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Follow-up shows favorable results with acalabrutinib in MCL
Acalabrutinib monotherapy can produce durable responses in relapsed/refractory mantle cell lymphoma (MCL), according to updated results from a phase 2 trial.
The drug produced an overall response rate (ORR) of 81%, and the median duration of response was 26 months.
These are the highest such figures reported “among all approved single-agent therapies for the treatment of relapsed/refractory MCL,” Michael Wang, MD, of the MD Anderson Cancer Center at the University of Texas in Houston and colleagues wrote in a letter in Leukemia.
Dr. Wang and colleagues reported updated results in 124 patients treated on the ACE-LY-004 trial. At baseline, the patients had a median age of 68 years (range, 42-90 years), and 80% were men. Three-quarters of patients had stage IV disease, 72% had extranodal disease, 21% had blastoid/pleomorphic MCL, and 26% had a Ki-67 proliferation index of 50% or greater.
At a median follow-up of 26 months, 40% (n = 49) of patients were still on acalabrutinib, and 61% (n = 76) were still in follow-up for survival. Six patients went on to allogeneic transplant at a median of 19 days after stopping acalabrutinib.
The ORR was 81% (100/124), and the complete response (CR) rate was 43% (n = 53). Four patients who initially had a partial response converted to a CR with longer follow-up. The estimated 24-month duration of response was 52.4%.
“ORR was consistent across patients with refractory disease and those with blastoid/pleomorphic MCL, despite those patients having a higher mean Ki-67 index [of 50% or greater], suggesting that some patients with poorer prognosis may also benefit from acalabrutinib,” Dr. Wang and colleagues wrote.
There were 29 patients evaluable for minimal residual disease (MRD) assessment. Seven patients (24%) had MRD-negative disease in the peripheral blood after they achieved a CR. An additional patient with a CR became MRD negative when a second blood sample was taken about 6 months after the first.
“Despite limited samples, these results demonstrate that continued use of acalabrutinib can lead to undetectable MRD in patients with CR,” Dr. Wang and his colleagues wrote. “Since most patients with MRD data are still on treatment (27/29), relationships between MRD negativity and durability of response cannot be made at this time.”
The median progression-free survival was 20 months, and the median overall survival was not reached. The estimated 24-month progression-free survival rate was 49.0%, and the estimated 24-month overall survival rate was 72.4%. Patients with low/intermediate Mantle Cell Lymphoma International Prognostic Index scores, classical MCL, and a Ki-67 index less than 50% had a longer duration of response and survival.
The adverse event profile was “largely consistent with earlier reporting,” Dr. Wang and colleagues wrote. The most frequent adverse events were headache (38%), diarrhea (36%), fatigue (28%), cough (22%), and myalgia (21%). The most common grade 3/4 adverse events were anemia (10%), neutropenia (10%), and pneumonia (6%).
Ten patients developed second primary cancers. There were no new atrial fibrillation events and no new hypertension events. The frequency of infections decreased over time, as did the number of bleeding events. However, two of three major hemorrhage events occurred after the previous report was published.
There were 43 deaths (35%), 29 of them because of disease progression. Six patients died of adverse events, two died of unknown causes, and two died of secondary acute myeloid leukemia. Other causes of death included multiorgan failure, intestinal obstruction, lung cancer, and graft-versus-host disease.
This study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The researchers reported relationships with AstraZeneca/Acerta Pharma and many other companies.
SOURCE: Wang M et al. Leukemia. 2019 Sep 26. doi: 10.1038/s41375-019-0575-9.
Acalabrutinib monotherapy can produce durable responses in relapsed/refractory mantle cell lymphoma (MCL), according to updated results from a phase 2 trial.
The drug produced an overall response rate (ORR) of 81%, and the median duration of response was 26 months.
These are the highest such figures reported “among all approved single-agent therapies for the treatment of relapsed/refractory MCL,” Michael Wang, MD, of the MD Anderson Cancer Center at the University of Texas in Houston and colleagues wrote in a letter in Leukemia.
Dr. Wang and colleagues reported updated results in 124 patients treated on the ACE-LY-004 trial. At baseline, the patients had a median age of 68 years (range, 42-90 years), and 80% were men. Three-quarters of patients had stage IV disease, 72% had extranodal disease, 21% had blastoid/pleomorphic MCL, and 26% had a Ki-67 proliferation index of 50% or greater.
