GINA 2016 and ERS/ATS support the use of BT in the context of adults with severe asthma, calling for more long-term studies to address delayed benefits and safety.

LABA Inhalers

A multicenter, double-blind, 26-week study of 11,693 patients randomized to ICS + LABA (budesonide/formoterol) vs ICS (budesonide) alone has shown no increased AEs in either arm. The study found that treatment with budesonide/formoterol was associated with lower risk of asthma exacerbations than using budesonide alone (16.5%; P = .002).⁶²

The safety of adding a LABA to fluticasone also has been evaluated recently. A 2016 study of almost 12,000 patients (aged > 12 years) compared fluticasone proprionate alone vs fluticasone with salmeterol.⁶³ There were no asthma-related deaths, but 2 patients in the fluticasone-only group were intubated with asthma complications. The risk of a severe asthma exacerbation seemed to be lower in the combination group (8% vs 10%; P < .001).⁶³

A 2014 Cochrane Review supported the view that LABAs in adults seem to be safe when used concurrently with an ICS with a A-level recommendation, based on consistent good-quality, patient-oriented evidence.⁶⁴ Multiple organizations have issued guidelines to this effect in the past, but previous results of studies showed that asthma deaths and a small increase in nonfatal serious AEs were noted in those using LABA monotherapy alone.⁶⁴

NAEPP (EPR-3) and ERS/ATS recommend stepwise increases in the dose of ICS in combination with a LABA. The GINA guidelines recommend controller therapy to include combination IHS and LABA but with the consideration of higher doses of ICS than are routinely recommended for general use.

Inhaler and Inhaler Combinations

Many different inhalers of ICS alone and ICS/LABA combinations exist on the market today. There are differences in delivery that affect patient preference but these differences have not been found to improve delivery. Small particle ICS therapy could possibly correlate with improved delivery to the small airways.⁶⁵ There are 3 preparations of inhaled steroids that fit in to this group, including beclomethasone, ciclesonide, and flunisolide. Other inhaled steroid formulations include budesonide, fluticasone propionate, fluticasone furoate, and mometasone.

Combination therapy (ICS + LABA) inhalers also are widely available. They include budesonide/formoterol, fluticasone proprionate/salmeterol, mometasone/formoterol, and the newer fluticasone furoate/vilanterol, a once-daily combination approved for those aged ≥ 18 years.

Conclusion

The treatment of severe asthma has progressed from simple manipulation of avoidance, bronchodilators, and corticosteroids to include many other treatments that have improved QOL for patients with refractory asthma. Although many of these options are delivered in coordination with an allergy and pulmonary specialist, it is important for the PCP to have a good knowledge base and awareness of additional treatments that are currently available.

Bone health remains one of the most important health care concerns in the United States today. In 2004, the Surgeon General released a report on bone health and osteoporosis. According to the report’s introduction:

This first-ever Surgeon General’s Report on bone health and osteoporosis illustrates the large burden that bone disease places on our Nation and its citizens. Like other chronic diseases that disproportionately affect the elderly, the prevalence of bone disease and fractures is projected to increase markedly as the population ages. If these predictions come true, bone disease and fractures will have a tremendous negative impact on the future well-being of Americans. But as this report makes clear, they need not come true: by working together we can change the picture of aging in America. Osteoporosis and fractures…no longer should be thought of as an inevitable part of growing old. By focusing on prevention and lifestyle changes, including physical activity and nutrition, as well as early diagnosis and appropriate treatment, Americans can avoid much of the damaging impact of bone disease.¹

Related article:
2016 Update on bone health

Although men also experience osteoporosis as they age, in women the rapid loss of bone at menopause makes their disease burden much greater. As women’s health care providers, we stand at the front line for preventing, diagnosing, and treating osteoporosis to reduce the impact of this disease. In this Update I focus on important information that has emerged in the past year.

Read about new ACP guidelines to assess fracture risk

Guidelines for therapy: How to assess fracture risk and when to treat

American College of Obstetricians and Gynecologists Committee on Practice Bulletins--Gynecology. ACOG Practice Bulletin No. 129: Osteoporosis. Obstet Gynecol. 2012;120(3):718-734.

Qaseem A, Forciea MA, McLean RM, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(11):818-839.

A crucial component for good bone health maintenance and osteoporotic fracture prevention is understanding the current guidelines for therapy. The most recent practice bulletin of the American College of Obstetricians and Gynecologists (ACOG) on osteoporosis was published in 2012. ACOG states that treatment be recommended for women who have a bone mineral density (BMD) T-score of -2.5 or lower.

For women in the low bone mass category (T-score between -1 and -2.5), use of the Fracture Risk Assessment Tool (FRAX) calculator can assist in making an informed treatment decision.² Based on the FRAX calculator, women who have a 10-year risk of major osteoporotic fracture of 20% or greater, or a risk of hip fracture of 3% or greater, are candidates for pharmacologic therapy.

Women who have experienced a low-trauma fracture (especially of the vertebra or hip) also are candidates for treatment, even in the absence of osteoporosis on a dual-energy x-ray absorptiometry (DXA) report.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Updated recommendations from the ACP

The 2017 guideline published by the American College of Physicians (ACP), whose target audience is "all clinicians," recommends that, for women who have known osteoporosis, clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures.

In addition, the ACP recommends that clinicians make the decision whether or not to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences, fracture risk profile, and benefits, harms, and costs of medications. This may seem somewhat contradictory to ACOG's guidance vis-a-vis women younger than 65 years of age.

The ACP further states that given the limited evidence supporting the benefit of treatment, the balance of benefits and harms in treating osteopenic women is most favorable when the risk for fracture is high. Women younger than 65 years with osteopenia and women older than 65 years with mild osteopenia (T-score between -1.0 and -1.5) will benefit less than women who are 65 years of age or older with severe osteopenia (T-score <-2.0).

Risk factors and risk assessment tools

Clinicians can use their own judgment based on risk factors for fracture (lower body weight, smoking, weight loss, family history of fractures, decreased physical activity, alcohol or caffeine use, low calcium and vitamin D intake, corticosteroid use), or they can use a risk assessment tool. Several risk assessment tools, such as the FRAX calculator mentioned earlier, are available to predict fracture risk among untreated people with low bone density. Although the FRAX calculator is widely used, there is no evidence from randomized controlled trials demonstrating a benefit of fracture reduction when FRAX scores are used in treatment decision making.

Duration of therapy. The ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. Bone density monitoring is not recommended during the 5-year treatment period for osteoporosis in women; current evidence does not show any benefit for bone density monitoring during treatment.

Moderate-quality evidence demonstrated that women treated with antiresorptive therapies (including bisphosphonates, raloxifene, and teriparatide) benefited from reduced fractures, even if no increase in BMD occurred or if BMD decreased.

Read about fracture risk after stopping HT

Another WHI update: No increase in fractures after stopping HT

Watts NB, Cauley JA, Jackson RD, et al; Women's Health Initiative Investigators. No increase in fractures after stopping hormone therapy: results from the Women's Health Initiative. J Clin Endocrinol Metab. 2017;102(1):302-308.

The analysis and reanalysis of the Women's Health Initiative (WHI) trial data seems never-ending, yet the article by Watts and colleagues is important. Although the WHI hormone therapy (HT) trials showed that treatment protects against hip and total fractures, a later observational report suggested loss of benefit and rebound increased risk after HT was discontinued.3 The purpose of the Watts' study was to examine fractures after stopping HT.

Related article:
Did long-term follow-up of WHI participants reveal any mortality increase among women who received HT?

Details of the study

Two placebo-controlled randomized trials served as the study setting. The study included WHI participants (n = 15,187) who continued to take active HT or placebo through the intervention period and who did not take HT in the postintervention period. The trial interventions included conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) for women with natural menopause and CEE alone for women with prior hysterectomy. The investigators recorded total fractures and hip fractures through 5 years after HT discontinuation.

Findings on fractures. Hip fractures occurred infrequently, with approximately 2.5 per 1,000 person-years. This finding was similar between trials and in former HT users and placebo groups.

No difference was found in total fractures in the CEE plus MPA trial for former HT users compared with former placebo users (28.9 per 1,000 person-years and 29.9 per 1,000 person-years, respectively; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.87-1.09; P = .63). In the CEE-alone trial, however, total fractures were higher in former placebo users (36.9 per 1,000 person-years) compared with the former active-treatment group (31.1 per 1,000 person-years). This finding suggests a residual benefit of CEE in reducing total fractures (HR, 0.85; 95% CI, 0.73-0.98; P = .03).

Investigators' takeaway. The authors concluded that, after discontinuing HT, there was no evidence of increased fracture risk (sustained or transient) in former HT users compared with former placebo users. In the CEE-alone trial, there was a residual benefit for total fracture reduction in former HT users compared with placebo users.

Read about reassessing FRAX scores

A new look at fracture risk assessment scores

Gourlay ML, Overman RA, Fine JP, et al; Women's Health Initiative Investigators. Time to clinically relevant fracture risk scores in postmenopausal women. Am J Med. 2017;130:862.e15-e23.

Jiang X, Gruner M, Trémollieres F, et al. Diagnostic accuracy of FRAX in predicting the 10-year risk of osteoporotic fractures using the USA treatment thresholds: a systematic review and meta-analysis. Bone. 2017;99:20-25.

The FRAX score has become a popular form of triage for women who do not yet meet the bone mass criteria of osteoporosis. Current practice guidelines recommend use of fracture risk scores for screening and pharmacologic therapeutic decision making. Some newer data, however, may give rise to questions about its utility, especially in younger women.

Fracture risk analysis in a large postmenopausal population

Gourlay and colleagues conducted a retrospective competing risk analysis of new occurrence of treatment-level and screening-level fracture risk scores. Study participants were postmenopausal women aged 50 years and older who had not previously received pharmacologic treatment and had not had a first hip or clinical vertebral facture.

Details of the study

In 54,280 postmenopausal women aged 50 to 64 years who did not have a bone mineral density test, the time for 10% to develop a treatment-level FRAX score could not be estimated accurately because the incidence of treatment-level scores was rare.

A total of 6,096 women had FRAX scores calculated with bone mineral density testing. In this group, the estimated unadjusted time to treatment-level FRAX scores was 7.6 years (95% CI, 6.6-8.7) for those aged 65 to 69, and 5.1 years (95% CI, 3.5-7.5) for women aged 75 to 79 at baseline.

Of 17,967 women aged 50 to 64 who had a screening-level FRAX at baseline, 100 (0.6%) experienced a hip or clinical vertebral fracture by age 65 years.

Age is key factor. Gourlay and colleagues concluded that postmenopausal women who had subthreshold fracture risk scores at baseline would be unlikely to develop a treatment-level FRAX score between ages 50 and 64. The increased incidence of treatment-level fracture risk scores, osteoporosis, and major osteoporotic fracture after age 65, however, supports more frequent consideration of FRAX assessment and bone mineral density testing.

Related article:
2015 Update on osteoporosis

Meta-analysis of FRAX tool accuracy

In another study, Jiang and colleagues conducted a systematic review and meta-analysis to determine how the FRAX score performed in predicting the 10-year risk of major osteoporotic fractures and hip fractures. The investigators used the US treatment thresholds.

Details of the study

Seven studies (n = 57,027) were analyzed to assess the diagnostic accuracy of FRAX in predicting major osteoporotic fractures; 20% was used as the 10-year fracture risk threshold for intervention. The mean sensitivity and specificity, along with their 95% CIs, were 10.25% (3.76%-25.06%) and 97.02% (91.17%-99.03%), respectively.

For hip fracture prediction, 6 studies (n = 50,944) were analyzed, and 3% was used as the 10-year fracture risk threshold. The mean sensitivity and specificity, along with their 95% CIs, were 45.70% (24.88%-68.13%) and 84.70% (76.41%-90.44%), respectively.

Predictive value of FRAX. The authors concluded that, using the 10-year intervention thresholds of 20% for major osteoporotic fracture and 3% for hip fracture, FRAX performed better in identifying individuals who will not have a major osteoporotic fracture or hip fracture within 10 years than in identifying those who will experience a fracture. A substantial number of those who developed fractures, especially major osteoporotic fracture within 10 years of follow up, were missed by the baseline FRAX assessment.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Bone health remains one of the most important health care concerns in the United States today. In 2004, the Surgeon General released a report on bone health and osteoporosis. According to the report’s introduction:

This first-ever Surgeon General’s Report on bone health and osteoporosis illustrates the large burden that bone disease places on our Nation and its citizens. Like other chronic diseases that disproportionately affect the elderly, the prevalence of bone disease and fractures is projected to increase markedly as the population ages. If these predictions come true, bone disease and fractures will have a tremendous negative impact on the future well-being of Americans. But as this report makes clear, they need not come true: by working together we can change the picture of aging in America. Osteoporosis and fractures…no longer should be thought of as an inevitable part of growing old. By focusing on prevention and lifestyle changes, including physical activity and nutrition, as well as early diagnosis and appropriate treatment, Americans can avoid much of the damaging impact of bone disease.¹

Related article:
2016 Update on bone health

Although men also experience osteoporosis as they age, in women the rapid loss of bone at menopause makes their disease burden much greater. As women’s health care providers, we stand at the front line for preventing, diagnosing, and treating osteoporosis to reduce the impact of this disease. In this Update I focus on important information that has emerged in the past year.

Read about new ACP guidelines to assess fracture risk

Guidelines for therapy: How to assess fracture risk and when to treat

American College of Obstetricians and Gynecologists Committee on Practice Bulletins--Gynecology. ACOG Practice Bulletin No. 129: Osteoporosis. Obstet Gynecol. 2012;120(3):718-734.

Qaseem A, Forciea MA, McLean RM, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(11):818-839.

A crucial component for good bone health maintenance and osteoporotic fracture prevention is understanding the current guidelines for therapy. The most recent practice bulletin of the American College of Obstetricians and Gynecologists (ACOG) on osteoporosis was published in 2012. ACOG states that treatment be recommended for women who have a bone mineral density (BMD) T-score of -2.5 or lower.

For women in the low bone mass category (T-score between -1 and -2.5), use of the Fracture Risk Assessment Tool (FRAX) calculator can assist in making an informed treatment decision.² Based on the FRAX calculator, women who have a 10-year risk of major osteoporotic fracture of 20% or greater, or a risk of hip fracture of 3% or greater, are candidates for pharmacologic therapy.

Women who have experienced a low-trauma fracture (especially of the vertebra or hip) also are candidates for treatment, even in the absence of osteoporosis on a dual-energy x-ray absorptiometry (DXA) report.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Updated recommendations from the ACP

The 2017 guideline published by the American College of Physicians (ACP), whose target audience is "all clinicians," recommends that, for women who have known osteoporosis, clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures.

In addition, the ACP recommends that clinicians make the decision whether or not to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences, fracture risk profile, and benefits, harms, and costs of medications. This may seem somewhat contradictory to ACOG's guidance vis-a-vis women younger than 65 years of age.

The ACP further states that given the limited evidence supporting the benefit of treatment, the balance of benefits and harms in treating osteopenic women is most favorable when the risk for fracture is high. Women younger than 65 years with osteopenia and women older than 65 years with mild osteopenia (T-score between -1.0 and -1.5) will benefit less than women who are 65 years of age or older with severe osteopenia (T-score <-2.0).

Risk factors and risk assessment tools

Clinicians can use their own judgment based on risk factors for fracture (lower body weight, smoking, weight loss, family history of fractures, decreased physical activity, alcohol or caffeine use, low calcium and vitamin D intake, corticosteroid use), or they can use a risk assessment tool. Several risk assessment tools, such as the FRAX calculator mentioned earlier, are available to predict fracture risk among untreated people with low bone density. Although the FRAX calculator is widely used, there is no evidence from randomized controlled trials demonstrating a benefit of fracture reduction when FRAX scores are used in treatment decision making.

Duration of therapy. The ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. Bone density monitoring is not recommended during the 5-year treatment period for osteoporosis in women; current evidence does not show any benefit for bone density monitoring during treatment.

Moderate-quality evidence demonstrated that women treated with antiresorptive therapies (including bisphosphonates, raloxifene, and teriparatide) benefited from reduced fractures, even if no increase in BMD occurred or if BMD decreased.

Read about fracture risk after stopping HT

Another WHI update: No increase in fractures after stopping HT

Watts NB, Cauley JA, Jackson RD, et al; Women's Health Initiative Investigators. No increase in fractures after stopping hormone therapy: results from the Women's Health Initiative. J Clin Endocrinol Metab. 2017;102(1):302-308.

The analysis and reanalysis of the Women's Health Initiative (WHI) trial data seems never-ending, yet the article by Watts and colleagues is important. Although the WHI hormone therapy (HT) trials showed that treatment protects against hip and total fractures, a later observational report suggested loss of benefit and rebound increased risk after HT was discontinued.3 The purpose of the Watts' study was to examine fractures after stopping HT.

Related article:
Did long-term follow-up of WHI participants reveal any mortality increase among women who received HT?

Details of the study

Two placebo-controlled randomized trials served as the study setting. The study included WHI participants (n = 15,187) who continued to take active HT or placebo through the intervention period and who did not take HT in the postintervention period. The trial interventions included conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) for women with natural menopause and CEE alone for women with prior hysterectomy. The investigators recorded total fractures and hip fractures through 5 years after HT discontinuation.

Findings on fractures. Hip fractures occurred infrequently, with approximately 2.5 per 1,000 person-years. This finding was similar between trials and in former HT users and placebo groups.

No difference was found in total fractures in the CEE plus MPA trial for former HT users compared with former placebo users (28.9 per 1,000 person-years and 29.9 per 1,000 person-years, respectively; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.87-1.09; P = .63). In the CEE-alone trial, however, total fractures were higher in former placebo users (36.9 per 1,000 person-years) compared with the former active-treatment group (31.1 per 1,000 person-years). This finding suggests a residual benefit of CEE in reducing total fractures (HR, 0.85; 95% CI, 0.73-0.98; P = .03).

Investigators' takeaway. The authors concluded that, after discontinuing HT, there was no evidence of increased fracture risk (sustained or transient) in former HT users compared with former placebo users. In the CEE-alone trial, there was a residual benefit for total fracture reduction in former HT users compared with placebo users.

Read about reassessing FRAX scores

A new look at fracture risk assessment scores

Gourlay ML, Overman RA, Fine JP, et al; Women's Health Initiative Investigators. Time to clinically relevant fracture risk scores in postmenopausal women. Am J Med. 2017;130:862.e15-e23.

Jiang X, Gruner M, Trémollieres F, et al. Diagnostic accuracy of FRAX in predicting the 10-year risk of osteoporotic fractures using the USA treatment thresholds: a systematic review and meta-analysis. Bone. 2017;99:20-25.

The FRAX score has become a popular form of triage for women who do not yet meet the bone mass criteria of osteoporosis. Current practice guidelines recommend use of fracture risk scores for screening and pharmacologic therapeutic decision making. Some newer data, however, may give rise to questions about its utility, especially in younger women.

Fracture risk analysis in a large postmenopausal population

Gourlay and colleagues conducted a retrospective competing risk analysis of new occurrence of treatment-level and screening-level fracture risk scores. Study participants were postmenopausal women aged 50 years and older who had not previously received pharmacologic treatment and had not had a first hip or clinical vertebral facture.

Details of the study

In 54,280 postmenopausal women aged 50 to 64 years who did not have a bone mineral density test, the time for 10% to develop a treatment-level FRAX score could not be estimated accurately because the incidence of treatment-level scores was rare.

A total of 6,096 women had FRAX scores calculated with bone mineral density testing. In this group, the estimated unadjusted time to treatment-level FRAX scores was 7.6 years (95% CI, 6.6-8.7) for those aged 65 to 69, and 5.1 years (95% CI, 3.5-7.5) for women aged 75 to 79 at baseline.

Of 17,967 women aged 50 to 64 who had a screening-level FRAX at baseline, 100 (0.6%) experienced a hip or clinical vertebral fracture by age 65 years.

Age is key factor. Gourlay and colleagues concluded that postmenopausal women who had subthreshold fracture risk scores at baseline would be unlikely to develop a treatment-level FRAX score between ages 50 and 64. The increased incidence of treatment-level fracture risk scores, osteoporosis, and major osteoporotic fracture after age 65, however, supports more frequent consideration of FRAX assessment and bone mineral density testing.

Related article:
2015 Update on osteoporosis

Meta-analysis of FRAX tool accuracy

In another study, Jiang and colleagues conducted a systematic review and meta-analysis to determine how the FRAX score performed in predicting the 10-year risk of major osteoporotic fractures and hip fractures. The investigators used the US treatment thresholds.

Details of the study

Seven studies (n = 57,027) were analyzed to assess the diagnostic accuracy of FRAX in predicting major osteoporotic fractures; 20% was used as the 10-year fracture risk threshold for intervention. The mean sensitivity and specificity, along with their 95% CIs, were 10.25% (3.76%-25.06%) and 97.02% (91.17%-99.03%), respectively.

For hip fracture prediction, 6 studies (n = 50,944) were analyzed, and 3% was used as the 10-year fracture risk threshold. The mean sensitivity and specificity, along with their 95% CIs, were 45.70% (24.88%-68.13%) and 84.70% (76.41%-90.44%), respectively.

Predictive value of FRAX. The authors concluded that, using the 10-year intervention thresholds of 20% for major osteoporotic fracture and 3% for hip fracture, FRAX performed better in identifying individuals who will not have a major osteoporotic fracture or hip fracture within 10 years than in identifying those who will experience a fracture. A substantial number of those who developed fractures, especially major osteoporotic fracture within 10 years of follow up, were missed by the baseline FRAX assessment.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Bone health remains one of the most important health care concerns in the United States today. In 2004, the Surgeon General released a report on bone health and osteoporosis. According to the report’s introduction:

This first-ever Surgeon General’s Report on bone health and osteoporosis illustrates the large burden that bone disease places on our Nation and its citizens. Like other chronic diseases that disproportionately affect the elderly, the prevalence of bone disease and fractures is projected to increase markedly as the population ages. If these predictions come true, bone disease and fractures will have a tremendous negative impact on the future well-being of Americans. But as this report makes clear, they need not come true: by working together we can change the picture of aging in America. Osteoporosis and fractures…no longer should be thought of as an inevitable part of growing old. By focusing on prevention and lifestyle changes, including physical activity and nutrition, as well as early diagnosis and appropriate treatment, Americans can avoid much of the damaging impact of bone disease.¹

Related article:
2016 Update on bone health

Although men also experience osteoporosis as they age, in women the rapid loss of bone at menopause makes their disease burden much greater. As women’s health care providers, we stand at the front line for preventing, diagnosing, and treating osteoporosis to reduce the impact of this disease. In this Update I focus on important information that has emerged in the past year.

Read about new ACP guidelines to assess fracture risk

Guidelines for therapy: How to assess fracture risk and when to treat

American College of Obstetricians and Gynecologists Committee on Practice Bulletins--Gynecology. ACOG Practice Bulletin No. 129: Osteoporosis. Obstet Gynecol. 2012;120(3):718-734.

Qaseem A, Forciea MA, McLean RM, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166(11):818-839.