At a median follow-up of 26 months, 40% (n = 49) of patients were still on acalabrutinib, and 61% (n = 76) were still in follow-up for survival. Six patients went on to allogeneic transplant at a median of 19 days after stopping acalabrutinib.
The ORR was 81% (100/124), and the complete response (CR) rate was 43% (n = 53). Four patients who initially had a partial response converted to a CR with longer follow-up. The estimated 24-month duration of response was 52.4%.
“ORR was consistent across patients with refractory disease and those with blastoid/pleomorphic MCL, despite those patients having a higher mean Ki-67 index [of 50% or greater], suggesting that some patients with poorer prognosis may also benefit from acalabrutinib,” Dr. Wang and colleagues wrote.
There were 29 patients evaluable for minimal residual disease (MRD) assessment. Seven patients (24%) had MRD-negative disease in the peripheral blood after they achieved a CR. An additional patient with a CR became MRD negative when a second blood sample was taken about 6 months after the first.
“Despite limited samples, these results demonstrate that continued use of acalabrutinib can lead to undetectable MRD in patients with CR,” Dr. Wang and his colleagues wrote. “Since most patients with MRD data are still on treatment (27/29), relationships between MRD negativity and durability of response cannot be made at this time.”
The median progression-free survival was 20 months, and the median overall survival was not reached. The estimated 24-month progression-free survival rate was 49.0%, and the estimated 24-month overall survival rate was 72.4%. Patients with low/intermediate Mantle Cell Lymphoma International Prognostic Index scores, classical MCL, and a Ki-67 index less than 50% had a longer duration of response and survival.
The adverse event profile was “largely consistent with earlier reporting,” Dr. Wang and colleagues wrote. The most frequent adverse events were headache (38%), diarrhea (36%), fatigue (28%), cough (22%), and myalgia (21%). The most common grade 3/4 adverse events were anemia (10%), neutropenia (10%), and pneumonia (6%).
Ten patients developed second primary cancers. There were no new atrial fibrillation events and no new hypertension events. The frequency of infections decreased over time, as did the number of bleeding events. However, two of three major hemorrhage events occurred after the previous report was published.
There were 43 deaths (35%), 29 of them because of disease progression. Six patients died of adverse events, two died of unknown causes, and two died of secondary acute myeloid leukemia. Other causes of death included multiorgan failure, intestinal obstruction, lung cancer, and graft-versus-host disease.
This study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The researchers reported relationships with AstraZeneca/Acerta Pharma and many other companies.
SOURCE: Wang M et al. Leukemia. 2019 Sep 26. doi: 10.1038/s41375-019-0575-9.
Acalabrutinib monotherapy can produce durable responses in relapsed/refractory mantle cell lymphoma (MCL), according to updated results from a phase 2 trial.
The drug produced an overall response rate (ORR) of 81%, and the median duration of response was 26 months.
These are the highest such figures reported “among all approved single-agent therapies for the treatment of relapsed/refractory MCL,” Michael Wang, MD, of the MD Anderson Cancer Center at the University of Texas in Houston and colleagues wrote in a letter in Leukemia.
Dr. Wang and colleagues reported updated results in 124 patients treated on the ACE-LY-004 trial. At baseline, the patients had a median age of 68 years (range, 42-90 years), and 80% were men. Three-quarters of patients had stage IV disease, 72% had extranodal disease, 21% had blastoid/pleomorphic MCL, and 26% had a Ki-67 proliferation index of 50% or greater.
At a median follow-up of 26 months, 40% (n = 49) of patients were still on acalabrutinib, and 61% (n = 76) were still in follow-up for survival. Six patients went on to allogeneic transplant at a median of 19 days after stopping acalabrutinib.
The ORR was 81% (100/124), and the complete response (CR) rate was 43% (n = 53). Four patients who initially had a partial response converted to a CR with longer follow-up. The estimated 24-month duration of response was 52.4%.
“ORR was consistent across patients with refractory disease and those with blastoid/pleomorphic MCL, despite those patients having a higher mean Ki-67 index [of 50% or greater], suggesting that some patients with poorer prognosis may also benefit from acalabrutinib,” Dr. Wang and colleagues wrote.