A crucial component for good bone health maintenance and osteoporotic fracture prevention is understanding the current guidelines for therapy. The most recent practice bulletin of the American College of Obstetricians and Gynecologists (ACOG) on osteoporosis was published in 2012. ACOG states that treatment be recommended for women who have a bone mineral density (BMD) T-score of -2.5 or lower.

For women in the low bone mass category (T-score between -1 and -2.5), use of the Fracture Risk Assessment Tool (FRAX) calculator can assist in making an informed treatment decision.² Based on the FRAX calculator, women who have a 10-year risk of major osteoporotic fracture of 20% or greater, or a risk of hip fracture of 3% or greater, are candidates for pharmacologic therapy.

Women who have experienced a low-trauma fracture (especially of the vertebra or hip) also are candidates for treatment, even in the absence of osteoporosis on a dual-energy x-ray absorptiometry (DXA) report.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Updated recommendations from the ACP

The 2017 guideline published by the American College of Physicians (ACP), whose target audience is "all clinicians," recommends that, for women who have known osteoporosis, clinicians offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk for hip and vertebral fractures.

In addition, the ACP recommends that clinicians make the decision whether or not to treat osteopenic women 65 years of age or older who are at a high risk for fracture based on a discussion of patient preferences, fracture risk profile, and benefits, harms, and costs of medications. This may seem somewhat contradictory to ACOG's guidance vis-a-vis women younger than 65 years of age.

The ACP further states that given the limited evidence supporting the benefit of treatment, the balance of benefits and harms in treating osteopenic women is most favorable when the risk for fracture is high. Women younger than 65 years with osteopenia and women older than 65 years with mild osteopenia (T-score between -1.0 and -1.5) will benefit less than women who are 65 years of age or older with severe osteopenia (T-score <-2.0).

Risk factors and risk assessment tools

Clinicians can use their own judgment based on risk factors for fracture (lower body weight, smoking, weight loss, family history of fractures, decreased physical activity, alcohol or caffeine use, low calcium and vitamin D intake, corticosteroid use), or they can use a risk assessment tool. Several risk assessment tools, such as the FRAX calculator mentioned earlier, are available to predict fracture risk among untreated people with low bone density. Although the FRAX calculator is widely used, there is no evidence from randomized controlled trials demonstrating a benefit of fracture reduction when FRAX scores are used in treatment decision making.

Duration of therapy. The ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. Bone density monitoring is not recommended during the 5-year treatment period for osteoporosis in women; current evidence does not show any benefit for bone density monitoring during treatment.

Moderate-quality evidence demonstrated that women treated with antiresorptive therapies (including bisphosphonates, raloxifene, and teriparatide) benefited from reduced fractures, even if no increase in BMD occurred or if BMD decreased.

Read about fracture risk after stopping HT

Another WHI update: No increase in fractures after stopping HT

Watts NB, Cauley JA, Jackson RD, et al; Women's Health Initiative Investigators. No increase in fractures after stopping hormone therapy: results from the Women's Health Initiative. J Clin Endocrinol Metab. 2017;102(1):302-308.

The analysis and reanalysis of the Women's Health Initiative (WHI) trial data seems never-ending, yet the article by Watts and colleagues is important. Although the WHI hormone therapy (HT) trials showed that treatment protects against hip and total fractures, a later observational report suggested loss of benefit and rebound increased risk after HT was discontinued.3 The purpose of the Watts' study was to examine fractures after stopping HT.

Related article:
Did long-term follow-up of WHI participants reveal any mortality increase among women who received HT?

Details of the study

Two placebo-controlled randomized trials served as the study setting. The study included WHI participants (n = 15,187) who continued to take active HT or placebo through the intervention period and who did not take HT in the postintervention period. The trial interventions included conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) for women with natural menopause and CEE alone for women with prior hysterectomy. The investigators recorded total fractures and hip fractures through 5 years after HT discontinuation.

Findings on fractures. Hip fractures occurred infrequently, with approximately 2.5 per 1,000 person-years. This finding was similar between trials and in former HT users and placebo groups.

No difference was found in total fractures in the CEE plus MPA trial for former HT users compared with former placebo users (28.9 per 1,000 person-years and 29.9 per 1,000 person-years, respectively; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.87-1.09; P = .63). In the CEE-alone trial, however, total fractures were higher in former placebo users (36.9 per 1,000 person-years) compared with the former active-treatment group (31.1 per 1,000 person-years). This finding suggests a residual benefit of CEE in reducing total fractures (HR, 0.85; 95% CI, 0.73-0.98; P = .03).

Investigators' takeaway. The authors concluded that, after discontinuing HT, there was no evidence of increased fracture risk (sustained or transient) in former HT users compared with former placebo users. In the CEE-alone trial, there was a residual benefit for total fracture reduction in former HT users compared with placebo users.

Read about reassessing FRAX scores

A new look at fracture risk assessment scores

Gourlay ML, Overman RA, Fine JP, et al; Women's Health Initiative Investigators. Time to clinically relevant fracture risk scores in postmenopausal women. Am J Med. 2017;130:862.e15-e23.

Jiang X, Gruner M, Trémollieres F, et al. Diagnostic accuracy of FRAX in predicting the 10-year risk of osteoporotic fractures using the USA treatment thresholds: a systematic review and meta-analysis. Bone. 2017;99:20-25.

The FRAX score has become a popular form of triage for women who do not yet meet the bone mass criteria of osteoporosis. Current practice guidelines recommend use of fracture risk scores for screening and pharmacologic therapeutic decision making. Some newer data, however, may give rise to questions about its utility, especially in younger women.

Fracture risk analysis in a large postmenopausal population

Gourlay and colleagues conducted a retrospective competing risk analysis of new occurrence of treatment-level and screening-level fracture risk scores. Study participants were postmenopausal women aged 50 years and older who had not previously received pharmacologic treatment and had not had a first hip or clinical vertebral facture.

Details of the study

In 54,280 postmenopausal women aged 50 to 64 years who did not have a bone mineral density test, the time for 10% to develop a treatment-level FRAX score could not be estimated accurately because the incidence of treatment-level scores was rare.

A total of 6,096 women had FRAX scores calculated with bone mineral density testing. In this group, the estimated unadjusted time to treatment-level FRAX scores was 7.6 years (95% CI, 6.6-8.7) for those aged 65 to 69, and 5.1 years (95% CI, 3.5-7.5) for women aged 75 to 79 at baseline.

Of 17,967 women aged 50 to 64 who had a screening-level FRAX at baseline, 100 (0.6%) experienced a hip or clinical vertebral fracture by age 65 years.

Age is key factor. Gourlay and colleagues concluded that postmenopausal women who had subthreshold fracture risk scores at baseline would be unlikely to develop a treatment-level FRAX score between ages 50 and 64. The increased incidence of treatment-level fracture risk scores, osteoporosis, and major osteoporotic fracture after age 65, however, supports more frequent consideration of FRAX assessment and bone mineral density testing.

Related article:
2015 Update on osteoporosis

Meta-analysis of FRAX tool accuracy

In another study, Jiang and colleagues conducted a systematic review and meta-analysis to determine how the FRAX score performed in predicting the 10-year risk of major osteoporotic fractures and hip fractures. The investigators used the US treatment thresholds.

Details of the study

Seven studies (n = 57,027) were analyzed to assess the diagnostic accuracy of FRAX in predicting major osteoporotic fractures; 20% was used as the 10-year fracture risk threshold for intervention. The mean sensitivity and specificity, along with their 95% CIs, were 10.25% (3.76%-25.06%) and 97.02% (91.17%-99.03%), respectively.

For hip fracture prediction, 6 studies (n = 50,944) were analyzed, and 3% was used as the 10-year fracture risk threshold. The mean sensitivity and specificity, along with their 95% CIs, were 45.70% (24.88%-68.13%) and 84.70% (76.41%-90.44%), respectively.

Predictive value of FRAX. The authors concluded that, using the 10-year intervention thresholds of 20% for major osteoporotic fracture and 3% for hip fracture, FRAX performed better in identifying individuals who will not have a major osteoporotic fracture or hip fracture within 10 years than in identifying those who will experience a fracture. A substantial number of those who developed fractures, especially major osteoporotic fracture within 10 years of follow up, were missed by the baseline FRAX assessment.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Over the past 3 decades, the prevalence of overweight and obesity has increased dramatically in the United States. A study published in 2016 showed the age-adjusted prevalence of obesity in 2013–2014 was 35% among men and 40.4% among women.¹ It comes as no surprise that increased reliance on inexpensive fast foods coupled with progressively more sedentary lifestyles have been implicated as causative factors.²

With the rise in obesity also has come an attendant rise in related chronic diseases, such as type 2 diabetes mellitus and cardiovascular disease. Women who are obese are also at risk for certain women’s health conditions, such as polycystic ovary syndrome, breast cancer, and endometrial cancer.

It is clear that curbing this public health crisis will require concerted efforts from individuals, clinicians, and policy makers, as well as changes in societal norms. OBG Management recently caught up with wellness expert Linda D. Bradley, MD, who shared in her latest book, “Us! Our Life. Our Health.” Our Legacy,” some practical strategies clinicians can use to help their patients manage their weight and prevent or reverse chronic diseases.

OBG Management: In your book you describe Jane, a patient who was severely overweight and who had low self-esteem. ³ You took 2 hours to convince Jane to talk about her clinical problems. That was clearly a heroic intervention on your part as the physician. What advice do you have for time-strapped clinicians who have patients who may need to face mental barriers in order to begin to address physical ailments?

Linda D. Bradley, MD: I think it is important for us not to lecture our patients. I could list all of the things that patients should or could do to prevent or even reverse disease states, in terms of eating right and exercising, but I think motivational interviewing is a more productive approach to elicit and evoke change (see “Principles and practice of motivational interviewing”). I used to preach to my patients. I would say, “You know, if you stay at this weight, you’re going to get diabetes, you’re going to increase your breast cancer risk, you’re going to have abnormal bleeding, you’re not going to be able to get pregnant,” and so on. It is easy to slip into that in the 7 minutes that you have with your patient, but to me, that is not the right way.

With motivational interviewing, our interactions with patients are shaped by:

• asking
• advising
• assisting
• arranging.

We begin by asking permission: “Do you mind if we talk about your weight?” or “Can we talk about your level of exercise?” Once the patient has granted permission, we ask open-ended questions and use reflective listening: “What I hear you saying is that you are concerned you will not be able to lose the weight,” or “It sounds like you don’t like to exercise, but you are worried about the health consequences of that.”

I find these skills useful for addressing anything from smoking to drinking to weight management to excessive shopping—any extreme behavior that is affecting a patient negatively. When a patient is not ready to talk about her clinical problems or make changes, I let her know my door is always open to her and that I have many resources available to help her when she is ready (TABLE).⁴ In those cases, I might say something like, “I have many patients who really don’t want to talk about this when I first ask them, but I just want you to know, Mrs. Jones, that I want you to succeed and I want you to be healthy. We have a team approach to taking care of all of you, and when you are ready, we are here to help.”

Related article:
2017 Update on fertility: Effects of obesity on reproduction

It is important to provide practical advice to patients—including how much to exercise, the importance of keeping a food journal, and determining a goal for slow, safe weight loss—and provide resources as necessary (such as for Weight Watchers, nutrition, and dieticians). Each day we have more than 30 opportunities to select foods to eat, drink, or purchase. Have a plan and advise your patients do the same. Recommend patients cook their own meals. Suggest weight loss apps. Counsel them to celebrate successes, find a buddy (for social support), practice positive self-talk (positive language), and plan for challenges (travel, parties, working late) and setbacks, which do not need to become a fall. Find an activity or exercise that the patient enjoys and tell them to seek professional help if needed.

Read about how to educate your patients on wellness.

OBG Management: You mention in your book that 70% to 80% of people now in hospitals are there because of diseases preventable through lifestyle choice. What are the women’s health conditions on that list?

Dr. Bradley: About 86% of the health care dollars spent in the United States are due to chronic diseases, and chronic diseases are the leading cause of death and disability in the country.⁵ The most common chronic diseases—cardiovascular disease, hypertension, type 2 diabetes, colon cancer, depression, dementia, cognitive problems, higher rates of fractures—all have been associated, at least in part, with unhealthy food choices and lack of exercise. That applies to breast cancer, too.

The good news is, we can prevent and even reverse disease. As Hippocrates said, let food be thy medicine and medicine be thy food. We have all seen success stories where consistent exercise and dietary changes definitely change the paradigm for what the disease state represents. A multiplicity of factors affect poor health—noncompliance, obesity, smoking—but when we begin to make consistent, healthy changes with diet and exercise, this creates a sort of domino effect.

OBG Management: You discuss chronic illness as preventable, manageable, and reversible. Where do you see the women’s health clinician’s role in the management of reversal?

Dr. Bradley: I think we need to get to the root cause of these clinical problems and provide the resources and support that patients need to reverse or even prevent these diseases. Clinicians need to become more aware—be an example and a role model. Our patients are watching us as much as we are watching them. Together, we can form good partnerships in order to promote better health.

OBG Management: Do you encourage your patients to write a wellness contract?

Dr. Bradley: I think when you are about to be a change agent for your body and become what I call the best version of yourself, you can have these great ideas, but you need to turn those ideas into actions and make them consistent. And we know that is difficult to do, so I do try to have patients write down specific goals, their plan for achieving them, and list the reasons why it is important for them to reach their goals. That gives them something tangible to look at when the going gets tough. It is also important to work into the contract ways to reward positive behaviors when goals are met, and to plan for challenges and setbacks and how to get back on track.

I also encourage patients to document their progress and learn how to make quick adjustments when necessary to get back on track. Another important element involves setting milestones—by what date are you going to reach this goal? Like any other contract, I have my patients date and sign their wellness contracts. I also encourage them to visualize what their new self is going to look like, how they will feel when they reach their goal, what they will wear, and what activities they will engage in.

Related article:
Obesity medicine: How to incorporate it into your practice

OBG Management: Do you think that physicians have a role in educating their patients on food labels and dietary intake?

Dr. Bradley: I do, but the amount of nutrition education that most of us get in medical school is minimal to nonexistent and not practical. As physicians, we know that food is health, exercise is fitness, and that our patients need both of them. We also know that we did not get this information in school and that our education was more about treating disease than preventing disease. Many of us were not trained in robot surgery either, because it did not exist. So what did we do? We took classes, attended lectures, read books, and learned. We can do the same with wellness. There are many courses around the country. We have to begin to relearn and reteach ourselves about health, nutrition, and exercise and then pass that information on to our patients—be a resource and a guide. We should be able to write a prescription for health as quickly as we can write a prescription for insulin or a statin.

I also bring up portion distortion with my patients. The National Institutes of Health has resources on their website (https://www.nhlbi.nih.gov/health/educational /wecan/eat-right/portion-distortion.html) that include great visuals that show portion sizes 20 years ago and what they are now. For instance, 20 years ago a bagel was 3 inches and 140 calories; today’s bagel is 6 inches and 350 calories (plus whatever toppings are added). I tell that to my patients and then explain how much more exercise is needed to burn off just that 1 bagel.

Related article:
How to help your patients control gestational weight gain

OBG Management: Epigenetics: Do patients know about it?

Dr. Bradley: They may not know that term directly, but I think people understand that you have the potential to pass on poor lifestyle and/or health issues related to how things are when you are in utero and later in life. It gets back to letting people know to be healthy in pregnancy and even pre-pregnancy, and that includes one’s emotional state, physical state, and spiritual state. We are what we are in our mother’s womb. Getting the best start in life starts with a healthy mom, healthy dad, and a healthy environment.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Over the past 3 decades, the prevalence of overweight and obesity has increased dramatically in the United States. A study published in 2016 showed the age-adjusted prevalence of obesity in 2013–2014 was 35% among men and 40.4% among women.¹ It comes as no surprise that increased reliance on inexpensive fast foods coupled with progressively more sedentary lifestyles have been implicated as causative factors.²

With the rise in obesity also has come an attendant rise in related chronic diseases, such as type 2 diabetes mellitus and cardiovascular disease. Women who are obese are also at risk for certain women’s health conditions, such as polycystic ovary syndrome, breast cancer, and endometrial cancer.

It is clear that curbing this public health crisis will require concerted efforts from individuals, clinicians, and policy makers, as well as changes in societal norms. OBG Management recently caught up with wellness expert Linda D. Bradley, MD, who shared in her latest book, “Us! Our Life. Our Health.” Our Legacy,” some practical strategies clinicians can use to help their patients manage their weight and prevent or reverse chronic diseases.

OBG Management: In your book you describe Jane, a patient who was severely overweight and who had low self-esteem. ³ You took 2 hours to convince Jane to talk about her clinical problems. That was clearly a heroic intervention on your part as the physician. What advice do you have for time-strapped clinicians who have patients who may need to face mental barriers in order to begin to address physical ailments?

Linda D. Bradley, MD: I think it is important for us not to lecture our patients. I could list all of the things that patients should or could do to prevent or even reverse disease states, in terms of eating right and exercising, but I think motivational interviewing is a more productive approach to elicit and evoke change (see “Principles and practice of motivational interviewing”). I used to preach to my patients. I would say, “You know, if you stay at this weight, you’re going to get diabetes, you’re going to increase your breast cancer risk, you’re going to have abnormal bleeding, you’re not going to be able to get pregnant,” and so on. It is easy to slip into that in the 7 minutes that you have with your patient, but to me, that is not the right way.

With motivational interviewing, our interactions with patients are shaped by:

• asking
• advising
• assisting
• arranging.

We begin by asking permission: “Do you mind if we talk about your weight?” or “Can we talk about your level of exercise?” Once the patient has granted permission, we ask open-ended questions and use reflective listening: “What I hear you saying is that you are concerned you will not be able to lose the weight,” or “It sounds like you don’t like to exercise, but you are worried about the health consequences of that.”

I find these skills useful for addressing anything from smoking to drinking to weight management to excessive shopping—any extreme behavior that is affecting a patient negatively. When a patient is not ready to talk about her clinical problems or make changes, I let her know my door is always open to her and that I have many resources available to help her when she is ready (TABLE).⁴ In those cases, I might say something like, “I have many patients who really don’t want to talk about this when I first ask them, but I just want you to know, Mrs. Jones, that I want you to succeed and I want you to be healthy. We have a team approach to taking care of all of you, and when you are ready, we are here to help.”

Related article:
2017 Update on fertility: Effects of obesity on reproduction

It is important to provide practical advice to patients—including how much to exercise, the importance of keeping a food journal, and determining a goal for slow, safe weight loss—and provide resources as necessary (such as for Weight Watchers, nutrition, and dieticians). Each day we have more than 30 opportunities to select foods to eat, drink, or purchase. Have a plan and advise your patients do the same. Recommend patients cook their own meals. Suggest weight loss apps. Counsel them to celebrate successes, find a buddy (for social support), practice positive self-talk (positive language), and plan for challenges (travel, parties, working late) and setbacks, which do not need to become a fall. Find an activity or exercise that the patient enjoys and tell them to seek professional help if needed.

Read about how to educate your patients on wellness.

OBG Management: You mention in your book that 70% to 80% of people now in hospitals are there because of diseases preventable through lifestyle choice. What are the women’s health conditions on that list?

Dr. Bradley: About 86% of the health care dollars spent in the United States are due to chronic diseases, and chronic diseases are the leading cause of death and disability in the country.⁵ The most common chronic diseases—cardiovascular disease, hypertension, type 2 diabetes, colon cancer, depression, dementia, cognitive problems, higher rates of fractures—all have been associated, at least in part, with unhealthy food choices and lack of exercise. That applies to breast cancer, too.

The good news is, we can prevent and even reverse disease. As Hippocrates said, let food be thy medicine and medicine be thy food. We have all seen success stories where consistent exercise and dietary changes definitely change the paradigm for what the disease state represents. A multiplicity of factors affect poor health—noncompliance, obesity, smoking—but when we begin to make consistent, healthy changes with diet and exercise, this creates a sort of domino effect.

OBG Management: You discuss chronic illness as preventable, manageable, and reversible. Where do you see the women’s health clinician’s role in the management of reversal?

Dr. Bradley: I think we need to get to the root cause of these clinical problems and provide the resources and support that patients need to reverse or even prevent these diseases. Clinicians need to become more aware—be an example and a role model. Our patients are watching us as much as we are watching them. Together, we can form good partnerships in order to promote better health.

OBG Management: Do you encourage your patients to write a wellness contract?

Dr. Bradley: I think when you are about to be a change agent for your body and become what I call the best version of yourself, you can have these great ideas, but you need to turn those ideas into actions and make them consistent. And we know that is difficult to do, so I do try to have patients write down specific goals, their plan for achieving them, and list the reasons why it is important for them to reach their goals. That gives them something tangible to look at when the going gets tough. It is also important to work into the contract ways to reward positive behaviors when goals are met, and to plan for challenges and setbacks and how to get back on track.

I also encourage patients to document their progress and learn how to make quick adjustments when necessary to get back on track. Another important element involves setting milestones—by what date are you going to reach this goal? Like any other contract, I have my patients date and sign their wellness contracts. I also encourage them to visualize what their new self is going to look like, how they will feel when they reach their goal, what they will wear, and what activities they will engage in.

Related article:
Obesity medicine: How to incorporate it into your practice

OBG Management: Do you think that physicians have a role in educating their patients on food labels and dietary intake?

Dr. Bradley: I do, but the amount of nutrition education that most of us get in medical school is minimal to nonexistent and not practical. As physicians, we know that food is health, exercise is fitness, and that our patients need both of them. We also know that we did not get this information in school and that our education was more about treating disease than preventing disease. Many of us were not trained in robot surgery either, because it did not exist. So what did we do? We took classes, attended lectures, read books, and learned. We can do the same with wellness. There are many courses around the country. We have to begin to relearn and reteach ourselves about health, nutrition, and exercise and then pass that information on to our patients—be a resource and a guide. We should be able to write a prescription for health as quickly as we can write a prescription for insulin or a statin.

I also bring up portion distortion with my patients. The National Institutes of Health has resources on their website (https://www.nhlbi.nih.gov/health/educational /wecan/eat-right/portion-distortion.html) that include great visuals that show portion sizes 20 years ago and what they are now. For instance, 20 years ago a bagel was 3 inches and 140 calories; today’s bagel is 6 inches and 350 calories (plus whatever toppings are added). I tell that to my patients and then explain how much more exercise is needed to burn off just that 1 bagel.

Related article:
How to help your patients control gestational weight gain

OBG Management: Epigenetics: Do patients know about it?

Dr. Bradley: They may not know that term directly, but I think people understand that you have the potential to pass on poor lifestyle and/or health issues related to how things are when you are in utero and later in life. It gets back to letting people know to be healthy in pregnancy and even pre-pregnancy, and that includes one’s emotional state, physical state, and spiritual state. We are what we are in our mother’s womb. Getting the best start in life starts with a healthy mom, healthy dad, and a healthy environment.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Over the past 3 decades, the prevalence of overweight and obesity has increased dramatically in the United States. A study published in 2016 showed the age-adjusted prevalence of obesity in 2013–2014 was 35% among men and 40.4% among women.¹ It comes as no surprise that increased reliance on inexpensive fast foods coupled with progressively more sedentary lifestyles have been implicated as causative factors.²

With the rise in obesity also has come an attendant rise in related chronic diseases, such as type 2 diabetes mellitus and cardiovascular disease. Women who are obese are also at risk for certain women’s health conditions, such as polycystic ovary syndrome, breast cancer, and endometrial cancer.

It is clear that curbing this public health crisis will require concerted efforts from individuals, clinicians, and policy makers, as well as changes in societal norms. OBG Management recently caught up with wellness expert Linda D. Bradley, MD, who shared in her latest book, “Us! Our Life. Our Health.” Our Legacy,” some practical strategies clinicians can use to help their patients manage their weight and prevent or reverse chronic diseases.

OBG Management: In your book you describe Jane, a patient who was severely overweight and who had low self-esteem. ³ You took 2 hours to convince Jane to talk about her clinical problems. That was clearly a heroic intervention on your part as the physician. What advice do you have for time-strapped clinicians who have patients who may need to face mental barriers in order to begin to address physical ailments?

Linda D. Bradley, MD: I think it is important for us not to lecture our patients. I could list all of the things that patients should or could do to prevent or even reverse disease states, in terms of eating right and exercising, but I think motivational interviewing is a more productive approach to elicit and evoke change (see “Principles and practice of motivational interviewing”). I used to preach to my patients. I would say, “You know, if you stay at this weight, you’re going to get diabetes, you’re going to increase your breast cancer risk, you’re going to have abnormal bleeding, you’re not going to be able to get pregnant,” and so on. It is easy to slip into that in the 7 minutes that you have with your patient, but to me, that is not the right way.

With motivational interviewing, our interactions with patients are shaped by:

• asking
• advising
• assisting
• arranging.

We begin by asking permission: “Do you mind if we talk about your weight?” or “Can we talk about your level of exercise?” Once the patient has granted permission, we ask open-ended questions and use reflective listening: “What I hear you saying is that you are concerned you will not be able to lose the weight,” or “It sounds like you don’t like to exercise, but you are worried about the health consequences of that.”

I find these skills useful for addressing anything from smoking to drinking to weight management to excessive shopping—any extreme behavior that is affecting a patient negatively. When a patient is not ready to talk about her clinical problems or make changes, I let her know my door is always open to her and that I have many resources available to help her when she is ready (TABLE).⁴ In those cases, I might say something like, “I have many patients who really don’t want to talk about this when I first ask them, but I just want you to know, Mrs. Jones, that I want you to succeed and I want you to be healthy. We have a team approach to taking care of all of you, and when you are ready, we are here to help.”

Related article:
2017 Update on fertility: Effects of obesity on reproduction

It is important to provide practical advice to patients—including how much to exercise, the importance of keeping a food journal, and determining a goal for slow, safe weight loss—and provide resources as necessary (such as for Weight Watchers, nutrition, and dieticians). Each day we have more than 30 opportunities to select foods to eat, drink, or purchase. Have a plan and advise your patients do the same. Recommend patients cook their own meals. Suggest weight loss apps. Counsel them to celebrate successes, find a buddy (for social support), practice positive self-talk (positive language), and plan for challenges (travel, parties, working late) and setbacks, which do not need to become a fall. Find an activity or exercise that the patient enjoys and tell them to seek professional help if needed.

Read about how to educate your patients on wellness.

OBG Management: You mention in your book that 70% to 80% of people now in hospitals are there because of diseases preventable through lifestyle choice. What are the women’s health conditions on that list?

Dr. Bradley: About 86% of the health care dollars spent in the United States are due to chronic diseases, and chronic diseases are the leading cause of death and disability in the country.⁵ The most common chronic diseases—cardiovascular disease, hypertension, type 2 diabetes, colon cancer, depression, dementia, cognitive problems, higher rates of fractures—all have been associated, at least in part, with unhealthy food choices and lack of exercise. That applies to breast cancer, too.

The good news is, we can prevent and even reverse disease. As Hippocrates said, let food be thy medicine and medicine be thy food. We have all seen success stories where consistent exercise and dietary changes definitely change the paradigm for what the disease state represents. A multiplicity of factors affect poor health—noncompliance, obesity, smoking—but when we begin to make consistent, healthy changes with diet and exercise, this creates a sort of domino effect.

OBG Management: You discuss chronic illness as preventable, manageable, and reversible. Where do you see the women’s health clinician’s role in the management of reversal?

Dr. Bradley: I think we need to get to the root cause of these clinical problems and provide the resources and support that patients need to reverse or even prevent these diseases. Clinicians need to become more aware—be an example and a role model. Our patients are watching us as much as we are watching them. Together, we can form good partnerships in order to promote better health.

OBG Management: Do you encourage your patients to write a wellness contract?

Dr. Bradley: I think when you are about to be a change agent for your body and become what I call the best version of yourself, you can have these great ideas, but you need to turn those ideas into actions and make them consistent. And we know that is difficult to do, so I do try to have patients write down specific goals, their plan for achieving them, and list the reasons why it is important for them to reach their goals. That gives them something tangible to look at when the going gets tough. It is also important to work into the contract ways to reward positive behaviors when goals are met, and to plan for challenges and setbacks and how to get back on track.

I also encourage patients to document their progress and learn how to make quick adjustments when necessary to get back on track. Another important element involves setting milestones—by what date are you going to reach this goal? Like any other contract, I have my patients date and sign their wellness contracts. I also encourage them to visualize what their new self is going to look like, how they will feel when they reach their goal, what they will wear, and what activities they will engage in.

Related article:
Obesity medicine: How to incorporate it into your practice

OBG Management: Do you think that physicians have a role in educating their patients on food labels and dietary intake?

Dr. Bradley: I do, but the amount of nutrition education that most of us get in medical school is minimal to nonexistent and not practical. As physicians, we know that food is health, exercise is fitness, and that our patients need both of them. We also know that we did not get this information in school and that our education was more about treating disease than preventing disease. Many of us were not trained in robot surgery either, because it did not exist. So what did we do? We took classes, attended lectures, read books, and learned. We can do the same with wellness. There are many courses around the country. We have to begin to relearn and reteach ourselves about health, nutrition, and exercise and then pass that information on to our patients—be a resource and a guide. We should be able to write a prescription for health as quickly as we can write a prescription for insulin or a statin.

I also bring up portion distortion with my patients. The National Institutes of Health has resources on their website (https://www.nhlbi.nih.gov/health/educational /wecan/eat-right/portion-distortion.html) that include great visuals that show portion sizes 20 years ago and what they are now. For instance, 20 years ago a bagel was 3 inches and 140 calories; today’s bagel is 6 inches and 350 calories (plus whatever toppings are added). I tell that to my patients and then explain how much more exercise is needed to burn off just that 1 bagel.

Related article:
How to help your patients control gestational weight gain

OBG Management: Epigenetics: Do patients know about it?

Dr. Bradley: They may not know that term directly, but I think people understand that you have the potential to pass on poor lifestyle and/or health issues related to how things are when you are in utero and later in life. It gets back to letting people know to be healthy in pregnancy and even pre-pregnancy, and that includes one’s emotional state, physical state, and spiritual state. We are what we are in our mother’s womb. Getting the best start in life starts with a healthy mom, healthy dad, and a healthy environment.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Introduction

Immune thrombocytopenia (ITP) is a common acquired autoimmune disease characterized by low platelet counts and an increased risk of bleeding. The incidence of ITP is approximately 3.3 per 100,000 adults.¹ There is considerable controversy about all aspects of the disease, with little “hard” data on which to base decisions given the lack of randomized clinical trials to address most clinical questions. This article reviews the presentation and diagnosis of ITP and its treatment options and discusses management of ITP in specific clinical situations.

Pathogenesis and Epidemiology

ITP is caused by autoantibodies binding to platelet surface proteins, most often to the platelet receptor GP IIb/IIIa.^2-4 These antibody-coated platelets then bind to Fc receptors in macrophages and are removed from circulation. The initiating event in ITP is unknown. It is speculated that the patient responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute response to viral infection and usually resolves. ITP in adults may occur in any age group but is seen especially in young women.

Despite the increased platelet destruction that occurs in ITP, the production of new platelets often is not significantly increased. This is most likely due to lack of an increase in thrombopoietin, the predominant platelet growth factor.⁵

It had been thought that most adult patients who present with ITP go on to have a chronic course, but more recent studies have shown this is not the case. In modern series the percentage of patients who are “cured” with steroids ranges from 30% to 70%.^6–9 In addition, it has been appreciated that even in patients with modest thrombocytopenia, no therapy is required if the platelet count remains higher than 30 × 10³/µL. However, this leaves a considerable number of patients who will require chronic therapy.

Clinical Presentation

Presentation can range from a symptomatic patient with low platelets found on a routine blood count to a patient with massive bleeding. Typically, patients first present with petechiae (small bruises 1 mm in size) on the shins. True petechiae are seen only in severe thrombocytopenia. Patients will also report frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice “wet purpura,” which is characterized by blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as the petechiae. The presence of splenomegaly or lymphadenopathy weighs strongly against a diagnosis of ITP. Many patients with ITP will note fatigue when their platelets counts are lower.¹⁰

Diagnosis

Extremely low platelet counts with a normal blood smear and an otherwise healthy patient are diagnostic of ITP. The platelet count cutoff for considering ITP is 100 × 10³/µL as the majority of patients with counts in the 100 to 150 × 10³/µL range will not develop greater thrombocytopenia.¹¹ Also, the platelet count decreases with age (9 × 10³/µL per decade in one study), and this also needs to be factored into the evaluation.¹² The finding of relatives with ITP should raise suspicion for congenital thrombocytopenia.¹³ One should question the patient carefully about drug exposure (see Drug-Induced Thrombocytopenia), especially about over-the-counter medicines, “natural” remedies, or recreational drugs.

There is no laboratory test that rules in ITP; rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow disease (blasts, teardrop cells), or any other evidence of a primary bone marrow disease. In ITP, the platelets can be larger than normal, but finding some platelets the size of red cells should raise the issue of congenital thrombocytopenia.¹⁴ Pseudo-thrombocytopenia, which is the clumping of platelets due to a reaction to the EDTA anticoagulant in the tube, should be excluded. The diagnosis is established by drawing the blood in a citrated (blue-top) tube to perform the platelet count. There is no role for antiplatelet antibody assay because this test lacks sensitivity and specificity. In a patient without a history of autoimmune disease or symptoms, empiric testing for autoimmune disease is not recommended.

Patients who present with ITP should be tested for both HIV and hepatitis C infection.^15,16 These are the most common viral causes of secondary ITP, and both have prognostic and treatment implications. Some authorities also recommend checking thyroid function as hypothyroidism can present or aggravate the thrombocytopenia.

The role of bone marrow examination is controversial.¹⁷ Patients with a classic presentation of ITP (young woman, normal blood smear) do not require a bone marrow exam before therapy is initiated, although patients who do not respond to initial therapy should have a bone marrow aspiration. The rare entity amegakaryocytic thrombocytopenia can present with a clinical picture similar to that of ITP, but amegakaryocytic thrombocytopenia will not respond to steroids. Bone marrow aspiration reveals the absence of megakaryocytes in this entity. It is rare, however, that another hematologic disease is diagnosed in patients with a classic clinical presentation of ITP.

In the future, measurement of thrombopoietin and reticulated platelets may provide clues to the diagnosis.⁴ Patients with ITP paradoxically have normal or only mildly elevated thrombopoietin levels. The finding of a significantly elevated thrombopoietin level should lead to questioning of the diagnosis. One can also measure “reticulated platelets,” which are analogous to red cell reticulocytes. Patients with ITP (or any platelet destructive disorders) will have high levels of reticulated platelets. These tests are not recommended for routine evaluation, but may be helpful in difficult cases.

Treatment

In general, therapy in ITP should be guided by the patient’s signs of bleeding and not by unquestioning adherence to measuring platelet levels,¹⁵ as patients tolerate thrombocytopenia well. It is unusual to have life-threatening bleeding with platelet counts greater than 5 × 10³/µL in the absence of mechanical lesions. Despite the low platelet count in patients with ITP, the overall mortality is estimated to be only 0.3% to 1.3%.¹⁸ It is sobering that in one study the rate of death from infections was twice as high as that from bleeding.¹⁹ Rare patients will have antibodies that interfere with the function of the platelet, and these patients can have profound bleeding with only modestly lowered platelet counts.²⁰ A suggested cut-off for treating newly diagnosed patients is 30 × 10³/µL.²¹

Initial Therapy

The primary therapy of ITP is glucocorticoids, either prednisone or dexamethasone. In the past prednisone at a dose of 60 to 80 mg/day was started at the time of diagnosis (Table 1).

For rapid induction of a response, there are 2 options. A single dose of intravenous immune globulin (IVIG) at 1 g/kg or intravenous anti-D immunoglobulin (anti-D) at 50 to 75 µg/kg can induce a response in more than 80% of patients in 24 to 48 hours.^21,24 IVIG has several drawbacks. It can cause aseptic meningitis, and in patients with vascular disease the increased viscosity can induce ischemia. There is also a considerable fluid load delivered with the IVIG, and it needs to be given over several hours.

The use of anti-D is limited to Rh-positive patients who have not had a splenectomy. It should not be used in patients who are Coombs positive due to the risk of provoking more hemolysis. Rarely anti-D has been reported to cause a severe hemolytic disseminated intravascular coagulation syndrome (1:20,000 patients), which has led to restrictions in its use.²⁵ Although the drug can be rapidly given over 15 minutes, due to these concerns current recommendations are now to observe patients for 8 hours after their dose and to perform a urine dipstick test for blood at 2, 4, and 8 hours. Concerns about this rare but serious side effect have led to a dramatic decrease in the use of anti-D.

For patients who are severely thrombocytopenic and do not respond to initial therapy, there are 2 options for raising the platelet counts. One is to use a combination of IVIG, methylprednisolone, vincristine, and/or anti-D.²⁶ The combination of IVIG and anti-D may be synergistic since these agents block different Fc receptors. A response of 71% has been reported for this 3- or 4-drug combination in a series of 35 patients.²⁶ The other option is to treat with a continuous infusion of platelets (1 unit over 6 hours) and IVIG 1 g/kg for 24 hours. Response rates of 62.7% have been reported with this combination, and this rapid rise in platelets can allow time for other therapies to take effect.^27,28

Patients with severe thrombocytopenia who relapse with reduction of steroids or who do not respond to steroids have several options for further management. Repeated doses of IVIG can transiently raise the platelet count, and some patients may only need several courses of therapy over the course of many months. One study showed that 60% of patients could delay or defer therapy by receiving multiple doses of anti-D. However, 30% of patients did eventually receive splenectomy and 20% of patients required ongoing therapy with anti-D.²⁹ In a randomized trial comparing early use of anti-D to steroids to avoid splenectomy, there was no difference in splenectomy rate (38% versus 42%).³⁰ Finally, an option as mentioned above is to try a 6-month course of pulse dexamethasone 40 mg/day for 4 days, repeated every 28 days.

Options for Refractory ITP

There are multiple options for patients who do not respond to initial ITP therapies. These can be divided into several broad groups: curative therapies (splenectomy and rituximab), thrombopoietin receptor agonists, and anecdotal therapies.

Splenectomy

In patients with severe thrombocytopenia who do not respond or who relapse with lower doses of prednisone, splenectomy should be strongly considered. Splenectomy will induce a good response in 60% to 70% of patients and is durable in most patients. In 2 recently published reviews of splenectomy, the complete response rate was 67% and the total response rate was 88% to 90%%.^8,31 Between 15% and 28% of patients relapsed over 5 years, with most recurrences occurring in the first 2 years. Splenectomy carries a short-term surgical risk, and the life-long risk of increased susceptibility to overwhelming sepsis is discussed below. However, the absolute magnitude of these risks is low and is often lower than the risks of continued prednisone therapy or of continued cytotoxic therapy.

Timing of splenectomy depends on the patient’s presentation. Most patients should be given a 6-month trial of steroids or other therapies before proceeding to splenectomy.³¹ However, patients who persist with severe thrombocytopenia despite initial therapies or who are suffering intolerable side effects from therapy should be considered sooner for splenectomy.³¹ In the George review, multiple factors such as responding to IVIG were found not to be predictive of response to splenectomy.⁸

Method of splenectomy appears not to matter.²¹ Rates of finding accessory spleens are just as high or higher with laparoscopic splenectomy and the patient can recover faster. In patients who are severely thrombocytopenic, open splenectomy can allow for quicker control of the vascular access of the spleen.

Rates of splenectomy in recent years have decreased for many reasons,³² including the acceptance of lower platelet counts in asymptomatic patients and the availability of alternative therapies such as rituximab. In addition, despite abundant data for good outcomes, there is a concern that splenectomy responses are not durable. Although splenectomy will not cure every patient with ITP, splenectomy is the therapy with the most patients, the longest follow-up, and the most consistent rate of cure, and it should be discussed with every ITP patient who does not respond to initial therapy and needs further treatment.

The risk of overwhelming sepsis varies by indications for splenectomy but appears to be about 1%.^33,34 The use of pneumococcal vaccine and recognition of this syndrome have helped reduce the risk. Asplenic patients need to be counseled about the risk of overwhelming infections, should be vaccinated for pneumococcus, meningococcus, and Haemophilus influenzae, and should wear an ID bracelet.^35–37 Patients previously vaccinated for pneumococcus should be re-vaccinated every 3 to 5 years. The role of prophylactic antibiotics in adults is controversial, but patients under the age of 18 should be on penicillin VK 250 mg orally twice daily.

Rituximab

Rituximab has been shown to be very active in ITP. Most studies used the standard dose of 375 mg/m² weekly for 4 weeks, but other studies have shown that 1000 mg twice 14 days apart (ie, on days 1 and 15) resulted in the same response rate and may be more convenient for patients.^38,39 The response time can vary, with patients either showing a rapid response or requiring up to 8 weeks for their counts to go up. Although experience is limited, the response seems to be durable, especially in those patients whose counts rise higher than 150 × 10³/µL; in patients who relapse, a response can be re-induced with a repeat course. Overall the response rate for rituximab is about 60%, but only approximately 20% to 40% of patients will remain in long-term remission.^40–42 There is no evidence yet that “maintenance” therapy or monitoring CD19/CD20 cells can help further the duration of remission.

Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.

There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.⁴³ The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.

Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.⁴⁰ Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.

Thrombopoietin Receptor Agonists

Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.⁴⁴ Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.⁴⁵ Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.

Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.⁴⁶ It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.⁴⁷ In a long-term extension study, the response was again high at 87%.⁴⁸ These studies have also shown a reduced incidence of bleeding.

The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.^47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.

Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,⁴⁹ but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.⁵⁰ These trials have shown no long-term concerns for other clinical problems such as liver disease.

Eltrombopag. The other available TPO-RA is eltrombopag,⁵¹ an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.^47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.^47,51

Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.^21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.

Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.⁵³

Other Options

In the literature there are numerous options for the treatment of ITP.^54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.

Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.⁵⁶ Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.⁵⁴

Vincristine 1.4 mg/m² weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.⁵⁴Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.⁵⁴ It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.⁵⁷

Cyclophosphamide 1 g/m² intravenously repeated every 28 days has been reported to have a response rate of up to 40%.⁵⁸ Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.⁵⁹

Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.⁶⁰ This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.

A Practical Approach to Refractory ITP

One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 10³/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 10³/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2).

Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.

Special Situations

Surgery

Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 10³/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.

Pregnancy

Up to 10% of pregnant women will develop low platelet counts during their pregnancy.^61,62 The most common etiology is gestational thrombocytopenia, which is an exaggeration of the lowered platelet count seen in pregnancy. Counts may fall as low as 50 × 10³/µL at the time of delivery. No therapy is required as the fetus is not affected and the mother does not have an increased risk of bleeding. Pregnancy complications such as HELLP syndrome and thrombotic microangiopathies also present with low platelet counts, but these can be diagnosed by history.^61,63

Women with ITP can either develop the disease during pregnancy or have a worsening of the symptoms.⁶⁴ Counts often drop dramatically during the first trimester. Early management should be conservative with low doses of prednisone to keep the count above 10 × 10³/µL.²¹ Immunoglobulin is also effective,⁶⁵ but there are rare reports of pulmonary edema. Rarely patients who are refractory will require splenectomy, which may be safely performed in the second trimester. For delivery the count should be greater than 30 × 10³/µL and for an epidural greater than 50 × 10³/µL.⁶⁴ There are reports of the use of TPO-RAs in pregnancy, and this can be considered for refractory cases.⁶⁶

Most controversy centers on management of the delivery. In the past it was feared that fetal thrombocytopenia could lead to intracranial hemorrhage, and Caesarean section was always recommended. It now appears that most cases of intracranial hemorrhage were due to alloimmune thrombocytopenia and not ITP. Furthermore, the nadir of the baby’s platelet count is not at birth but several days after. It appears the safest course is to proceed with a vaginal or C-section delivery determined by obstetrical indications and then immediately check the baby’s platelet count. If the platelet count is low in the neonate, immunoglobulin will raise the count. Since the neonatal thrombocytopenia is due to passive transfer of maternal antibody, the platelet destruction will abate in 4 to 6 weeks.

Pediatric Patients

The incidence of ITP in children is 2.2 to 5.3 per 100,000 children.¹ There are several distinct differences in pediatric ITP. Most cases will resolve in weeks, with only a minority of patients transforming into chronic ITP (5%–10%). Also, the rates of serious bleeding are lower in children than in adults, with intracranial hemorrhage rates of 0.1% to 0.5% being seen.⁶⁷ For most patients with no or mild bleeding, management now is observation alone regardless of platelet count because it is felt that the risks of therapies are higher than the risk of bleeding.²¹ For patients with bleeding, IVIG, anti-D, or a short course of steroids can be used. Given the risk of overwhelming sepsis, splenectomy is often deferred as long as possible. Rituximab is increasingly being used in children due to concerns about use of agents such a cyclophosphamide or azathioprine in children.⁶⁸ Abundant data on use of TPO-RAs in children showing high response rates and safety support their use, and these should be considered in refractory ITP before any cytotoxic agent.^69–71

Helicobacter Pylori Infection

There has been much interest in the relationship between H. pylori and ITP.^16,72,73H. pylori infections have been associated with a variety of autoimmune diseases, and there is a confusing literature on this infection and ITP. Several meta-analyses have shown that eradication of H. pylori will result in an ITP response rate of 20% to 30%, but responses curiously appear to be limited to certain geographic areas such as Japan and Italy but not the United States. In patients with recalcitrant ITP, especially in geographic areas with high incidence, it may be worthwhile to check for H. pylori infection and treat accordingly if positive.

Drug-Induced Thrombocytopenia

Patients with drug-induced thrombocytopenia present with very low (< 10 × 10³/µL) platelet counts 1 to 3 weeks after starting a new medication.^74–76 In patients with a possible drug-induced thrombocytopenia, the primary therapy is to stop the suspect drug.⁷⁷ If there are multiple new medications, the best approach is to stop any drug that has been strongly associated with thrombocytopenia (Table 3).^74,78,79

Immune globulin, corticosteroids, or intravenous anti‑D have been suggested as useful in drug‑related thrombocytopenia. However, since most of these thrombocytopenic patients recover when the agent is cleared from the body, this therapy is probably not necessary and withholding treatment avoids exposing the patients to the adverse events associated with further therapy.

Evans Syndrome

Evans syndrome is defined as the combination of autoimmune hemolytic anemia (AIHA) and ITP.^80,81 These cytopenias can present simultaneously or sequentially. Patients with Evans syndrome are thought to have a more severe disease process, to be more prone to bleeding, and to be more difficult to treat, but the rarity of this syndrome makes this hard to quantify.

The classic clinical presentation of Evans syndrome is severe anemia and thrombocytopenia. Children with Evans syndrome often have complex immunodeficiencies such as autoimmune lymphoproliferative syndrome.^82,83 In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans syndrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.

In theory the diagnostic approach is straightforward by showing a Coombs-positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocytopenia. The blood smear will show spherocytes and a diminished platelet count. The presence of other abnormal red cell forms should raise the possibility of an alternative diagnosis. It is unclear how vigorously one should search for other underlying diseases. Many patients will already have the diagnosis of an underlying autoimmune disease. The presence of lymphadenopathy should raise concern for lymphoma.

Initial therapy is high-dose steroids (2 mg/kg/day). IVIG should be added if severe thrombocytopenia is present. Patients who cannot be weaned off prednisone or relapse after prednisone should be considered for splenectomy, although these patients are at higher risk of relapsing.⁸⁰ Increasingly rituximab is being used with success.^84,85 For patients who fail splenectomy and rituximab, aggressive immunosuppression should be considered. Increasing data support the benefits of sirolimus, and this should be considered for refractory patients.⁸⁶ For patients with Evans syndrome due to underlying lymphoma, antineoplastic therapy often results in prompt resolution of the symptoms. Recurrence of the autoimmune cytopenias often heralds relapse.

Introduction

Immune thrombocytopenia (ITP) is a common acquired autoimmune disease characterized by low platelet counts and an increased risk of bleeding. The incidence of ITP is approximately 3.3 per 100,000 adults.¹ There is considerable controversy about all aspects of the disease, with little “hard” data on which to base decisions given the lack of randomized clinical trials to address most clinical questions. This article reviews the presentation and diagnosis of ITP and its treatment options and discusses management of ITP in specific clinical situations.

Pathogenesis and Epidemiology

ITP is caused by autoantibodies binding to platelet surface proteins, most often to the platelet receptor GP IIb/IIIa.^2-4 These antibody-coated platelets then bind to Fc receptors in macrophages and are removed from circulation. The initiating event in ITP is unknown. It is speculated that the patient responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute response to viral infection and usually resolves. ITP in adults may occur in any age group but is seen especially in young women.

Despite the increased platelet destruction that occurs in ITP, the production of new platelets often is not significantly increased. This is most likely due to lack of an increase in thrombopoietin, the predominant platelet growth factor.⁵

It had been thought that most adult patients who present with ITP go on to have a chronic course, but more recent studies have shown this is not the case. In modern series the percentage of patients who are “cured” with steroids ranges from 30% to 70%.^6–9 In addition, it has been appreciated that even in patients with modest thrombocytopenia, no therapy is required if the platelet count remains higher than 30 × 10³/µL. However, this leaves a considerable number of patients who will require chronic therapy.

Clinical Presentation

Presentation can range from a symptomatic patient with low platelets found on a routine blood count to a patient with massive bleeding. Typically, patients first present with petechiae (small bruises 1 mm in size) on the shins. True petechiae are seen only in severe thrombocytopenia. Patients will also report frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice “wet purpura,” which is characterized by blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as the petechiae. The presence of splenomegaly or lymphadenopathy weighs strongly against a diagnosis of ITP. Many patients with ITP will note fatigue when their platelets counts are lower.¹⁰

Diagnosis

Extremely low platelet counts with a normal blood smear and an otherwise healthy patient are diagnostic of ITP. The platelet count cutoff for considering ITP is 100 × 10³/µL as the majority of patients with counts in the 100 to 150 × 10³/µL range will not develop greater thrombocytopenia.¹¹ Also, the platelet count decreases with age (9 × 10³/µL per decade in one study), and this also needs to be factored into the evaluation.¹² The finding of relatives with ITP should raise suspicion for congenital thrombocytopenia.¹³ One should question the patient carefully about drug exposure (see Drug-Induced Thrombocytopenia), especially about over-the-counter medicines, “natural” remedies, or recreational drugs.

There is no laboratory test that rules in ITP; rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow disease (blasts, teardrop cells), or any other evidence of a primary bone marrow disease. In ITP, the platelets can be larger than normal, but finding some platelets the size of red cells should raise the issue of congenital thrombocytopenia.¹⁴ Pseudo-thrombocytopenia, which is the clumping of platelets due to a reaction to the EDTA anticoagulant in the tube, should be excluded. The diagnosis is established by drawing the blood in a citrated (blue-top) tube to perform the platelet count. There is no role for antiplatelet antibody assay because this test lacks sensitivity and specificity. In a patient without a history of autoimmune disease or symptoms, empiric testing for autoimmune disease is not recommended.

Patients who present with ITP should be tested for both HIV and hepatitis C infection.^15,16 These are the most common viral causes of secondary ITP, and both have prognostic and treatment implications. Some authorities also recommend checking thyroid function as hypothyroidism can present or aggravate the thrombocytopenia.

The role of bone marrow examination is controversial.¹⁷ Patients with a classic presentation of ITP (young woman, normal blood smear) do not require a bone marrow exam before therapy is initiated, although patients who do not respond to initial therapy should have a bone marrow aspiration. The rare entity amegakaryocytic thrombocytopenia can present with a clinical picture similar to that of ITP, but amegakaryocytic thrombocytopenia will not respond to steroids. Bone marrow aspiration reveals the absence of megakaryocytes in this entity. It is rare, however, that another hematologic disease is diagnosed in patients with a classic clinical presentation of ITP.

In the future, measurement of thrombopoietin and reticulated platelets may provide clues to the diagnosis.⁴ Patients with ITP paradoxically have normal or only mildly elevated thrombopoietin levels. The finding of a significantly elevated thrombopoietin level should lead to questioning of the diagnosis. One can also measure “reticulated platelets,” which are analogous to red cell reticulocytes. Patients with ITP (or any platelet destructive disorders) will have high levels of reticulated platelets. These tests are not recommended for routine evaluation, but may be helpful in difficult cases.

Treatment

In general, therapy in ITP should be guided by the patient’s signs of bleeding and not by unquestioning adherence to measuring platelet levels,¹⁵ as patients tolerate thrombocytopenia well. It is unusual to have life-threatening bleeding with platelet counts greater than 5 × 10³/µL in the absence of mechanical lesions. Despite the low platelet count in patients with ITP, the overall mortality is estimated to be only 0.3% to 1.3%.¹⁸ It is sobering that in one study the rate of death from infections was twice as high as that from bleeding.¹⁹ Rare patients will have antibodies that interfere with the function of the platelet, and these patients can have profound bleeding with only modestly lowered platelet counts.²⁰ A suggested cut-off for treating newly diagnosed patients is 30 × 10³/µL.²¹

Initial Therapy

The primary therapy of ITP is glucocorticoids, either prednisone or dexamethasone. In the past prednisone at a dose of 60 to 80 mg/day was started at the time of diagnosis (Table 1).

For rapid induction of a response, there are 2 options. A single dose of intravenous immune globulin (IVIG) at 1 g/kg or intravenous anti-D immunoglobulin (anti-D) at 50 to 75 µg/kg can induce a response in more than 80% of patients in 24 to 48 hours.^21,24 IVIG has several drawbacks. It can cause aseptic meningitis, and in patients with vascular disease the increased viscosity can induce ischemia. There is also a considerable fluid load delivered with the IVIG, and it needs to be given over several hours.

The use of anti-D is limited to Rh-positive patients who have not had a splenectomy. It should not be used in patients who are Coombs positive due to the risk of provoking more hemolysis. Rarely anti-D has been reported to cause a severe hemolytic disseminated intravascular coagulation syndrome (1:20,000 patients), which has led to restrictions in its use.²⁵ Although the drug can be rapidly given over 15 minutes, due to these concerns current recommendations are now to observe patients for 8 hours after their dose and to perform a urine dipstick test for blood at 2, 4, and 8 hours. Concerns about this rare but serious side effect have led to a dramatic decrease in the use of anti-D.

For patients who are severely thrombocytopenic and do not respond to initial therapy, there are 2 options for raising the platelet counts. One is to use a combination of IVIG, methylprednisolone, vincristine, and/or anti-D.²⁶ The combination of IVIG and anti-D may be synergistic since these agents block different Fc receptors. A response of 71% has been reported for this 3- or 4-drug combination in a series of 35 patients.²⁶ The other option is to treat with a continuous infusion of platelets (1 unit over 6 hours) and IVIG 1 g/kg for 24 hours. Response rates of 62.7% have been reported with this combination, and this rapid rise in platelets can allow time for other therapies to take effect.^27,28

Patients with severe thrombocytopenia who relapse with reduction of steroids or who do not respond to steroids have several options for further management. Repeated doses of IVIG can transiently raise the platelet count, and some patients may only need several courses of therapy over the course of many months. One study showed that 60% of patients could delay or defer therapy by receiving multiple doses of anti-D. However, 30% of patients did eventually receive splenectomy and 20% of patients required ongoing therapy with anti-D.²⁹ In a randomized trial comparing early use of anti-D to steroids to avoid splenectomy, there was no difference in splenectomy rate (38% versus 42%).³⁰ Finally, an option as mentioned above is to try a 6-month course of pulse dexamethasone 40 mg/day for 4 days, repeated every 28 days.

Options for Refractory ITP

There are multiple options for patients who do not respond to initial ITP therapies. These can be divided into several broad groups: curative therapies (splenectomy and rituximab), thrombopoietin receptor agonists, and anecdotal therapies.

Splenectomy

In patients with severe thrombocytopenia who do not respond or who relapse with lower doses of prednisone, splenectomy should be strongly considered. Splenectomy will induce a good response in 60% to 70% of patients and is durable in most patients. In 2 recently published reviews of splenectomy, the complete response rate was 67% and the total response rate was 88% to 90%%.^8,31 Between 15% and 28% of patients relapsed over 5 years, with most recurrences occurring in the first 2 years. Splenectomy carries a short-term surgical risk, and the life-long risk of increased susceptibility to overwhelming sepsis is discussed below. However, the absolute magnitude of these risks is low and is often lower than the risks of continued prednisone therapy or of continued cytotoxic therapy.

Timing of splenectomy depends on the patient’s presentation. Most patients should be given a 6-month trial of steroids or other therapies before proceeding to splenectomy.³¹ However, patients who persist with severe thrombocytopenia despite initial therapies or who are suffering intolerable side effects from therapy should be considered sooner for splenectomy.³¹ In the George review, multiple factors such as responding to IVIG were found not to be predictive of response to splenectomy.⁸

Method of splenectomy appears not to matter.²¹ Rates of finding accessory spleens are just as high or higher with laparoscopic splenectomy and the patient can recover faster. In patients who are severely thrombocytopenic, open splenectomy can allow for quicker control of the vascular access of the spleen.

Rates of splenectomy in recent years have decreased for many reasons,³² including the acceptance of lower platelet counts in asymptomatic patients and the availability of alternative therapies such as rituximab. In addition, despite abundant data for good outcomes, there is a concern that splenectomy responses are not durable. Although splenectomy will not cure every patient with ITP, splenectomy is the therapy with the most patients, the longest follow-up, and the most consistent rate of cure, and it should be discussed with every ITP patient who does not respond to initial therapy and needs further treatment.

The risk of overwhelming sepsis varies by indications for splenectomy but appears to be about 1%.^33,34 The use of pneumococcal vaccine and recognition of this syndrome have helped reduce the risk. Asplenic patients need to be counseled about the risk of overwhelming infections, should be vaccinated for pneumococcus, meningococcus, and Haemophilus influenzae, and should wear an ID bracelet.^35–37 Patients previously vaccinated for pneumococcus should be re-vaccinated every 3 to 5 years. The role of prophylactic antibiotics in adults is controversial, but patients under the age of 18 should be on penicillin VK 250 mg orally twice daily.

Rituximab

Rituximab has been shown to be very active in ITP. Most studies used the standard dose of 375 mg/m² weekly for 4 weeks, but other studies have shown that 1000 mg twice 14 days apart (ie, on days 1 and 15) resulted in the same response rate and may be more convenient for patients.^38,39 The response time can vary, with patients either showing a rapid response or requiring up to 8 weeks for their counts to go up. Although experience is limited, the response seems to be durable, especially in those patients whose counts rise higher than 150 × 10³/µL; in patients who relapse, a response can be re-induced with a repeat course. Overall the response rate for rituximab is about 60%, but only approximately 20% to 40% of patients will remain in long-term remission.^40–42 There is no evidence yet that “maintenance” therapy or monitoring CD19/CD20 cells can help further the duration of remission.

Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.

There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.⁴³ The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.

Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.⁴⁰ Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.

Thrombopoietin Receptor Agonists

Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.⁴⁴ Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.⁴⁵ Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.

Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.⁴⁶ It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.⁴⁷ In a long-term extension study, the response was again high at 87%.⁴⁸ These studies have also shown a reduced incidence of bleeding.

The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.^47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.

Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,⁴⁹ but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.⁵⁰ These trials have shown no long-term concerns for other clinical problems such as liver disease.

Eltrombopag. The other available TPO-RA is eltrombopag,⁵¹ an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.^47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.^47,51

Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.^21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.

Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.⁵³

Other Options

In the literature there are numerous options for the treatment of ITP.^54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.

Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.⁵⁶ Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.⁵⁴

Vincristine 1.4 mg/m² weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.⁵⁴Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.⁵⁴ It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.⁵⁷

Cyclophosphamide 1 g/m² intravenously repeated every 28 days has been reported to have a response rate of up to 40%.⁵⁸ Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.⁵⁹

Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.⁶⁰ This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.

A Practical Approach to Refractory ITP

One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 10³/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 10³/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2).

Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.

Special Situations

Surgery

Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 10³/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.

Pregnancy

Up to 10% of pregnant women will develop low platelet counts during their pregnancy.^61,62 The most common etiology is gestational thrombocytopenia, which is an exaggeration of the lowered platelet count seen in pregnancy. Counts may fall as low as 50 × 10³/µL at the time of delivery. No therapy is required as the fetus is not affected and the mother does not have an increased risk of bleeding. Pregnancy complications such as HELLP syndrome and thrombotic microangiopathies also present with low platelet counts, but these can be diagnosed by history.^61,63

Women with ITP can either develop the disease during pregnancy or have a worsening of the symptoms.⁶⁴ Counts often drop dramatically during the first trimester. Early management should be conservative with low doses of prednisone to keep the count above 10 × 10³/µL.²¹ Immunoglobulin is also effective,⁶⁵ but there are rare reports of pulmonary edema. Rarely patients who are refractory will require splenectomy, which may be safely performed in the second trimester. For delivery the count should be greater than 30 × 10³/µL and for an epidural greater than 50 × 10³/µL.⁶⁴ There are reports of the use of TPO-RAs in pregnancy, and this can be considered for refractory cases.⁶⁶

Most controversy centers on management of the delivery. In the past it was feared that fetal thrombocytopenia could lead to intracranial hemorrhage, and Caesarean section was always recommended. It now appears that most cases of intracranial hemorrhage were due to alloimmune thrombocytopenia and not ITP. Furthermore, the nadir of the baby’s platelet count is not at birth but several days after. It appears the safest course is to proceed with a vaginal or C-section delivery determined by obstetrical indications and then immediately check the baby’s platelet count. If the platelet count is low in the neonate, immunoglobulin will raise the count. Since the neonatal thrombocytopenia is due to passive transfer of maternal antibody, the platelet destruction will abate in 4 to 6 weeks.

Pediatric Patients

The incidence of ITP in children is 2.2 to 5.3 per 100,000 children.¹ There are several distinct differences in pediatric ITP. Most cases will resolve in weeks, with only a minority of patients transforming into chronic ITP (5%–10%). Also, the rates of serious bleeding are lower in children than in adults, with intracranial hemorrhage rates of 0.1% to 0.5% being seen.⁶⁷ For most patients with no or mild bleeding, management now is observation alone regardless of platelet count because it is felt that the risks of therapies are higher than the risk of bleeding.²¹ For patients with bleeding, IVIG, anti-D, or a short course of steroids can be used. Given the risk of overwhelming sepsis, splenectomy is often deferred as long as possible. Rituximab is increasingly being used in children due to concerns about use of agents such a cyclophosphamide or azathioprine in children.⁶⁸ Abundant data on use of TPO-RAs in children showing high response rates and safety support their use, and these should be considered in refractory ITP before any cytotoxic agent.^69–71

Helicobacter Pylori Infection

There has been much interest in the relationship between H. pylori and ITP.^16,72,73H. pylori infections have been associated with a variety of autoimmune diseases, and there is a confusing literature on this infection and ITP. Several meta-analyses have shown that eradication of H. pylori will result in an ITP response rate of 20% to 30%, but responses curiously appear to be limited to certain geographic areas such as Japan and Italy but not the United States. In patients with recalcitrant ITP, especially in geographic areas with high incidence, it may be worthwhile to check for H. pylori infection and treat accordingly if positive.

Drug-Induced Thrombocytopenia

Patients with drug-induced thrombocytopenia present with very low (< 10 × 10³/µL) platelet counts 1 to 3 weeks after starting a new medication.^74–76 In patients with a possible drug-induced thrombocytopenia, the primary therapy is to stop the suspect drug.⁷⁷ If there are multiple new medications, the best approach is to stop any drug that has been strongly associated with thrombocytopenia (Table 3).^74,78,79

Immune globulin, corticosteroids, or intravenous anti‑D have been suggested as useful in drug‑related thrombocytopenia. However, since most of these thrombocytopenic patients recover when the agent is cleared from the body, this therapy is probably not necessary and withholding treatment avoids exposing the patients to the adverse events associated with further therapy.

Evans Syndrome

Evans syndrome is defined as the combination of autoimmune hemolytic anemia (AIHA) and ITP.^80,81 These cytopenias can present simultaneously or sequentially. Patients with Evans syndrome are thought to have a more severe disease process, to be more prone to bleeding, and to be more difficult to treat, but the rarity of this syndrome makes this hard to quantify.

The classic clinical presentation of Evans syndrome is severe anemia and thrombocytopenia. Children with Evans syndrome often have complex immunodeficiencies such as autoimmune lymphoproliferative syndrome.^82,83 In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans syndrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.

In theory the diagnostic approach is straightforward by showing a Coombs-positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocytopenia. The blood smear will show spherocytes and a diminished platelet count. The presence of other abnormal red cell forms should raise the possibility of an alternative diagnosis. It is unclear how vigorously one should search for other underlying diseases. Many patients will already have the diagnosis of an underlying autoimmune disease. The presence of lymphadenopathy should raise concern for lymphoma.

Initial therapy is high-dose steroids (2 mg/kg/day). IVIG should be added if severe thrombocytopenia is present. Patients who cannot be weaned off prednisone or relapse after prednisone should be considered for splenectomy, although these patients are at higher risk of relapsing.⁸⁰ Increasingly rituximab is being used with success.^84,85 For patients who fail splenectomy and rituximab, aggressive immunosuppression should be considered. Increasing data support the benefits of sirolimus, and this should be considered for refractory patients.⁸⁶ For patients with Evans syndrome due to underlying lymphoma, antineoplastic therapy often results in prompt resolution of the symptoms. Recurrence of the autoimmune cytopenias often heralds relapse.

Introduction

Immune thrombocytopenia (ITP) is a common acquired autoimmune disease characterized by low platelet counts and an increased risk of bleeding. The incidence of ITP is approximately 3.3 per 100,000 adults.¹ There is considerable controversy about all aspects of the disease, with little “hard” data on which to base decisions given the lack of randomized clinical trials to address most clinical questions. This article reviews the presentation and diagnosis of ITP and its treatment options and discusses management of ITP in specific clinical situations.

Pathogenesis and Epidemiology

ITP is caused by autoantibodies binding to platelet surface proteins, most often to the platelet receptor GP IIb/IIIa.^2-4 These antibody-coated platelets then bind to Fc receptors in macrophages and are removed from circulation. The initiating event in ITP is unknown. It is speculated that the patient responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute response to viral infection and usually resolves. ITP in adults may occur in any age group but is seen especially in young women.

Despite the increased platelet destruction that occurs in ITP, the production of new platelets often is not significantly increased. This is most likely due to lack of an increase in thrombopoietin, the predominant platelet growth factor.⁵

It had been thought that most adult patients who present with ITP go on to have a chronic course, but more recent studies have shown this is not the case. In modern series the percentage of patients who are “cured” with steroids ranges from 30% to 70%.^6–9 In addition, it has been appreciated that even in patients with modest thrombocytopenia, no therapy is required if the platelet count remains higher than 30 × 10³/µL. However, this leaves a considerable number of patients who will require chronic therapy.

Clinical Presentation

Presentation can range from a symptomatic patient with low platelets found on a routine blood count to a patient with massive bleeding. Typically, patients first present with petechiae (small bruises 1 mm in size) on the shins. True petechiae are seen only in severe thrombocytopenia. Patients will also report frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice “wet purpura,” which is characterized by blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as the petechiae. The presence of splenomegaly or lymphadenopathy weighs strongly against a diagnosis of ITP. Many patients with ITP will note fatigue when their platelets counts are lower.¹⁰

Diagnosis

Extremely low platelet counts with a normal blood smear and an otherwise healthy patient are diagnostic of ITP. The platelet count cutoff for considering ITP is 100 × 10³/µL as the majority of patients with counts in the 100 to 150 × 10³/µL range will not develop greater thrombocytopenia.¹¹ Also, the platelet count decreases with age (9 × 10³/µL per decade in one study), and this also needs to be factored into the evaluation.¹² The finding of relatives with ITP should raise suspicion for congenital thrombocytopenia.¹³ One should question the patient carefully about drug exposure (see Drug-Induced Thrombocytopenia), especially about over-the-counter medicines, “natural” remedies, or recreational drugs.

There is no laboratory test that rules in ITP; rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow disease (blasts, teardrop cells), or any other evidence of a primary bone marrow disease. In ITP, the platelets can be larger than normal, but finding some platelets the size of red cells should raise the issue of congenital thrombocytopenia.¹⁴ Pseudo-thrombocytopenia, which is the clumping of platelets due to a reaction to the EDTA anticoagulant in the tube, should be excluded. The diagnosis is established by drawing the blood in a citrated (blue-top) tube to perform the platelet count. There is no role for antiplatelet antibody assay because this test lacks sensitivity and specificity. In a patient without a history of autoimmune disease or symptoms, empiric testing for autoimmune disease is not recommended.

Patients who present with ITP should be tested for both HIV and hepatitis C infection.^15,16 These are the most common viral causes of secondary ITP, and both have prognostic and treatment implications. Some authorities also recommend checking thyroid function as hypothyroidism can present or aggravate the thrombocytopenia.

The role of bone marrow examination is controversial.¹⁷ Patients with a classic presentation of ITP (young woman, normal blood smear) do not require a bone marrow exam before therapy is initiated, although patients who do not respond to initial therapy should have a bone marrow aspiration. The rare entity amegakaryocytic thrombocytopenia can present with a clinical picture similar to that of ITP, but amegakaryocytic thrombocytopenia will not respond to steroids. Bone marrow aspiration reveals the absence of megakaryocytes in this entity. It is rare, however, that another hematologic disease is diagnosed in patients with a classic clinical presentation of ITP.

In the future, measurement of thrombopoietin and reticulated platelets may provide clues to the diagnosis.⁴ Patients with ITP paradoxically have normal or only mildly elevated thrombopoietin levels. The finding of a significantly elevated thrombopoietin level should lead to questioning of the diagnosis. One can also measure “reticulated platelets,” which are analogous to red cell reticulocytes. Patients with ITP (or any platelet destructive disorders) will have high levels of reticulated platelets. These tests are not recommended for routine evaluation, but may be helpful in difficult cases.

Treatment

In general, therapy in ITP should be guided by the patient’s signs of bleeding and not by unquestioning adherence to measuring platelet levels,¹⁵ as patients tolerate thrombocytopenia well. It is unusual to have life-threatening bleeding with platelet counts greater than 5 × 10³/µL in the absence of mechanical lesions. Despite the low platelet count in patients with ITP, the overall mortality is estimated to be only 0.3% to 1.3%.¹⁸ It is sobering that in one study the rate of death from infections was twice as high as that from bleeding.¹⁹ Rare patients will have antibodies that interfere with the function of the platelet, and these patients can have profound bleeding with only modestly lowered platelet counts.²⁰ A suggested cut-off for treating newly diagnosed patients is 30 × 10³/µL.²¹

Initial Therapy

The primary therapy of ITP is glucocorticoids, either prednisone or dexamethasone. In the past prednisone at a dose of 60 to 80 mg/day was started at the time of diagnosis (Table 1).

For rapid induction of a response, there are 2 options. A single dose of intravenous immune globulin (IVIG) at 1 g/kg or intravenous anti-D immunoglobulin (anti-D) at 50 to 75 µg/kg can induce a response in more than 80% of patients in 24 to 48 hours.^21,24 IVIG has several drawbacks. It can cause aseptic meningitis, and in patients with vascular disease the increased viscosity can induce ischemia. There is also a considerable fluid load delivered with the IVIG, and it needs to be given over several hours.

The use of anti-D is limited to Rh-positive patients who have not had a splenectomy. It should not be used in patients who are Coombs positive due to the risk of provoking more hemolysis. Rarely anti-D has been reported to cause a severe hemolytic disseminated intravascular coagulation syndrome (1:20,000 patients), which has led to restrictions in its use.²⁵ Although the drug can be rapidly given over 15 minutes, due to these concerns current recommendations are now to observe patients for 8 hours after their dose and to perform a urine dipstick test for blood at 2, 4, and 8 hours. Concerns about this rare but serious side effect have led to a dramatic decrease in the use of anti-D.

For patients who are severely thrombocytopenic and do not respond to initial therapy, there are 2 options for raising the platelet counts. One is to use a combination of IVIG, methylprednisolone, vincristine, and/or anti-D.²⁶ The combination of IVIG and anti-D may be synergistic since these agents block different Fc receptors. A response of 71% has been reported for this 3- or 4-drug combination in a series of 35 patients.²⁶ The other option is to treat with a continuous infusion of platelets (1 unit over 6 hours) and IVIG 1 g/kg for 24 hours. Response rates of 62.7% have been reported with this combination, and this rapid rise in platelets can allow time for other therapies to take effect.^27,28

Patients with severe thrombocytopenia who relapse with reduction of steroids or who do not respond to steroids have several options for further management. Repeated doses of IVIG can transiently raise the platelet count, and some patients may only need several courses of therapy over the course of many months. One study showed that 60% of patients could delay or defer therapy by receiving multiple doses of anti-D. However, 30% of patients did eventually receive splenectomy and 20% of patients required ongoing therapy with anti-D.²⁹ In a randomized trial comparing early use of anti-D to steroids to avoid splenectomy, there was no difference in splenectomy rate (38% versus 42%).³⁰ Finally, an option as mentioned above is to try a 6-month course of pulse dexamethasone 40 mg/day for 4 days, repeated every 28 days.

Options for Refractory ITP

There are multiple options for patients who do not respond to initial ITP therapies. These can be divided into several broad groups: curative therapies (splenectomy and rituximab), thrombopoietin receptor agonists, and anecdotal therapies.

Splenectomy

In patients with severe thrombocytopenia who do not respond or who relapse with lower doses of prednisone, splenectomy should be strongly considered. Splenectomy will induce a good response in 60% to 70% of patients and is durable in most patients. In 2 recently published reviews of splenectomy, the complete response rate was 67% and the total response rate was 88% to 90%%.^8,31 Between 15% and 28% of patients relapsed over 5 years, with most recurrences occurring in the first 2 years. Splenectomy carries a short-term surgical risk, and the life-long risk of increased susceptibility to overwhelming sepsis is discussed below. However, the absolute magnitude of these risks is low and is often lower than the risks of continued prednisone therapy or of continued cytotoxic therapy.

Timing of splenectomy depends on the patient’s presentation. Most patients should be given a 6-month trial of steroids or other therapies before proceeding to splenectomy.³¹ However, patients who persist with severe thrombocytopenia despite initial therapies or who are suffering intolerable side effects from therapy should be considered sooner for splenectomy.³¹ In the George review, multiple factors such as responding to IVIG were found not to be predictive of response to splenectomy.⁸

Method of splenectomy appears not to matter.²¹ Rates of finding accessory spleens are just as high or higher with laparoscopic splenectomy and the patient can recover faster. In patients who are severely thrombocytopenic, open splenectomy can allow for quicker control of the vascular access of the spleen.

Rates of splenectomy in recent years have decreased for many reasons,³² including the acceptance of lower platelet counts in asymptomatic patients and the availability of alternative therapies such as rituximab. In addition, despite abundant data for good outcomes, there is a concern that splenectomy responses are not durable. Although splenectomy will not cure every patient with ITP, splenectomy is the therapy with the most patients, the longest follow-up, and the most consistent rate of cure, and it should be discussed with every ITP patient who does not respond to initial therapy and needs further treatment.

The risk of overwhelming sepsis varies by indications for splenectomy but appears to be about 1%.^33,34 The use of pneumococcal vaccine and recognition of this syndrome have helped reduce the risk. Asplenic patients need to be counseled about the risk of overwhelming infections, should be vaccinated for pneumococcus, meningococcus, and Haemophilus influenzae, and should wear an ID bracelet.^35–37 Patients previously vaccinated for pneumococcus should be re-vaccinated every 3 to 5 years. The role of prophylactic antibiotics in adults is controversial, but patients under the age of 18 should be on penicillin VK 250 mg orally twice daily.

Rituximab

Rituximab has been shown to be very active in ITP. Most studies used the standard dose of 375 mg/m² weekly for 4 weeks, but other studies have shown that 1000 mg twice 14 days apart (ie, on days 1 and 15) resulted in the same response rate and may be more convenient for patients.^38,39 The response time can vary, with patients either showing a rapid response or requiring up to 8 weeks for their counts to go up. Although experience is limited, the response seems to be durable, especially in those patients whose counts rise higher than 150 × 10³/µL; in patients who relapse, a response can be re-induced with a repeat course. Overall the response rate for rituximab is about 60%, but only approximately 20% to 40% of patients will remain in long-term remission.^40–42 There is no evidence yet that “maintenance” therapy or monitoring CD19/CD20 cells can help further the duration of remission.

Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.

There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.⁴³ The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.

Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.⁴⁰ Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.

Thrombopoietin Receptor Agonists

Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.⁴⁴ Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.⁴⁵ Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.

Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.⁴⁶ It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.⁴⁷ In a long-term extension study, the response was again high at 87%.⁴⁸ These studies have also shown a reduced incidence of bleeding.

The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.^47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.

Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,⁴⁹ but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.⁵⁰ These trials have shown no long-term concerns for other clinical problems such as liver disease.

Eltrombopag. The other available TPO-RA is eltrombopag,⁵¹ an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.^47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.^47,51

Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.^21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.

Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.⁵³

Other Options

In the literature there are numerous options for the treatment of ITP.^54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.

Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.⁵⁶ Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.⁵⁴

Vincristine 1.4 mg/m² weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.⁵⁴Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.⁵⁴ It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.⁵⁷

Cyclophosphamide 1 g/m² intravenously repeated every 28 days has been reported to have a response rate of up to 40%.⁵⁸ Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.⁵⁹

Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.⁶⁰ This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.

A Practical Approach to Refractory ITP

One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 10³/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 10³/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2).

Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.

Special Situations

Surgery

Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 10³/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.

Pregnancy

Up to 10% of pregnant women will develop low platelet counts during their pregnancy.^61,62 The most common etiology is gestational thrombocytopenia, which is an exaggeration of the lowered platelet count seen in pregnancy. Counts may fall as low as 50 × 10³/µL at the time of delivery. No therapy is required as the fetus is not affected and the mother does not have an increased risk of bleeding. Pregnancy complications such as HELLP syndrome and thrombotic microangiopathies also present with low platelet counts, but these can be diagnosed by history.^61,63

Women with ITP can either develop the disease during pregnancy or have a worsening of the symptoms.⁶⁴ Counts often drop dramatically during the first trimester. Early management should be conservative with low doses of prednisone to keep the count above 10 × 10³/µL.²¹ Immunoglobulin is also effective,⁶⁵ but there are rare reports of pulmonary edema. Rarely patients who are refractory will require splenectomy, which may be safely performed in the second trimester. For delivery the count should be greater than 30 × 10³/µL and for an epidural greater than 50 × 10³/µL.⁶⁴ There are reports of the use of TPO-RAs in pregnancy, and this can be considered for refractory cases.⁶⁶

Most controversy centers on management of the delivery. In the past it was feared that fetal thrombocytopenia could lead to intracranial hemorrhage, and Caesarean section was always recommended. It now appears that most cases of intracranial hemorrhage were due to alloimmune thrombocytopenia and not ITP. Furthermore, the nadir of the baby’s platelet count is not at birth but several days after. It appears the safest course is to proceed with a vaginal or C-section delivery determined by obstetrical indications and then immediately check the baby’s platelet count. If the platelet count is low in the neonate, immunoglobulin will raise the count. Since the neonatal thrombocytopenia is due to passive transfer of maternal antibody, the platelet destruction will abate in 4 to 6 weeks.

Pediatric Patients

The incidence of ITP in children is 2.2 to 5.3 per 100,000 children.¹ There are several distinct differences in pediatric ITP. Most cases will resolve in weeks, with only a minority of patients transforming into chronic ITP (5%–10%). Also, the rates of serious bleeding are lower in children than in adults, with intracranial hemorrhage rates of 0.1% to 0.5% being seen.⁶⁷ For most patients with no or mild bleeding, management now is observation alone regardless of platelet count because it is felt that the risks of therapies are higher than the risk of bleeding.²¹ For patients with bleeding, IVIG, anti-D, or a short course of steroids can be used. Given the risk of overwhelming sepsis, splenectomy is often deferred as long as possible. Rituximab is increasingly being used in children due to concerns about use of agents such a cyclophosphamide or azathioprine in children.⁶⁸ Abundant data on use of TPO-RAs in children showing high response rates and safety support their use, and these should be considered in refractory ITP before any cytotoxic agent.^69–71

Helicobacter Pylori Infection

There has been much interest in the relationship between H. pylori and ITP.^16,72,73H. pylori infections have been associated with a variety of autoimmune diseases, and there is a confusing literature on this infection and ITP. Several meta-analyses have shown that eradication of H. pylori will result in an ITP response rate of 20% to 30%, but responses curiously appear to be limited to certain geographic areas such as Japan and Italy but not the United States. In patients with recalcitrant ITP, especially in geographic areas with high incidence, it may be worthwhile to check for H. pylori infection and treat accordingly if positive.

Drug-Induced Thrombocytopenia

Patients with drug-induced thrombocytopenia present with very low (< 10 × 10³/µL) platelet counts 1 to 3 weeks after starting a new medication.^74–76 In patients with a possible drug-induced thrombocytopenia, the primary therapy is to stop the suspect drug.⁷⁷ If there are multiple new medications, the best approach is to stop any drug that has been strongly associated with thrombocytopenia (Table 3).^74,78,79

Immune globulin, corticosteroids, or intravenous anti‑D have been suggested as useful in drug‑related thrombocytopenia. However, since most of these thrombocytopenic patients recover when the agent is cleared from the body, this therapy is probably not necessary and withholding treatment avoids exposing the patients to the adverse events associated with further therapy.

Evans Syndrome

Evans syndrome is defined as the combination of autoimmune hemolytic anemia (AIHA) and ITP.^80,81 These cytopenias can present simultaneously or sequentially. Patients with Evans syndrome are thought to have a more severe disease process, to be more prone to bleeding, and to be more difficult to treat, but the rarity of this syndrome makes this hard to quantify.

The classic clinical presentation of Evans syndrome is severe anemia and thrombocytopenia. Children with Evans syndrome often have complex immunodeficiencies such as autoimmune lymphoproliferative syndrome.^82,83 In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans syndrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.

In theory the diagnostic approach is straightforward by showing a Coombs-positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocytopenia. The blood smear will show spherocytes and a diminished platelet count. The presence of other abnormal red cell forms should raise the possibility of an alternative diagnosis. It is unclear how vigorously one should search for other underlying diseases. Many patients will already have the diagnosis of an underlying autoimmune disease. The presence of lymphadenopathy should raise concern for lymphoma.

Initial therapy is high-dose steroids (2 mg/kg/day). IVIG should be added if severe thrombocytopenia is present. Patients who cannot be weaned off prednisone or relapse after prednisone should be considered for splenectomy, although these patients are at higher risk of relapsing.⁸⁰ Increasingly rituximab is being used with success.^84,85 For patients who fail splenectomy and rituximab, aggressive immunosuppression should be considered. Increasing data support the benefits of sirolimus, and this should be considered for refractory patients.⁸⁶ For patients with Evans syndrome due to underlying lymphoma, antineoplastic therapy often results in prompt resolution of the symptoms. Recurrence of the autoimmune cytopenias often heralds relapse.

Introduction

Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder, with only approximately 2000 new cases diagnosed in the United States each year.¹ It is now recognized that there are 2 distinct categories of HCL, classic HCL (cHCL) and variant HCL (vHCL), with vHCL now classified as a separate entity under the World Health Organization Classification of Hematopoietic Tumors.² For this reason, the 2 diseases will be discussed separately. However, they do bear many clinical and microscopic similarities and because of this were originally indistinguishable using diagnostic techniques previously available. Even in the modern era using immunophenotypic, molecular, and genetic testing, differentiating between the classic and variant disease subtypes is sometimes difficult.

For cHCL the median age of diagnosis is 55 years, with vHCL occurring in patients who are somewhat older; HCL has been described only in the adult population, with 1 exception.^3,4 There is a 4:1 male predominance, and Caucasians are more frequently affected than other ethnic groups. While the cause of the disease remains largely unknown, it has been observed to occur more frequently in farmers and in persons exposed to pesticides and/or herbicides, petroleum products, and ionizing radiation.⁴ The Institute of Medicine recently updated their position regarding veterans and Agent Orange, stating that there is sufficient evidence of an association between herbicides and chronic lymphoid leukemias (including HCL) to consider these diseases linked to exposure.⁵ Familial forms have also been described that are associated with specific HLA haplotypes, indicating a possible hereditary component.⁶ Most likely, a combination of environmental and genetic factors ultimately contributes to the development of HCL.

In recent years enormous progress has been made with respect to new insights into the biology of cHCL and vHCL, with significant refinement of diagnostic criteria. In addition, tremendous advances have occurred in both treatment and supportive care regimens, which have resulted in a dramatically increased overall life expectancy as well as decreased disease-related morbidity. This has meant that more patients are affected by HCL over time and are more likely to require care for relapsed HCL or associated comorbidities. Although no curative treatment options exist outside of allogeneic transplantation, therapeutic improvements have resulted in patients with cHCL having a life expectancy similar to that of unaffected patients, increasing the need for vigilance to prevent foreseeable complications.

Biology and Patheogenisis

The family of HCLs are chronic B-cell malignancies that account for approximately 2% of all diagnosed leukemias.⁷ The first detailed characterization of HCL as a distinct clinical entity was performed by Dr. Bouroncle and colleagues at the Ohio State University in 1958.⁸ Originally called leukemic reticuloendotheliosis, it was renamed HCL following more detailed description of the unique morphology of these malignant cells.⁹ Significant advances have recently been made in identifying distinctive genetic, immunophenotypic, and morphologic features that distinguish HCL from other B-cell malignancies.

HCL B cells tend to accumulate in the bone marrow, splenic red pulp, and (in some cases) peripheral blood. Unlike other lymphoproliferative disorders, HCL only rarely results in lymphadenopathy. HCL derives its name from the distinct appearance of the malignant hairy cells (Figure). Morphologically, HCL cells are mature, small lymphoid B-cells with a round or oval nucleus and abundant pale blue cytoplasm. Irregular projections of cytoplasm and microvilli give the cells a serrated, “hairy” appearance.¹⁰ The biological significance of these fine hair-like projections remains unknown and is an area of ongoing investigation. Gene expression profiling has revealed that HCL B cells are most similar to splenic marginal zone B cells and memory B cells.^11–13 A recent analysis of common genetic alterations in HCL suggests that the cell of origin is in fact the hematopoietic stem cell.¹⁴

Compared to other hematologic malignancies, the genomic profile of HCL is relatively stable, with few chromosomal defects or translocations observed. A seminal study by Tiacci and colleagues revealed that the BRAF V600E mutation was present in 47 out of 47 cHCL cases examined, results that have since been replicated by other groups, confirming that BRAF V600E is a hallmark mutation in cHCL.¹⁵ The BRAF V600E gain-of-function mutation results in constitutive activation of the serine-threonine protein kinase B-Raf, which regulates the mitogen-activated protein kinase (MAPK)/RAF-MEK-ERK pathway. Indeed, cHCL B cells have elevated MAPK signaling, leading to enhancement of growth and survival.¹⁶ This specific mutation in the BRAF gene is also seen in a number of solid tumor malignancies including melanoma and thyroid cancer, and represents a therapeutic target using BRAF inhibitors already developed to treat these malignancies.¹⁷ Testing for BRAF V600E by polymerase chain reaction or immunohistochemical staining is now routinely performed when HCL is suspected.

While BRAF V600E is identified in nearly all cases of cHCL, it is rare in vHCL.¹⁸ The variant type of HCL was classified as a distinct clinical entity in 2008 and can now often be distinguished from cHCL on the basis of BRAF mutational status, among other differences. Interestingly, in the rare cases of BRAF V600E–negative cHCL, other mutations in BRAF or downstream targets as well as aberrant activation of the RAF-MEK-ERK signaling cascade are observed, indicating that this pathway is critical in HCL and may still represent a viable therapeutic target. Expression of the IGHV4-34 immunoglobulin rearrangement, while more common in vHCL, has also been identified in 10% of cHCL cases and appears to confer poor prognosis.¹⁹ Other mutated genes that have been identified in HCL include CDKN1B, TP53, U2AF1, ARID1A, EZH2, and KDM6A.²⁰

Classic HCL is characterized by the immunophenotypic expression of CD11c, CD25, CD103, and CD123, with kappa or lambda light chain restriction indicating clonality; HCL B cells are generally negative for CD5, CD10, CD23, CD27, and CD79b. In contrast, vHCL often lacks expression of CD25 and CD123.¹⁸ The B-cell receptor (BCR) is expressed on hairy cells and its activation promotes proliferation and survival in vitro.²¹ The role of BCR signaling in B-cell malignancies is increasingly recognized, and therapies that target the BCR and associated signaling molecules offer an attractive treatment strategy.²² HCL B cells also typically express CD19, CD20, CD22, CD79a, CD200, CD1d, and annexin A1. Tartrate-resistant acid phosphatase (TRAP) positivity by immunohistochemistry is a hallmark of cHCL. Interestingly, changes to the patient’s original immunophenotype have been observed following treatment and upon disease recurrence, highlighting the importance of tracking immunophenotype throughout the course of disease.

Diagnosis

Prior to the advent of annual screening evaluations with routine examination of complete blood counts (CBC), patients were most often diagnosed with HCL when they presented with symptoms of the disease such as splenomegaly, infections, or complications of anemia or thrombocytopenia.²³ In the current era, patients are more likely to be incidentally diagnosed when they are found to have an abnormal value on a CBC. Any blood lineage may be affected and patients may have pancytopenia or isolated cytopenias. Of note, monocytopenia is a common finding in cHCL that is not entirely understood. The cells typical of cHCL do not usually circulate in the peripheral blood, but if present would appear as mature lymphocytes with villous cytoplasmic projections, pale blue cytoplasm, and reniform nuclei with open chromatin (Figure).⁹ Even if the morphologic examination is highly suggestive of HCL, additional testing is required to differentiate between cHCL, vHCL, and other hematologic malignancies which may also have cytoplasmic projections. A complete assessment of the immunophenotype, molecular profile, and cytogenetic features is required to arrive at this diagnosis.

The international Hairy Cell Leukemia Foundation recently published consensus guidelines for the diagnosis and treatment of HCL.²⁴ These guidelines recommend that patients undergo examination of the peripheral blood for morphology and immunophenotyping and further recommend obtaining bone marrow core and aspirate biopsy samples for immunophenotyping via immunohistochemical staining and flow cytometry. The characteristic immunophenotype of cHCL is a population of monoclonal B lymphocytes which co-express CD19, CD20, CD11c, CD25, CD103, and CD123. Variant HCL is characterized by a very similar immunophenotype but is usually negative for CD25 and CD123. It is notable that CD25 positivity may be lost following treatment, and the absence of this marker should not be used as the sole basis of a cHCL versus vHCL diagnosis. Because marrow fibrosis in HCL may prevent a marrow aspirate from being obtained, many of the key diagnostic studies are performed on the core biopsy, including morphological evaluation and immunohistochemical stains such as CD20 (a pan-B cell antigen), annexin-1 (an anti-inflammatory protein expressed only in cHCL), and VE1 (a BRAF V600E stain).

As noted above, recurrent cytogenetic abnormalities have now been identified that may inform the diagnosis or prognosis of HCL. Next-generation sequencing and other testing of the genetic landscape are taking on a larger role in subtype differentiation, and it is likely that future guidelines will recommend evaluation for significant mutations. Given that BRAF V600E mutation status is a key feature of cHCL and is absent in vHCL, it is important to perform this testing at the time of diagnosis whenever possible. The mutation may be detected via VE1 immunohistochemical staining, allele-specific polymerase chain reaction, or next-generation sequencing. Other less sensitive tests exist but are utilized less frequently.

Minimal Residual Disease

There is currently no accepted standard for minimal residual disease (MRD) monitoring in HCL. While detection of MRD has been clearly associated with increased risk of disease progression, cHCL cells typically do not circulate in the peripheral blood, limiting the use of peripheral blood immunophenotyping for quantitative MRD assessment. For quantitative monitoring of marrow involvement by HCL, immunohistochemical staining of the bone marrow core biopsy is usually required. Staining may be performed for CD20, or, in patients who have received anti-CD20 therapy, DBA.44, VE-1, or CD79a. There is currently not a consensus regarding what level of disease involvement constitutes MRD. One group studied this issue and found that relapse could be predicted by evaluating MRD by percentage of positive cells in the marrow by immunohistochemical staining, with less than 1% involvement having the lowest risk for disease relapse and greater than 5% having the highest risk for disease relapse.²⁵ A recent study evaluated MRD patterns in the peripheral blood of 32 cHCL patients who had completed frontline therapy. This group performed flow cytometry on the peripheral blood of patients at 1, 3, 6, and 12 months following therapy. All patients had achieved a complete response with initial therapy and peripheral blood MRD negativity at the completion of therapy. At a median follow-up of 100 months post therapy, 5 patients converted from peripheral blood–MRD negative to peripheral blood–MRD positive, and 6 patients developed overt disease progression. In all patients who progressed, progression was preceded by an increase in detectable peripheral blood MRD cells.²⁶ Although larger studies are needed, peripheral blood flow cytometric monitoring for MRD may be a useful adjunct to predict ongoing response or impending relapse. In addition, newer, more sensitive methods of disease monitoring may ultimately supplant flow cytometry.

Risk Stratification

Although much progress has been made in the risk stratification profiling of hematologic malignancies in general, HCL has unfortunately lagged behind in this effort. The most recent risk stratification analysis was performed in 1982 by Jansen and colleagues.²⁷ This group of researchers performed a retrospective analysis of 391 HCL patients treated at 22 centers. One of the central questions in their analysis was survival time from diagnosis in patients who had not yet undergone splenectomy (a standard treatment at the time). This group consisted of a total of 154 patients. As this study predated modern pathological and molecular testing, clinical and laboratory features were examined, and these mostly consisted of physical exam findings and analysis of the peripheral blood. This group found that several factors influenced the survival of these patients, including duration of symptoms prior to diagnosis, the degree of splenomegaly, hemoglobin level, and number of hairy cells in the peripheral blood. However, because of interobserver variation for the majority of these variables, only hemoglobin and spleen size were included in the proportional hazard model. Using only these 2 variables, the authors were able to determine 3 clinical stages for HCL (Table 1). The stages were found to correlate with median survival: patients with stage 1 disease had a median survival not reached at 72 months, but patients with stage 2 disease had a median survival of 18 months, which decreased to only 12 months in patients with stage 3 disease.

Because the majority of patients with HCL in the modern era will be diagnosed prior to reaching stage 3, a risk stratification system incorporating clinical features, laboratory parameters, and molecular and genetic testing is of considerable interest and is a subject of ongoing research. Ultimately, the goal will be to identify patients at higher risk of early relapse so that more intensive therapies can be applied to initial treatment that will result in longer treatment-free intervals.

Treatment

Because there is no curative treatment for either cHCL or vHCL outside allogeneic transplantation, and it is not clear that early treatment leads to better outcomes in HCL, patients do not always receive treatment at the time of diagnosis or relapse. The general consensus is that patients should be treated if there is a declining trend in hematologic parameters or they experience symptoms from the disease.²⁴ Current consensus guidelines recommend treatment when any of the following hematologic parameters are met: hemoglobin less than 11 g/dL, platelet count less than 100 × 10³/µL, or absolute neutrophil count less than 1000/µL.²⁴ These parameters are surrogate markers that indicate compromised bone marrow function. Cytopenias may also be caused by splenomegaly, and symptomatic splenomegaly with or without cytopenias is an indication for treatment. A small number of patients with HCL (approximately 10%) do not require immediate therapy after diagnosis and are monitored by their provider until treatment is indicated.

First-Line Therapy

Despite advances in targeted therapies for HCL, because no treatment has been shown to extend the treatment-free interval longer than chemotherapy, treatment with a purine nucleoside analog is usually the recommended first-line therapy. This includes either cladribine or pentostatin. Both agents appear to be equally effective, and the choice of therapy is determined by the treating physician based on his or her experience. Cladribine administration has been studied using a number of different schedules and routes: intravenous continuous infusion (0.1 mg/kg) for 7 days, intravenous infusion (0.14 mg/kg/day) over 2 hours on a 5-day regimen, or alternatively subcutaneously (0.1–0.14 mg/kg/day) on a once-per-day or once-per-week regimen (Table 2).^28,29

Unlike cHCL, vHCL remains difficult to treat and early disease progression is common. The best outcomes have been seen in patients who have received combination chemo-immunotherapy such as purine nucleoside analog therapy plus rituximab or bendamustine plus rituximab.³¹ One pilot study of bendamustine plus rituximab in 12 patients found an overall response rate of 100%, with the majority of patients achieving a complete response.³¹ For patients who achieved a complete response, the median duration of response had not been reached, but patients achieving only a partial response had a median duration of response of only 20 months, indicating there is a subgroup of patients who will require a different treatment approach.³² A randomized phase 2 trial of rituximab with either pentostatin or bendamustine is ongoing.³³

Assessment of Response

Response assessment involves physical examination for estimation of spleen size, assessment of hematologic parameters, and a bone marrow biopsy for evaluation of marrow response. It is recommended that the bone marrow biopsy be performed 4 to 6 months following cladribine administration, or after completion of 12 doses of pentostatin. Detailed response assessment criteria are shown in Table 3.

Second-Line Therapy

Although the majority of patients treated with purine analogs will achieve durable remissions, approximately 40% of patients will eventually require second-line therapy. Criteria for treatment at relapse are the same as the criteria for initial therapy, including symptomatic disease or progressive anemia, thrombocytopenia, or neutropenia. The choice of treatment is based on clinical parameters and the duration of the previous remission. If the initial remission was longer than 65 months and the patient is eligible to receive chemotherapy, re-treatment with initial therapy is recommended. For a remission between 24 and 65 months, re-treatment with a purine analog combined with an anti-CD20 monoclonal antibody may be considered.³⁴ If the first remission is shorter than 24 months, confirmation of the original diagnosis as well as consideration for testing for additional mutations with therapeutic targets (BRAF V600E, MAP2K1) should be considered before a treatment decision is made. For these patients, alternative therapies, including investigational agents, should be considered.²⁴

Monoclonal antibody therapy has been studied in both the up-front setting and in relapsed or refractory HCL.³⁵ An initial study of 15 patients with relapsed HCL found an overall response rate of 80%, with 8 patients achieving a complete response. A subsequent study of 26 patients who relapsed after cladribine therapy found an overall response rate of 80%, with a complete response rate of 32%. Median relapse-free survival was 27 months.³⁶ Ravandi and others studied rituximab in the up-front setting in combination with cladribine, and found an overall response rate of 100%, including in patients with vHCL. At the time of publication of the study results, the median survival had not been reached.³⁷ As has been seen with other lymphoid malignancies, concurrent therapy with rituximab appears to enhance the activity of the agent with which it is combined. While its use in the up-front setting remains an area of active investigation, there is a clear role for chemo-immunotherapy in the relapsed setting.

In patients with cHCL, excellent results including complete remissions have been reported with the use of BRAF inhibitors, both as a single agent and when combined with anti-CD20 therapy. The 2 commercially available BRAF inhibitors are vemurafenib and dabrafenib, and both have been tested in relapsed cHCL.^38,39 The first study of vemurafenib was reported by Tiacci and colleagues, who found an overall response rate of 96% after a median of 8 weeks and a 100% response rate after a median of 12 weeks, with complete response rates up to 42%.³⁸ The median relapse-free survival was 23 months (decreasing to only 6 months in patients who achieved only a partial remission), indicating that these agents will likely need to be administered in combination with other effective therapies with non-overlapping toxicities. Vemurafenib has been administered concurrently with rituximab, and preliminary results of this combination therapy showed early rates of complete responses.⁴⁰ Dabrafenib has been reported for use as a single agent in cHCL and clinical trials are underway evaluating its efficacy when administered with trametinib, a MEK inhibitor.^39,41 Of note, patients receiving BRAF inhibitors frequently develop cutaneous complications of RAF inhibition including cutaneous squamous cell carcinomas and keratoacanthomas, and close dermatologic surveillance is required.

Variant HCL does not harbor the BRAF V600E mutation, but up to half of patients have been found to have mutations of MAP2K1, which upregulates MEK1 expression.⁴² Trametinib is approved by the US Food and Drug Administration for the treatment of patients with melanoma at a dose of 2 mg orally daily, and has been successfully used to treat 1 patient with vHCL.⁴³ Further evaluation of this targeted therapy is underway.

Ibrutinib, a Bruton tyrosine kinase inhibitor, and moxetumomab pasudotox, an immunotoxin conjugate, are currently being studied in National Institutes of Health–sponsored multi-institutional trials for patients with HCL. Ibrutinib is administered orally at 420 mg per day until relapse.⁴⁴ Moxetumomab pasudotox was tested at different doses between 5 and 50 μg/kg intravenously every other day for 3 doses for up to 16 cycles unless they experienced disease progression or developed neutralizing antibodies.⁴⁵ Both agents have been shown to have significant activity in cHCL and vHCL and will likely be included in the treatment armamentarium once trials are completed. Second-line therapy options are summarized in Table 4.

Complications and Supportive Care

The complications of HCL may be separated into the pre-, intra-, and post-treatment periods. At the time of diagnosis and prior to the initiation of therapy, marrow infiltration by HCL frequently leads to cytopenias which cause symptomatic anemia, infection, and/or bleeding complications. Many patients develop splenomegaly, which may further lower the blood counts and which is experienced as abdominal fullness or distention, with early satiety leading to weight loss. Patients may also experience constitutional symptoms with fatigue, fevers in the absence of infection, and unintentional weight loss even without splenomegaly.

For patients who initiate therapy with purine nucleoside analogs, the early part of treatment is associated with the greatest risk of morbidity and mortality. Chemotherapy leads to both immunosuppression (altered cellular immunity) as well as myelosuppression. Thus, patients who are already in need of treatment because of disease-related cytopenias will experience an abrupt and sometimes significant decline in the peripheral blood counts. The treatment period prior to recovery of neutrophils requires the greatest vigilance. Because patients are profoundly immunocompromised, febrile neutropenia is a common complication leading to hospital admission and the cause is often difficult to identify. Treatment with broad-spectrum antibiotics, investigation for opportunistic and viral infections, and considerations for antifungal prophylaxis or therapy are required in this setting. It is recommended that all patients treated with purine nucleoside analogs receive prophylactic antimicrobials for herpes simplex virus and varicella zoster virus, as well as prophylaxis against Pneumocystis jirovecii. Unfortunately, growth factor support has not proven successful in this patient population but is not contraindicated.⁴⁶

Following successful completion of therapy, patients may remain functionally immunocompromised for a significant period of time even with a normal neutrophil count. Monitoring of the CD4 count may help to determine when prophylactic antimicrobials may be discontinued. A CD4 count greater than 200 cells/µL is generally considered to be adequate for prevention of opportunistic infections. Although immunizations have not been well studied in HCL, it is recommended that patients receive annual influenza immunizations as well as age-appropriate immunizations against Streptococcus pneumoniae and other infectious illnesses as indicated. Live viral vaccines such as the currently available herpes zoster vaccine can lead to infections in this patient population and are not recommended.

Like many hematologic malignancies, HCL may be associated with comorbid conditions related to immune dysfunction. There is a known association with an increased risk of second primary malignancies, which may predate the diagnosis of HCL.⁴⁷ Therefore, it is recommended that patients continue annual cancer screenings as well as undergo prompt evaluation for potential symptoms of second malignancies. In addition, it is thought that there may be an increased risk for autoimmune disorders such as inflammatory arthritis or immune-mediated cytopenias. One case-control study found a possible association between autoimmune diseases and HCL, noting that at times these diseases are diagnosed concurrently.⁴⁸ However, because of the rarity of the disease it has been difficult to quantify these associated conditions in a systematic way. There is currently an international patient data registry under development for the systematic study of HCL and its complications which may answer many of these questions.

Survivorship and quality of life are important considerations in chronic diseases. It is not uncommon for patients to develop anxiety related to the trauma of diagnosis and treatment, especially when intensive care has been required. Patients may have lingering fears regarding concerns of developing infections due to exposure to ill persons or fears regarding risk of relapse and need for re-treatment. A proactive approach with partnership with psychosocial oncology may be of benefit, especially when symptoms of post-traumatic stress disorder are evident.

Conclusion

HCL is a rare, chronic lymphoid malignancy that is now subclassified into classic and variant HCL. Further investigations into the disease subtypes will allow more precise disease definitions, and these studies are underway. Renewed efforts toward updated risk stratification and clinical staging systems will be important aspects of these investigations. Refinements in treatment and supportive care have resulted in greatly improved overall survival, which has translated into larger numbers of people living with HCL. However, new treatment paradigms for vHCL are needed as the progression-free survival in this disease remains significantly lower than that of cHCL. Future efforts toward understanding survivorship issues and management of long-term treatment and disease-related complications will be critical for ensuring good quality of life for patients living with HCL.

Introduction

Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder, with only approximately 2000 new cases diagnosed in the United States each year.¹ It is now recognized that there are 2 distinct categories of HCL, classic HCL (cHCL) and variant HCL (vHCL), with vHCL now classified as a separate entity under the World Health Organization Classification of Hematopoietic Tumors.² For this reason, the 2 diseases will be discussed separately. However, they do bear many clinical and microscopic similarities and because of this were originally indistinguishable using diagnostic techniques previously available. Even in the modern era using immunophenotypic, molecular, and genetic testing, differentiating between the classic and variant disease subtypes is sometimes difficult.

For cHCL the median age of diagnosis is 55 years, with vHCL occurring in patients who are somewhat older; HCL has been described only in the adult population, with 1 exception.^3,4 There is a 4:1 male predominance, and Caucasians are more frequently affected than other ethnic groups. While the cause of the disease remains largely unknown, it has been observed to occur more frequently in farmers and in persons exposed to pesticides and/or herbicides, petroleum products, and ionizing radiation.⁴ The Institute of Medicine recently updated their position regarding veterans and Agent Orange, stating that there is sufficient evidence of an association between herbicides and chronic lymphoid leukemias (including HCL) to consider these diseases linked to exposure.⁵ Familial forms have also been described that are associated with specific HLA haplotypes, indicating a possible hereditary component.⁶ Most likely, a combination of environmental and genetic factors ultimately contributes to the development of HCL.

In recent years enormous progress has been made with respect to new insights into the biology of cHCL and vHCL, with significant refinement of diagnostic criteria. In addition, tremendous advances have occurred in both treatment and supportive care regimens, which have resulted in a dramatically increased overall life expectancy as well as decreased disease-related morbidity. This has meant that more patients are affected by HCL over time and are more likely to require care for relapsed HCL or associated comorbidities. Although no curative treatment options exist outside of allogeneic transplantation, therapeutic improvements have resulted in patients with cHCL having a life expectancy similar to that of unaffected patients, increasing the need for vigilance to prevent foreseeable complications.

Biology and Patheogenisis

The family of HCLs are chronic B-cell malignancies that account for approximately 2% of all diagnosed leukemias.⁷ The first detailed characterization of HCL as a distinct clinical entity was performed by Dr. Bouroncle and colleagues at the Ohio State University in 1958.⁸ Originally called leukemic reticuloendotheliosis, it was renamed HCL following more detailed description of the unique morphology of these malignant cells.⁹ Significant advances have recently been made in identifying distinctive genetic, immunophenotypic, and morphologic features that distinguish HCL from other B-cell malignancies.

HCL B cells tend to accumulate in the bone marrow, splenic red pulp, and (in some cases) peripheral blood. Unlike other lymphoproliferative disorders, HCL only rarely results in lymphadenopathy. HCL derives its name from the distinct appearance of the malignant hairy cells (Figure). Morphologically, HCL cells are mature, small lymphoid B-cells with a round or oval nucleus and abundant pale blue cytoplasm. Irregular projections of cytoplasm and microvilli give the cells a serrated, “hairy” appearance.¹⁰ The biological significance of these fine hair-like projections remains unknown and is an area of ongoing investigation. Gene expression profiling has revealed that HCL B cells are most similar to splenic marginal zone B cells and memory B cells.^11–13 A recent analysis of common genetic alterations in HCL suggests that the cell of origin is in fact the hematopoietic stem cell.¹⁴

Compared to other hematologic malignancies, the genomic profile of HCL is relatively stable, with few chromosomal defects or translocations observed. A seminal study by Tiacci and colleagues revealed that the BRAF V600E mutation was present in 47 out of 47 cHCL cases examined, results that have since been replicated by other groups, confirming that BRAF V600E is a hallmark mutation in cHCL.¹⁵ The BRAF V600E gain-of-function mutation results in constitutive activation of the serine-threonine protein kinase B-Raf, which regulates the mitogen-activated protein kinase (MAPK)/RAF-MEK-ERK pathway. Indeed, cHCL B cells have elevated MAPK signaling, leading to enhancement of growth and survival.¹⁶ This specific mutation in the BRAF gene is also seen in a number of solid tumor malignancies including melanoma and thyroid cancer, and represents a therapeutic target using BRAF inhibitors already developed to treat these malignancies.¹⁷ Testing for BRAF V600E by polymerase chain reaction or immunohistochemical staining is now routinely performed when HCL is suspected.

While BRAF V600E is identified in nearly all cases of cHCL, it is rare in vHCL.¹⁸ The variant type of HCL was classified as a distinct clinical entity in 2008 and can now often be distinguished from cHCL on the basis of BRAF mutational status, among other differences. Interestingly, in the rare cases of BRAF V600E–negative cHCL, other mutations in BRAF or downstream targets as well as aberrant activation of the RAF-MEK-ERK signaling cascade are observed, indicating that this pathway is critical in HCL and may still represent a viable therapeutic target. Expression of the IGHV4-34 immunoglobulin rearrangement, while more common in vHCL, has also been identified in 10% of cHCL cases and appears to confer poor prognosis.¹⁹ Other mutated genes that have been identified in HCL include CDKN1B, TP53, U2AF1, ARID1A, EZH2, and KDM6A.²⁰

Classic HCL is characterized by the immunophenotypic expression of CD11c, CD25, CD103, and CD123, with kappa or lambda light chain restriction indicating clonality; HCL B cells are generally negative for CD5, CD10, CD23, CD27, and CD79b. In contrast, vHCL often lacks expression of CD25 and CD123.¹⁸ The B-cell receptor (BCR) is expressed on hairy cells and its activation promotes proliferation and survival in vitro.²¹ The role of BCR signaling in B-cell malignancies is increasingly recognized, and therapies that target the BCR and associated signaling molecules offer an attractive treatment strategy.²² HCL B cells also typically express CD19, CD20, CD22, CD79a, CD200, CD1d, and annexin A1. Tartrate-resistant acid phosphatase (TRAP) positivity by immunohistochemistry is a hallmark of cHCL. Interestingly, changes to the patient’s original immunophenotype have been observed following treatment and upon disease recurrence, highlighting the importance of tracking immunophenotype throughout the course of disease.

Diagnosis

Prior to the advent of annual screening evaluations with routine examination of complete blood counts (CBC), patients were most often diagnosed with HCL when they presented with symptoms of the disease such as splenomegaly, infections, or complications of anemia or thrombocytopenia.²³ In the current era, patients are more likely to be incidentally diagnosed when they are found to have an abnormal value on a CBC. Any blood lineage may be affected and patients may have pancytopenia or isolated cytopenias. Of note, monocytopenia is a common finding in cHCL that is not entirely understood. The cells typical of cHCL do not usually circulate in the peripheral blood, but if present would appear as mature lymphocytes with villous cytoplasmic projections, pale blue cytoplasm, and reniform nuclei with open chromatin (Figure).⁹ Even if the morphologic examination is highly suggestive of HCL, additional testing is required to differentiate between cHCL, vHCL, and other hematologic malignancies which may also have cytoplasmic projections. A complete assessment of the immunophenotype, molecular profile, and cytogenetic features is required to arrive at this diagnosis.

The international Hairy Cell Leukemia Foundation recently published consensus guidelines for the diagnosis and treatment of HCL.²⁴ These guidelines recommend that patients undergo examination of the peripheral blood for morphology and immunophenotyping and further recommend obtaining bone marrow core and aspirate biopsy samples for immunophenotyping via immunohistochemical staining and flow cytometry. The characteristic immunophenotype of cHCL is a population of monoclonal B lymphocytes which co-express CD19, CD20, CD11c, CD25, CD103, and CD123. Variant HCL is characterized by a very similar immunophenotype but is usually negative for CD25 and CD123. It is notable that CD25 positivity may be lost following treatment, and the absence of this marker should not be used as the sole basis of a cHCL versus vHCL diagnosis. Because marrow fibrosis in HCL may prevent a marrow aspirate from being obtained, many of the key diagnostic studies are performed on the core biopsy, including morphological evaluation and immunohistochemical stains such as CD20 (a pan-B cell antigen), annexin-1 (an anti-inflammatory protein expressed only in cHCL), and VE1 (a BRAF V600E stain).

As noted above, recurrent cytogenetic abnormalities have now been identified that may inform the diagnosis or prognosis of HCL. Next-generation sequencing and other testing of the genetic landscape are taking on a larger role in subtype differentiation, and it is likely that future guidelines will recommend evaluation for significant mutations. Given that BRAF V600E mutation status is a key feature of cHCL and is absent in vHCL, it is important to perform this testing at the time of diagnosis whenever possible. The mutation may be detected via VE1 immunohistochemical staining, allele-specific polymerase chain reaction, or next-generation sequencing. Other less sensitive tests exist but are utilized less frequently.

Minimal Residual Disease

There is currently no accepted standard for minimal residual disease (MRD) monitoring in HCL. While detection of MRD has been clearly associated with increased risk of disease progression, cHCL cells typically do not circulate in the peripheral blood, limiting the use of peripheral blood immunophenotyping for quantitative MRD assessment. For quantitative monitoring of marrow involvement by HCL, immunohistochemical staining of the bone marrow core biopsy is usually required. Staining may be performed for CD20, or, in patients who have received anti-CD20 therapy, DBA.44, VE-1, or CD79a. There is currently not a consensus regarding what level of disease involvement constitutes MRD. One group studied this issue and found that relapse could be predicted by evaluating MRD by percentage of positive cells in the marrow by immunohistochemical staining, with less than 1% involvement having the lowest risk for disease relapse and greater than 5% having the highest risk for disease relapse.²⁵ A recent study evaluated MRD patterns in the peripheral blood of 32 cHCL patients who had completed frontline therapy. This group performed flow cytometry on the peripheral blood of patients at 1, 3, 6, and 12 months following therapy. All patients had achieved a complete response with initial therapy and peripheral blood MRD negativity at the completion of therapy. At a median follow-up of 100 months post therapy, 5 patients converted from peripheral blood–MRD negative to peripheral blood–MRD positive, and 6 patients developed overt disease progression. In all patients who progressed, progression was preceded by an increase in detectable peripheral blood MRD cells.²⁶ Although larger studies are needed, peripheral blood flow cytometric monitoring for MRD may be a useful adjunct to predict ongoing response or impending relapse. In addition, newer, more sensitive methods of disease monitoring may ultimately supplant flow cytometry.

Risk Stratification

Although much progress has been made in the risk stratification profiling of hematologic malignancies in general, HCL has unfortunately lagged behind in this effort. The most recent risk stratification analysis was performed in 1982 by Jansen and colleagues.²⁷ This group of researchers performed a retrospective analysis of 391 HCL patients treated at 22 centers. One of the central questions in their analysis was survival time from diagnosis in patients who had not yet undergone splenectomy (a standard treatment at the time). This group consisted of a total of 154 patients. As this study predated modern pathological and molecular testing, clinical and laboratory features were examined, and these mostly consisted of physical exam findings and analysis of the peripheral blood. This group found that several factors influenced the survival of these patients, including duration of symptoms prior to diagnosis, the degree of splenomegaly, hemoglobin level, and number of hairy cells in the peripheral blood. However, because of interobserver variation for the majority of these variables, only hemoglobin and spleen size were included in the proportional hazard model. Using only these 2 variables, the authors were able to determine 3 clinical stages for HCL (Table 1). The stages were found to correlate with median survival: patients with stage 1 disease had a median survival not reached at 72 months, but patients with stage 2 disease had a median survival of 18 months, which decreased to only 12 months in patients with stage 3 disease.

Because the majority of patients with HCL in the modern era will be diagnosed prior to reaching stage 3, a risk stratification system incorporating clinical features, laboratory parameters, and molecular and genetic testing is of considerable interest and is a subject of ongoing research. Ultimately, the goal will be to identify patients at higher risk of early relapse so that more intensive therapies can be applied to initial treatment that will result in longer treatment-free intervals.

Treatment

Because there is no curative treatment for either cHCL or vHCL outside allogeneic transplantation, and it is not clear that early treatment leads to better outcomes in HCL, patients do not always receive treatment at the time of diagnosis or relapse. The general consensus is that patients should be treated if there is a declining trend in hematologic parameters or they experience symptoms from the disease.²⁴ Current consensus guidelines recommend treatment when any of the following hematologic parameters are met: hemoglobin less than 11 g/dL, platelet count less than 100 × 10³/µL, or absolute neutrophil count less than 1000/µL.²⁴ These parameters are surrogate markers that indicate compromised bone marrow function. Cytopenias may also be caused by splenomegaly, and symptomatic splenomegaly with or without cytopenias is an indication for treatment. A small number of patients with HCL (approximately 10%) do not require immediate therapy after diagnosis and are monitored by their provider until treatment is indicated.

First-Line Therapy

Despite advances in targeted therapies for HCL, because no treatment has been shown to extend the treatment-free interval longer than chemotherapy, treatment with a purine nucleoside analog is usually the recommended first-line therapy. This includes either cladribine or pentostatin. Both agents appear to be equally effective, and the choice of therapy is determined by the treating physician based on his or her experience. Cladribine administration has been studied using a number of different schedules and routes: intravenous continuous infusion (0.1 mg/kg) for 7 days, intravenous infusion (0.14 mg/kg/day) over 2 hours on a 5-day regimen, or alternatively subcutaneously (0.1–0.14 mg/kg/day) on a once-per-day or once-per-week regimen (Table 2).^28,29

Unlike cHCL, vHCL remains difficult to treat and early disease progression is common. The best outcomes have been seen in patients who have received combination chemo-immunotherapy such as purine nucleoside analog therapy plus rituximab or bendamustine plus rituximab.³¹ One pilot study of bendamustine plus rituximab in 12 patients found an overall response rate of 100%, with the majority of patients achieving a complete response.³¹ For patients who achieved a complete response, the median duration of response had not been reached, but patients achieving only a partial response had a median duration of response of only 20 months, indicating there is a subgroup of patients who will require a different treatment approach.³² A randomized phase 2 trial of rituximab with either pentostatin or bendamustine is ongoing.³³

Assessment of Response

Response assessment involves physical examination for estimation of spleen size, assessment of hematologic parameters, and a bone marrow biopsy for evaluation of marrow response. It is recommended that the bone marrow biopsy be performed 4 to 6 months following cladribine administration, or after completion of 12 doses of pentostatin. Detailed response assessment criteria are shown in Table 3.

Second-Line Therapy

Although the majority of patients treated with purine analogs will achieve durable remissions, approximately 40% of patients will eventually require second-line therapy. Criteria for treatment at relapse are the same as the criteria for initial therapy, including symptomatic disease or progressive anemia, thrombocytopenia, or neutropenia. The choice of treatment is based on clinical parameters and the duration of the previous remission. If the initial remission was longer than 65 months and the patient is eligible to receive chemotherapy, re-treatment with initial therapy is recommended. For a remission between 24 and 65 months, re-treatment with a purine analog combined with an anti-CD20 monoclonal antibody may be considered.³⁴ If the first remission is shorter than 24 months, confirmation of the original diagnosis as well as consideration for testing for additional mutations with therapeutic targets (BRAF V600E, MAP2K1) should be considered before a treatment decision is made. For these patients, alternative therapies, including investigational agents, should be considered.²⁴

Monoclonal antibody therapy has been studied in both the up-front setting and in relapsed or refractory HCL.³⁵ An initial study of 15 patients with relapsed HCL found an overall response rate of 80%, with 8 patients achieving a complete response. A subsequent study of 26 patients who relapsed after cladribine therapy found an overall response rate of 80%, with a complete response rate of 32%. Median relapse-free survival was 27 months.³⁶ Ravandi and others studied rituximab in the up-front setting in combination with cladribine, and found an overall response rate of 100%, including in patients with vHCL. At the time of publication of the study results, the median survival had not been reached.³⁷ As has been seen with other lymphoid malignancies, concurrent therapy with rituximab appears to enhance the activity of the agent with which it is combined. While its use in the up-front setting remains an area of active investigation, there is a clear role for chemo-immunotherapy in the relapsed setting.

In patients with cHCL, excellent results including complete remissions have been reported with the use of BRAF inhibitors, both as a single agent and when combined with anti-CD20 therapy. The 2 commercially available BRAF inhibitors are vemurafenib and dabrafenib, and both have been tested in relapsed cHCL.^38,39 The first study of vemurafenib was reported by Tiacci and colleagues, who found an overall response rate of 96% after a median of 8 weeks and a 100% response rate after a median of 12 weeks, with complete response rates up to 42%.³⁸ The median relapse-free survival was 23 months (decreasing to only 6 months in patients who achieved only a partial remission), indicating that these agents will likely need to be administered in combination with other effective therapies with non-overlapping toxicities. Vemurafenib has been administered concurrently with rituximab, and preliminary results of this combination therapy showed early rates of complete responses.⁴⁰ Dabrafenib has been reported for use as a single agent in cHCL and clinical trials are underway evaluating its efficacy when administered with trametinib, a MEK inhibitor.^39,41 Of note, patients receiving BRAF inhibitors frequently develop cutaneous complications of RAF inhibition including cutaneous squamous cell carcinomas and keratoacanthomas, and close dermatologic surveillance is required.

Variant HCL does not harbor the BRAF V600E mutation, but up to half of patients have been found to have mutations of MAP2K1, which upregulates MEK1 expression.⁴² Trametinib is approved by the US Food and Drug Administration for the treatment of patients with melanoma at a dose of 2 mg orally daily, and has been successfully used to treat 1 patient with vHCL.⁴³ Further evaluation of this targeted therapy is underway.

Ibrutinib, a Bruton tyrosine kinase inhibitor, and moxetumomab pasudotox, an immunotoxin conjugate, are currently being studied in National Institutes of Health–sponsored multi-institutional trials for patients with HCL. Ibrutinib is administered orally at 420 mg per day until relapse.⁴⁴ Moxetumomab pasudotox was tested at different doses between 5 and 50 μg/kg intravenously every other day for 3 doses for up to 16 cycles unless they experienced disease progression or developed neutralizing antibodies.⁴⁵ Both agents have been shown to have significant activity in cHCL and vHCL and will likely be included in the treatment armamentarium once trials are completed. Second-line therapy options are summarized in Table 4.

Complications and Supportive Care

The complications of HCL may be separated into the pre-, intra-, and post-treatment periods. At the time of diagnosis and prior to the initiation of therapy, marrow infiltration by HCL frequently leads to cytopenias which cause symptomatic anemia, infection, and/or bleeding complications. Many patients develop splenomegaly, which may further lower the blood counts and which is experienced as abdominal fullness or distention, with early satiety leading to weight loss. Patients may also experience constitutional symptoms with fatigue, fevers in the absence of infection, and unintentional weight loss even without splenomegaly.

For patients who initiate therapy with purine nucleoside analogs, the early part of treatment is associated with the greatest risk of morbidity and mortality. Chemotherapy leads to both immunosuppression (altered cellular immunity) as well as myelosuppression. Thus, patients who are already in need of treatment because of disease-related cytopenias will experience an abrupt and sometimes significant decline in the peripheral blood counts. The treatment period prior to recovery of neutrophils requires the greatest vigilance. Because patients are profoundly immunocompromised, febrile neutropenia is a common complication leading to hospital admission and the cause is often difficult to identify. Treatment with broad-spectrum antibiotics, investigation for opportunistic and viral infections, and considerations for antifungal prophylaxis or therapy are required in this setting. It is recommended that all patients treated with purine nucleoside analogs receive prophylactic antimicrobials for herpes simplex virus and varicella zoster virus, as well as prophylaxis against Pneumocystis jirovecii. Unfortunately, growth factor support has not proven successful in this patient population but is not contraindicated.⁴⁶

Following successful completion of therapy, patients may remain functionally immunocompromised for a significant period of time even with a normal neutrophil count. Monitoring of the CD4 count may help to determine when prophylactic antimicrobials may be discontinued. A CD4 count greater than 200 cells/µL is generally considered to be adequate for prevention of opportunistic infections. Although immunizations have not been well studied in HCL, it is recommended that patients receive annual influenza immunizations as well as age-appropriate immunizations against Streptococcus pneumoniae and other infectious illnesses as indicated. Live viral vaccines such as the currently available herpes zoster vaccine can lead to infections in this patient population and are not recommended.

Like many hematologic malignancies, HCL may be associated with comorbid conditions related to immune dysfunction. There is a known association with an increased risk of second primary malignancies, which may predate the diagnosis of HCL.⁴⁷ Therefore, it is recommended that patients continue annual cancer screenings as well as undergo prompt evaluation for potential symptoms of second malignancies. In addition, it is thought that there may be an increased risk for autoimmune disorders such as inflammatory arthritis or immune-mediated cytopenias. One case-control study found a possible association between autoimmune diseases and HCL, noting that at times these diseases are diagnosed concurrently.⁴⁸ However, because of the rarity of the disease it has been difficult to quantify these associated conditions in a systematic way. There is currently an international patient data registry under development for the systematic study of HCL and its complications which may answer many of these questions.

Survivorship and quality of life are important considerations in chronic diseases. It is not uncommon for patients to develop anxiety related to the trauma of diagnosis and treatment, especially when intensive care has been required. Patients may have lingering fears regarding concerns of developing infections due to exposure to ill persons or fears regarding risk of relapse and need for re-treatment. A proactive approach with partnership with psychosocial oncology may be of benefit, especially when symptoms of post-traumatic stress disorder are evident.

Conclusion

HCL is a rare, chronic lymphoid malignancy that is now subclassified into classic and variant HCL. Further investigations into the disease subtypes will allow more precise disease definitions, and these studies are underway. Renewed efforts toward updated risk stratification and clinical staging systems will be important aspects of these investigations. Refinements in treatment and supportive care have resulted in greatly improved overall survival, which has translated into larger numbers of people living with HCL. However, new treatment paradigms for vHCL are needed as the progression-free survival in this disease remains significantly lower than that of cHCL. Future efforts toward understanding survivorship issues and management of long-term treatment and disease-related complications will be critical for ensuring good quality of life for patients living with HCL.

Introduction

Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder, with only approximately 2000 new cases diagnosed in the United States each year.¹ It is now recognized that there are 2 distinct categories of HCL, classic HCL (cHCL) and variant HCL (vHCL), with vHCL now classified as a separate entity under the World Health Organization Classification of Hematopoietic Tumors.² For this reason, the 2 diseases will be discussed separately. However, they do bear many clinical and microscopic similarities and because of this were originally indistinguishable using diagnostic techniques previously available. Even in the modern era using immunophenotypic, molecular, and genetic testing, differentiating between the classic and variant disease subtypes is sometimes difficult.

For cHCL the median age of diagnosis is 55 years, with vHCL occurring in patients who are somewhat older; HCL has been described only in the adult population, with 1 exception.^3,4 There is a 4:1 male predominance, and Caucasians are more frequently affected than other ethnic groups. While the cause of the disease remains largely unknown, it has been observed to occur more frequently in farmers and in persons exposed to pesticides and/or herbicides, petroleum products, and ionizing radiation.⁴ The Institute of Medicine recently updated their position regarding veterans and Agent Orange, stating that there is sufficient evidence of an association between herbicides and chronic lymphoid leukemias (including HCL) to consider these diseases linked to exposure.⁵ Familial forms have also been described that are associated with specific HLA haplotypes, indicating a possible hereditary component.⁶ Most likely, a combination of environmental and genetic factors ultimately contributes to the development of HCL.

In recent years enormous progress has been made with respect to new insights into the biology of cHCL and vHCL, with significant refinement of diagnostic criteria. In addition, tremendous advances have occurred in both treatment and supportive care regimens, which have resulted in a dramatically increased overall life expectancy as well as decreased disease-related morbidity. This has meant that more patients are affected by HCL over time and are more likely to require care for relapsed HCL or associated comorbidities. Although no curative treatment options exist outside of allogeneic transplantation, therapeutic improvements have resulted in patients with cHCL having a life expectancy similar to that of unaffected patients, increasing the need for vigilance to prevent foreseeable complications.

Biology and Patheogenisis

The family of HCLs are chronic B-cell malignancies that account for approximately 2% of all diagnosed leukemias.⁷ The first detailed characterization of HCL as a distinct clinical entity was performed by Dr. Bouroncle and colleagues at the Ohio State University in 1958.⁸ Originally called leukemic reticuloendotheliosis, it was renamed HCL following more detailed description of the unique morphology of these malignant cells.⁹ Significant advances have recently been made in identifying distinctive genetic, immunophenotypic, and morphologic features that distinguish HCL from other B-cell malignancies.

HCL B cells tend to accumulate in the bone marrow, splenic red pulp, and (in some cases) peripheral blood. Unlike other lymphoproliferative disorders, HCL only rarely results in lymphadenopathy. HCL derives its name from the distinct appearance of the malignant hairy cells (Figure). Morphologically, HCL cells are mature, small lymphoid B-cells with a round or oval nucleus and abundant pale blue cytoplasm. Irregular projections of cytoplasm and microvilli give the cells a serrated, “hairy” appearance.¹⁰ The biological significance of these fine hair-like projections remains unknown and is an area of ongoing investigation. Gene expression profiling has revealed that HCL B cells are most similar to splenic marginal zone B cells and memory B cells.^11–13 A recent analysis of common genetic alterations in HCL suggests that the cell of origin is in fact the hematopoietic stem cell.¹⁴

Compared to other hematologic malignancies, the genomic profile of HCL is relatively stable, with few chromosomal defects or translocations observed. A seminal study by Tiacci and colleagues revealed that the BRAF V600E mutation was present in 47 out of 47 cHCL cases examined, results that have since been replicated by other groups, confirming that BRAF V600E is a hallmark mutation in cHCL.¹⁵ The BRAF V600E gain-of-function mutation results in constitutive activation of the serine-threonine protein kinase B-Raf, which regulates the mitogen-activated protein kinase (MAPK)/RAF-MEK-ERK pathway. Indeed, cHCL B cells have elevated MAPK signaling, leading to enhancement of growth and survival.¹⁶ This specific mutation in the BRAF gene is also seen in a number of solid tumor malignancies including melanoma and thyroid cancer, and represents a therapeutic target using BRAF inhibitors already developed to treat these malignancies.¹⁷ Testing for BRAF V600E by polymerase chain reaction or immunohistochemical staining is now routinely performed when HCL is suspected.

While BRAF V600E is identified in nearly all cases of cHCL, it is rare in vHCL.¹⁸ The variant type of HCL was classified as a distinct clinical entity in 2008 and can now often be distinguished from cHCL on the basis of BRAF mutational status, among other differences. Interestingly, in the rare cases of BRAF V600E–negative cHCL, other mutations in BRAF or downstream targets as well as aberrant activation of the RAF-MEK-ERK signaling cascade are observed, indicating that this pathway is critical in HCL and may still represent a viable therapeutic target. Expression of the IGHV4-34 immunoglobulin rearrangement, while more common in vHCL, has also been identified in 10% of cHCL cases and appears to confer poor prognosis.¹⁹ Other mutated genes that have been identified in HCL include CDKN1B, TP53, U2AF1, ARID1A, EZH2, and KDM6A.²⁰

Classic HCL is characterized by the immunophenotypic expression of CD11c, CD25, CD103, and CD123, with kappa or lambda light chain restriction indicating clonality; HCL B cells are generally negative for CD5, CD10, CD23, CD27, and CD79b. In contrast, vHCL often lacks expression of CD25 and CD123.¹⁸ The B-cell receptor (BCR) is expressed on hairy cells and its activation promotes proliferation and survival in vitro.²¹ The role of BCR signaling in B-cell malignancies is increasingly recognized, and therapies that target the BCR and associated signaling molecules offer an attractive treatment strategy.²² HCL B cells also typically express CD19, CD20, CD22, CD79a, CD200, CD1d, and annexin A1. Tartrate-resistant acid phosphatase (TRAP) positivity by immunohistochemistry is a hallmark of cHCL. Interestingly, changes to the patient’s original immunophenotype have been observed following treatment and upon disease recurrence, highlighting the importance of tracking immunophenotype throughout the course of disease.

Diagnosis

Prior to the advent of annual screening evaluations with routine examination of complete blood counts (CBC), patients were most often diagnosed with HCL when they presented with symptoms of the disease such as splenomegaly, infections, or complications of anemia or thrombocytopenia.²³ In the current era, patients are more likely to be incidentally diagnosed when they are found to have an abnormal value on a CBC. Any blood lineage may be affected and patients may have pancytopenia or isolated cytopenias. Of note, monocytopenia is a common finding in cHCL that is not entirely understood. The cells typical of cHCL do not usually circulate in the peripheral blood, but if present would appear as mature lymphocytes with villous cytoplasmic projections, pale blue cytoplasm, and reniform nuclei with open chromatin (Figure).⁹ Even if the morphologic examination is highly suggestive of HCL, additional testing is required to differentiate between cHCL, vHCL, and other hematologic malignancies which may also have cytoplasmic projections. A complete assessment of the immunophenotype, molecular profile, and cytogenetic features is required to arrive at this diagnosis.

The international Hairy Cell Leukemia Foundation recently published consensus guidelines for the diagnosis and treatment of HCL.²⁴ These guidelines recommend that patients undergo examination of the peripheral blood for morphology and immunophenotyping and further recommend obtaining bone marrow core and aspirate biopsy samples for immunophenotyping via immunohistochemical staining and flow cytometry. The characteristic immunophenotype of cHCL is a population of monoclonal B lymphocytes which co-express CD19, CD20, CD11c, CD25, CD103, and CD123. Variant HCL is characterized by a very similar immunophenotype but is usually negative for CD25 and CD123. It is notable that CD25 positivity may be lost following treatment, and the absence of this marker should not be used as the sole basis of a cHCL versus vHCL diagnosis. Because marrow fibrosis in HCL may prevent a marrow aspirate from being obtained, many of the key diagnostic studies are performed on the core biopsy, including morphological evaluation and immunohistochemical stains such as CD20 (a pan-B cell antigen), annexin-1 (an anti-inflammatory protein expressed only in cHCL), and VE1 (a BRAF V600E stain).

As noted above, recurrent cytogenetic abnormalities have now been identified that may inform the diagnosis or prognosis of HCL. Next-generation sequencing and other testing of the genetic landscape are taking on a larger role in subtype differentiation, and it is likely that future guidelines will recommend evaluation for significant mutations. Given that BRAF V600E mutation status is a key feature of cHCL and is absent in vHCL, it is important to perform this testing at the time of diagnosis whenever possible. The mutation may be detected via VE1 immunohistochemical staining, allele-specific polymerase chain reaction, or next-generation sequencing. Other less sensitive tests exist but are utilized less frequently.

Minimal Residual Disease

There is currently no accepted standard for minimal residual disease (MRD) monitoring in HCL. While detection of MRD has been clearly associated with increased risk of disease progression, cHCL cells typically do not circulate in the peripheral blood, limiting the use of peripheral blood immunophenotyping for quantitative MRD assessment. For quantitative monitoring of marrow involvement by HCL, immunohistochemical staining of the bone marrow core biopsy is usually required. Staining may be performed for CD20, or, in patients who have received anti-CD20 therapy, DBA.44, VE-1, or CD79a. There is currently not a consensus regarding what level of disease involvement constitutes MRD. One group studied this issue and found that relapse could be predicted by evaluating MRD by percentage of positive cells in the marrow by immunohistochemical staining, with less than 1% involvement having the lowest risk for disease relapse and greater than 5% having the highest risk for disease relapse.²⁵ A recent study evaluated MRD patterns in the peripheral blood of 32 cHCL patients who had completed frontline therapy. This group performed flow cytometry on the peripheral blood of patients at 1, 3, 6, and 12 months following therapy. All patients had achieved a complete response with initial therapy and peripheral blood MRD negativity at the completion of therapy. At a median follow-up of 100 months post therapy, 5 patients converted from peripheral blood–MRD negative to peripheral blood–MRD positive, and 6 patients developed overt disease progression. In all patients who progressed, progression was preceded by an increase in detectable peripheral blood MRD cells.²⁶ Although larger studies are needed, peripheral blood flow cytometric monitoring for MRD may be a useful adjunct to predict ongoing response or impending relapse. In addition, newer, more sensitive methods of disease monitoring may ultimately supplant flow cytometry.

Risk Stratification

Although much progress has been made in the risk stratification profiling of hematologic malignancies in general, HCL has unfortunately lagged behind in this effort. The most recent risk stratification analysis was performed in 1982 by Jansen and colleagues.²⁷ This group of researchers performed a retrospective analysis of 391 HCL patients treated at 22 centers. One of the central questions in their analysis was survival time from diagnosis in patients who had not yet undergone splenectomy (a standard treatment at the time). This group consisted of a total of 154 patients. As this study predated modern pathological and molecular testing, clinical and laboratory features were examined, and these mostly consisted of physical exam findings and analysis of the peripheral blood. This group found that several factors influenced the survival of these patients, including duration of symptoms prior to diagnosis, the degree of splenomegaly, hemoglobin level, and number of hairy cells in the peripheral blood. However, because of interobserver variation for the majority of these variables, only hemoglobin and spleen size were included in the proportional hazard model. Using only these 2 variables, the authors were able to determine 3 clinical stages for HCL (Table 1). The stages were found to correlate with median survival: patients with stage 1 disease had a median survival not reached at 72 months, but patients with stage 2 disease had a median survival of 18 months, which decreased to only 12 months in patients with stage 3 disease.

Because the majority of patients with HCL in the modern era will be diagnosed prior to reaching stage 3, a risk stratification system incorporating clinical features, laboratory parameters, and molecular and genetic testing is of considerable interest and is a subject of ongoing research. Ultimately, the goal will be to identify patients at higher risk of early relapse so that more intensive therapies can be applied to initial treatment that will result in longer treatment-free intervals.

Treatment

Because there is no curative treatment for either cHCL or vHCL outside allogeneic transplantation, and it is not clear that early treatment leads to better outcomes in HCL, patients do not always receive treatment at the time of diagnosis or relapse. The general consensus is that patients should be treated if there is a declining trend in hematologic parameters or they experience symptoms from the disease.²⁴ Current consensus guidelines recommend treatment when any of the following hematologic parameters are met: hemoglobin less than 11 g/dL, platelet count less than 100 × 10³/µL, or absolute neutrophil count less than 1000/µL.²⁴ These parameters are surrogate markers that indicate compromised bone marrow function. Cytopenias may also be caused by splenomegaly, and symptomatic splenomegaly with or without cytopenias is an indication for treatment. A small number of patients with HCL (approximately 10%) do not require immediate therapy after diagnosis and are monitored by their provider until treatment is indicated.

First-Line Therapy

Despite advances in targeted therapies for HCL, because no treatment has been shown to extend the treatment-free interval longer than chemotherapy, treatment with a purine nucleoside analog is usually the recommended first-line therapy. This includes either cladribine or pentostatin. Both agents appear to be equally effective, and the choice of therapy is determined by the treating physician based on his or her experience. Cladribine administration has been studied using a number of different schedules and routes: intravenous continuous infusion (0.1 mg/kg) for 7 days, intravenous infusion (0.14 mg/kg/day) over 2 hours on a 5-day regimen, or alternatively subcutaneously (0.1–0.14 mg/kg/day) on a once-per-day or once-per-week regimen (Table 2).^28,29

Unlike cHCL, vHCL remains difficult to treat and early disease progression is common. The best outcomes have been seen in patients who have received combination chemo-immunotherapy such as purine nucleoside analog therapy plus rituximab or bendamustine plus rituximab.³¹ One pilot study of bendamustine plus rituximab in 12 patients found an overall response rate of 100%, with the majority of patients achieving a complete response.³¹ For patients who achieved a complete response, the median duration of response had not been reached, but patients achieving only a partial response had a median duration of response of only 20 months, indicating there is a subgroup of patients who will require a different treatment approach.³² A randomized phase 2 trial of rituximab with either pentostatin or bendamustine is ongoing.³³

Assessment of Response

Response assessment involves physical examination for estimation of spleen size, assessment of hematologic parameters, and a bone marrow biopsy for evaluation of marrow response. It is recommended that the bone marrow biopsy be performed 4 to 6 months following cladribine administration, or after completion of 12 doses of pentostatin. Detailed response assessment criteria are shown in Table 3.

Second-Line Therapy

Although the majority of patients treated with purine analogs will achieve durable remissions, approximately 40% of patients will eventually require second-line therapy. Criteria for treatment at relapse are the same as the criteria for initial therapy, including symptomatic disease or progressive anemia, thrombocytopenia, or neutropenia. The choice of treatment is based on clinical parameters and the duration of the previous remission. If the initial remission was longer than 65 months and the patient is eligible to receive chemotherapy, re-treatment with initial therapy is recommended. For a remission between 24 and 65 months, re-treatment with a purine analog combined with an anti-CD20 monoclonal antibody may be considered.³⁴ If the first remission is shorter than 24 months, confirmation of the original diagnosis as well as consideration for testing for additional mutations with therapeutic targets (BRAF V600E, MAP2K1) should be considered before a treatment decision is made. For these patients, alternative therapies, including investigational agents, should be considered.²⁴

Monoclonal antibody therapy has been studied in both the up-front setting and in relapsed or refractory HCL.³⁵ An initial study of 15 patients with relapsed HCL found an overall response rate of 80%, with 8 patients achieving a complete response. A subsequent study of 26 patients who relapsed after cladribine therapy found an overall response rate of 80%, with a complete response rate of 32%. Median relapse-free survival was 27 months.³⁶ Ravandi and others studied rituximab in the up-front setting in combination with cladribine, and found an overall response rate of 100%, including in patients with vHCL. At the time of publication of the study results, the median survival had not been reached.³⁷ As has been seen with other lymphoid malignancies, concurrent therapy with rituximab appears to enhance the activity of the agent with which it is combined. While its use in the up-front setting remains an area of active investigation, there is a clear role for chemo-immunotherapy in the relapsed setting.

In patients with cHCL, excellent results including complete remissions have been reported with the use of BRAF inhibitors, both as a single agent and when combined with anti-CD20 therapy. The 2 commercially available BRAF inhibitors are vemurafenib and dabrafenib, and both have been tested in relapsed cHCL.^38,39 The first study of vemurafenib was reported by Tiacci and colleagues, who found an overall response rate of 96% after a median of 8 weeks and a 100% response rate after a median of 12 weeks, with complete response rates up to 42%.³⁸ The median relapse-free survival was 23 months (decreasing to only 6 months in patients who achieved only a partial remission), indicating that these agents will likely need to be administered in combination with other effective therapies with non-overlapping toxicities. Vemurafenib has been administered concurrently with rituximab, and preliminary results of this combination therapy showed early rates of complete responses.⁴⁰ Dabrafenib has been reported for use as a single agent in cHCL and clinical trials are underway evaluating its efficacy when administered with trametinib, a MEK inhibitor.^39,41 Of note, patients receiving BRAF inhibitors frequently develop cutaneous complications of RAF inhibition including cutaneous squamous cell carcinomas and keratoacanthomas, and close dermatologic surveillance is required.

Variant HCL does not harbor the BRAF V600E mutation, but up to half of patients have been found to have mutations of MAP2K1, which upregulates MEK1 expression.⁴² Trametinib is approved by the US Food and Drug Administration for the treatment of patients with melanoma at a dose of 2 mg orally daily, and has been successfully used to treat 1 patient with vHCL.⁴³ Further evaluation of this targeted therapy is underway.

Ibrutinib, a Bruton tyrosine kinase inhibitor, and moxetumomab pasudotox, an immunotoxin conjugate, are currently being studied in National Institutes of Health–sponsored multi-institutional trials for patients with HCL. Ibrutinib is administered orally at 420 mg per day until relapse.⁴⁴ Moxetumomab pasudotox was tested at different doses between 5 and 50 μg/kg intravenously every other day for 3 doses for up to 16 cycles unless they experienced disease progression or developed neutralizing antibodies.⁴⁵ Both agents have been shown to have significant activity in cHCL and vHCL and will likely be included in the treatment armamentarium once trials are completed. Second-line therapy options are summarized in Table 4.

Complications and Supportive Care

The complications of HCL may be separated into the pre-, intra-, and post-treatment periods. At the time of diagnosis and prior to the initiation of therapy, marrow infiltration by HCL frequently leads to cytopenias which cause symptomatic anemia, infection, and/or bleeding complications. Many patients develop splenomegaly, which may further lower the blood counts and which is experienced as abdominal fullness or distention, with early satiety leading to weight loss. Patients may also experience constitutional symptoms with fatigue, fevers in the absence of infection, and unintentional weight loss even without splenomegaly.

For patients who initiate therapy with purine nucleoside analogs, the early part of treatment is associated with the greatest risk of morbidity and mortality. Chemotherapy leads to both immunosuppression (altered cellular immunity) as well as myelosuppression. Thus, patients who are already in need of treatment because of disease-related cytopenias will experience an abrupt and sometimes significant decline in the peripheral blood counts. The treatment period prior to recovery of neutrophils requires the greatest vigilance. Because patients are profoundly immunocompromised, febrile neutropenia is a common complication leading to hospital admission and the cause is often difficult to identify. Treatment with broad-spectrum antibiotics, investigation for opportunistic and viral infections, and considerations for antifungal prophylaxis or therapy are required in this setting. It is recommended that all patients treated with purine nucleoside analogs receive prophylactic antimicrobials for herpes simplex virus and varicella zoster virus, as well as prophylaxis against Pneumocystis jirovecii. Unfortunately, growth factor support has not proven successful in this patient population but is not contraindicated.⁴⁶

Following successful completion of therapy, patients may remain functionally immunocompromised for a significant period of time even with a normal neutrophil count. Monitoring of the CD4 count may help to determine when prophylactic antimicrobials may be discontinued. A CD4 count greater than 200 cells/µL is generally considered to be adequate for prevention of opportunistic infections. Although immunizations have not been well studied in HCL, it is recommended that patients receive annual influenza immunizations as well as age-appropriate immunizations against Streptococcus pneumoniae and other infectious illnesses as indicated. Live viral vaccines such as the currently available herpes zoster vaccine can lead to infections in this patient population and are not recommended.

Like many hematologic malignancies, HCL may be associated with comorbid conditions related to immune dysfunction. There is a known association with an increased risk of second primary malignancies, which may predate the diagnosis of HCL.⁴⁷ Therefore, it is recommended that patients continue annual cancer screenings as well as undergo prompt evaluation for potential symptoms of second malignancies. In addition, it is thought that there may be an increased risk for autoimmune disorders such as inflammatory arthritis or immune-mediated cytopenias. One case-control study found a possible association between autoimmune diseases and HCL, noting that at times these diseases are diagnosed concurrently.⁴⁸ However, because of the rarity of the disease it has been difficult to quantify these associated conditions in a systematic way. There is currently an international patient data registry under development for the systematic study of HCL and its complications which may answer many of these questions.

Survivorship and quality of life are important considerations in chronic diseases. It is not uncommon for patients to develop anxiety related to the trauma of diagnosis and treatment, especially when intensive care has been required. Patients may have lingering fears regarding concerns of developing infections due to exposure to ill persons or fears regarding risk of relapse and need for re-treatment. A proactive approach with partnership with psychosocial oncology may be of benefit, especially when symptoms of post-traumatic stress disorder are evident.

Conclusion

HCL is a rare, chronic lymphoid malignancy that is now subclassified into classic and variant HCL. Further investigations into the disease subtypes will allow more precise disease definitions, and these studies are underway. Renewed efforts toward updated risk stratification and clinical staging systems will be important aspects of these investigations. Refinements in treatment and supportive care have resulted in greatly improved overall survival, which has translated into larger numbers of people living with HCL. However, new treatment paradigms for vHCL are needed as the progression-free survival in this disease remains significantly lower than that of cHCL. Future efforts toward understanding survivorship issues and management of long-term treatment and disease-related complications will be critical for ensuring good quality of life for patients living with HCL.

Introduction

Over the past several decades, while the incidence of breast cancer has increased, breast cancer mortality has decreased. This decrease is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns about potential overdiagnosis of cancer.¹ One key challenge is that breast cancer is a heterogeneous disease. Improved tools for determining breast cancer biology can help physicians individualize treatments. Patients with low-risk cancers can be approached with less aggressive treatments, thus preventing unnecessary toxicities, while those with higher-risk cancers remain treated appropriately with more aggressive therapies.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment approaches, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, women with low-risk hormone receptor (HR)–positive, HER2-negative breast cancers could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given over extended periods of time. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the National Cancer Institute of Canada Clinical Trials Group’s MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34%.² However, the overall survival was similar between the 2 groups and the disease-free survival benefits were not confirmed in other studies.^3–5 Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple-negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Tests for Guiding Adjuvant Chemotherapy Decisions

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2-negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy recommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. HR-positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for patients with HR-positive breast cancer,⁶ the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B.⁷ These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors.⁸ Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

Ki-67 Assays, Including IHC4 and PEPI

Proliferation is a hallmark of cancer cells.⁹ Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation.¹⁰ Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates.^11,12 Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang and colleagues determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors.¹³ However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This immunohistochemical 4 (IHC4) score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy.¹⁴ The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology and intra-observer variability in interpreting the Ki-67 results.¹⁵ Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point.¹⁶ These issues continue to impact the clinical utility of Ki-67 for decision-making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease.¹⁷ The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial¹⁸ to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. The score was subsequently validated in an independent data set from the IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial.¹⁹ Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors that are higher risk for early relapse.²⁰ The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Onco type DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer related genes and 5 reference genes using quantitative polymerase chain reaction (PCR). The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling.²¹ Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy.²² Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival.²¹ Inferior breast cancer survival in cancers with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease.^23–25

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores.²⁶ However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low or intermediate risk did not have an improved freedom from distant recurrence with chemotherapy.²⁷ Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores.²⁴

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive/HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard-of-care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to chemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98%.²⁸ Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score,²⁴ due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like.^7,29 Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials.^30,31 In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy.³⁰ The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5%, indicating lack of benefit from additional chemotherapy.³¹ A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis.³² Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy.³³ Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results.³⁴ In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue.³⁵

Summary

These genomic and biomarker assays can identify different subsets of HR-positive breast cancers, including those patients who have tumors with an excellent prognosis with endocrine therapies alone. Thus, we now have the tools to help avoid the toxicities of chemotherapy in many women with early-stage breast cancer.

Tests for Assessing Risk for Late Recurrence

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemotherapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole.⁴¹ She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer.⁴² Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease.⁴³ Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care.⁴⁴ AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen.⁴⁵

Due to the risk for later recurrences with HR-positive breast cancer, more patients and oncologists are considering extended endocrine therapy. This is based on results from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTOM (Adjuvant Tamoxifen–To Offer More?) studies, both of which showed that women with HR-positive breast cancer who continued tamoxifen for 10 years had a lower late recurrence rate and a lower breast cancer mortality rate compared with those who stopped at 5 years.^46,47 Furthermore, the NCIC MA.17 trial evaluated extended endocrine therapy in postmenopausal women with 5 years of letrozole following 5 years of tamoxifen. Letrozole was shown to improve both disease-free and distant disease-free survival. The overall survival benefit was limited to patients with node-positive disease.⁴⁸ A summary of studies of extended endocrine therapy for HR-positive breast cancers is shown in Table 2.^2,3,46–49

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66, P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference.² Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years.³ Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group.⁵⁰ Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse.⁵¹

EndoPredict

EndoPredict is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EndoPredict low- and high-risk groups. EndoPredict has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive/HER2-negative early breast cancer.³⁷ More important, EndoPredict has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy.⁵² Recently, EndoPredict and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EndoPredict and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events.⁵³ EndoPredict is the first multigene expression assay that could be routinely performed in decentralized molecular pathological laboratories with a short turnaround time.⁵⁴

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial.³⁸ In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%).³⁸

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease.^39,55 The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence.⁵⁶ BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence.⁴⁰

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety.⁵⁷

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays has been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10, which is consistent with a low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patients’ compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple-negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Introduction

Over the past several decades, while the incidence of breast cancer has increased, breast cancer mortality has decreased. This decrease is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns about potential overdiagnosis of cancer.¹ One key challenge is that breast cancer is a heterogeneous disease. Improved tools for determining breast cancer biology can help physicians individualize treatments. Patients with low-risk cancers can be approached with less aggressive treatments, thus preventing unnecessary toxicities, while those with higher-risk cancers remain treated appropriately with more aggressive therapies.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment approaches, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, women with low-risk hormone receptor (HR)–positive, HER2-negative breast cancers could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given over extended periods of time. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the National Cancer Institute of Canada Clinical Trials Group’s MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34%.² However, the overall survival was similar between the 2 groups and the disease-free survival benefits were not confirmed in other studies.^3–5 Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple-negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Tests for Guiding Adjuvant Chemotherapy Decisions

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2-negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy recommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. HR-positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for patients with HR-positive breast cancer,⁶ the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B.⁷ These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors.⁸ Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

Ki-67 Assays, Including IHC4 and PEPI

Proliferation is a hallmark of cancer cells.⁹ Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation.¹⁰ Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates.^11,12 Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang and colleagues determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors.¹³ However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This immunohistochemical 4 (IHC4) score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy.¹⁴ The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology and intra-observer variability in interpreting the Ki-67 results.¹⁵ Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point.¹⁶ These issues continue to impact the clinical utility of Ki-67 for decision-making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease.¹⁷ The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial¹⁸ to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. The score was subsequently validated in an independent data set from the IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial.¹⁹ Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors that are higher risk for early relapse.²⁰ The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Onco type DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer related genes and 5 reference genes using quantitative polymerase chain reaction (PCR). The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling.²¹ Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy.²² Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival.²¹ Inferior breast cancer survival in cancers with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease.^23–25

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores.²⁶ However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low or intermediate risk did not have an improved freedom from distant recurrence with chemotherapy.²⁷ Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores.²⁴

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive/HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard-of-care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to chemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98%.²⁸ Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score,²⁴ due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like.^7,29 Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials.^30,31 In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy.³⁰ The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5%, indicating lack of benefit from additional chemotherapy.³¹ A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis.³² Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy.³³ Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results.³⁴ In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue.³⁵

Summary

These genomic and biomarker assays can identify different subsets of HR-positive breast cancers, including those patients who have tumors with an excellent prognosis with endocrine therapies alone. Thus, we now have the tools to help avoid the toxicities of chemotherapy in many women with early-stage breast cancer.

Tests for Assessing Risk for Late Recurrence

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemotherapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole.⁴¹ She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer.⁴² Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease.⁴³ Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care.⁴⁴ AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen.⁴⁵

Due to the risk for later recurrences with HR-positive breast cancer, more patients and oncologists are considering extended endocrine therapy. This is based on results from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTOM (Adjuvant Tamoxifen–To Offer More?) studies, both of which showed that women with HR-positive breast cancer who continued tamoxifen for 10 years had a lower late recurrence rate and a lower breast cancer mortality rate compared with those who stopped at 5 years.^46,47 Furthermore, the NCIC MA.17 trial evaluated extended endocrine therapy in postmenopausal women with 5 years of letrozole following 5 years of tamoxifen. Letrozole was shown to improve both disease-free and distant disease-free survival. The overall survival benefit was limited to patients with node-positive disease.⁴⁸ A summary of studies of extended endocrine therapy for HR-positive breast cancers is shown in Table 2.^2,3,46–49

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66, P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference.² Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years.³ Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group.⁵⁰ Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse.⁵¹

EndoPredict

EndoPredict is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EndoPredict low- and high-risk groups. EndoPredict has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive/HER2-negative early breast cancer.³⁷ More important, EndoPredict has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy.⁵² Recently, EndoPredict and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EndoPredict and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events.⁵³ EndoPredict is the first multigene expression assay that could be routinely performed in decentralized molecular pathological laboratories with a short turnaround time.⁵⁴

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial.³⁸ In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%).³⁸

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease.^39,55 The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence.⁵⁶ BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence.⁴⁰

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety.⁵⁷

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays has been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10, which is consistent with a low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patients’ compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple-negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Introduction

Over the past several decades, while the incidence of breast cancer has increased, breast cancer mortality has decreased. This decrease is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns about potential overdiagnosis of cancer.¹ One key challenge is that breast cancer is a heterogeneous disease. Improved tools for determining breast cancer biology can help physicians individualize treatments. Patients with low-risk cancers can be approached with less aggressive treatments, thus preventing unnecessary toxicities, while those with higher-risk cancers remain treated appropriately with more aggressive therapies.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment approaches, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, women with low-risk hormone receptor (HR)–positive, HER2-negative breast cancers could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given over extended periods of time. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the National Cancer Institute of Canada Clinical Trials Group’s MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34%.² However, the overall survival was similar between the 2 groups and the disease-free survival benefits were not confirmed in other studies.^3–5 Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple-negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Tests for Guiding Adjuvant Chemotherapy Decisions

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2-negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy recommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. HR-positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for patients with HR-positive breast cancer,⁶ the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B.⁷ These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors.⁸ Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

Ki-67 Assays, Including IHC4 and PEPI

Proliferation is a hallmark of cancer cells.⁹ Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation.¹⁰ Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates.^11,12 Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang and colleagues determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors.¹³ However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This immunohistochemical 4 (IHC4) score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy.¹⁴ The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology and intra-observer variability in interpreting the Ki-67 results.¹⁵ Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point.¹⁶ These issues continue to impact the clinical utility of Ki-67 for decision-making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease.¹⁷ The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial¹⁸ to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. The score was subsequently validated in an independent data set from the IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial.¹⁹ Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors that are higher risk for early relapse.²⁰ The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Onco type DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer related genes and 5 reference genes using quantitative polymerase chain reaction (PCR). The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling.²¹ Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy.²² Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival.²¹ Inferior breast cancer survival in cancers with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease.^23–25

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores.²⁶ However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low or intermediate risk did not have an improved freedom from distant recurrence with chemotherapy.²⁷ Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores.²⁴

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive/HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard-of-care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to chemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98%.²⁸ Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score,²⁴ due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like.^7,29 Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials.^30,31 In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy.³⁰ The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5%, indicating lack of benefit from additional chemotherapy.³¹ A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis.³² Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy.³³ Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results.³⁴ In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue.³⁵

Summary

These genomic and biomarker assays can identify different subsets of HR-positive breast cancers, including those patients who have tumors with an excellent prognosis with endocrine therapies alone. Thus, we now have the tools to help avoid the toxicities of chemotherapy in many women with early-stage breast cancer.

Tests for Assessing Risk for Late Recurrence

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemotherapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole.⁴¹ She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer.⁴² Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease.⁴³ Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care.⁴⁴ AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen.⁴⁵

Due to the risk for later recurrences with HR-positive breast cancer, more patients and oncologists are considering extended endocrine therapy. This is based on results from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTOM (Adjuvant Tamoxifen–To Offer More?) studies, both of which showed that women with HR-positive breast cancer who continued tamoxifen for 10 years had a lower late recurrence rate and a lower breast cancer mortality rate compared with those who stopped at 5 years.^46,47 Furthermore, the NCIC MA.17 trial evaluated extended endocrine therapy in postmenopausal women with 5 years of letrozole following 5 years of tamoxifen. Letrozole was shown to improve both disease-free and distant disease-free survival. The overall survival benefit was limited to patients with node-positive disease.⁴⁸ A summary of studies of extended endocrine therapy for HR-positive breast cancers is shown in Table 2.^2,3,46–49

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66, P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference.² Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years.³ Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group.⁵⁰ Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse.⁵¹

EndoPredict

EndoPredict is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EndoPredict low- and high-risk groups. EndoPredict has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive/HER2-negative early breast cancer.³⁷ More important, EndoPredict has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy.⁵² Recently, EndoPredict and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EndoPredict and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events.⁵³ EndoPredict is the first multigene expression assay that could be routinely performed in decentralized molecular pathological laboratories with a short turnaround time.⁵⁴

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial.³⁸ In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%).³⁸

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease.^39,55 The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence.⁵⁶ BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence.⁴⁰

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety.⁵⁷

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays has been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10, which is consistent with a low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patients’ compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple-negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.