There were 29 patients evaluable for minimal residual disease (MRD) assessment. Seven patients (24%) had MRD-negative disease in the peripheral blood after they achieved a CR. An additional patient with a CR became MRD negative when a second blood sample was taken about 6 months after the first.
“Despite limited samples, these results demonstrate that continued use of acalabrutinib can lead to undetectable MRD in patients with CR,” Dr. Wang and his colleagues wrote. “Since most patients with MRD data are still on treatment (27/29), relationships between MRD negativity and durability of response cannot be made at this time.”
The median progression-free survival was 20 months, and the median overall survival was not reached. The estimated 24-month progression-free survival rate was 49.0%, and the estimated 24-month overall survival rate was 72.4%. Patients with low/intermediate Mantle Cell Lymphoma International Prognostic Index scores, classical MCL, and a Ki-67 index less than 50% had a longer duration of response and survival.
The adverse event profile was “largely consistent with earlier reporting,” Dr. Wang and colleagues wrote. The most frequent adverse events were headache (38%), diarrhea (36%), fatigue (28%), cough (22%), and myalgia (21%). The most common grade 3/4 adverse events were anemia (10%), neutropenia (10%), and pneumonia (6%).
Ten patients developed second primary cancers. There were no new atrial fibrillation events and no new hypertension events. The frequency of infections decreased over time, as did the number of bleeding events. However, two of three major hemorrhage events occurred after the previous report was published.
There were 43 deaths (35%), 29 of them because of disease progression. Six patients died of adverse events, two died of unknown causes, and two died of secondary acute myeloid leukemia. Other causes of death included multiorgan failure, intestinal obstruction, lung cancer, and graft-versus-host disease.
This study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The researchers reported relationships with AstraZeneca/Acerta Pharma and many other companies.
SOURCE: Wang M et al. Leukemia. 2019 Sep 26. doi: 10.1038/s41375-019-0575-9.
FROM LEUKEMIA
FDA approves afamelanotide for treatment of rare condition with light-induced pain
The Food and Drug Administration has approved , a rare condition that causes extremely painful reactions when skin is exposed to light, according to an FDA announcement.
This is the first treatment approved to help patients with this condition increase their exposure to light, according to the release.
Afamelanotide, administered in a subcutaneous implant, is a melanocortin-1 receptor (MC1-R) agonist, which “increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources,” the release says.
Approval is based on a pair of parallel-group clinical trials that compared the number of hours spent in sunlight in the treatment and placebo groups. The first trial enrolled 93 patients; 48 received afamelanotide. The treated patients spent a median of 61 hours in total over 180 days in direct sunlight between 10 a.m. and 6 p.m. on days with no pain, compared with 41 hours for patients taking placebo.
The second trial assessed the total number of hours over 270 days spent outdoors between 10 a.m. and 3 p.m. on days with no pain for which “most of the day” was spent in direct sunlight. In this study, 38 patients treated with afamelanotide spent a median total of 6 hours, compared with 0.75 hours among the remaining 36 who were taking a placebo.
The most common side effects include implant site reaction, nausea, and oropharyngeal pain. The implant should be administered only by trained professionals. Because afamelanotide may cause skin darkening, it’s recommended that patients should undergo twice-yearly skin examinations. Patients are also encouraged to maintain sun protection measures to help prevent phototoxic reactions.
“Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible,” said Julie Beitz, MD, director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III in the FDA release.
The Food and Drug Administration has approved , a rare condition that causes extremely painful reactions when skin is exposed to light, according to an FDA announcement.
This is the first treatment approved to help patients with this condition increase their exposure to light, according to the release.
Afamelanotide, administered in a subcutaneous implant, is a melanocortin-1 receptor (MC1-R) agonist, which “increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources,” the release says.
Approval is based on a pair of parallel-group clinical trials that compared the number of hours spent in sunlight in the treatment and placebo groups. The first trial enrolled 93 patients; 48 received afamelanotide. The treated patients spent a median of 61 hours in total over 180 days in direct sunlight between 10 a.m. and 6 p.m. on days with no pain, compared with 41 hours for patients taking placebo.
The second trial assessed the total number of hours over 270 days spent outdoors between 10 a.m. and 3 p.m. on days with no pain for which “most of the day” was spent in direct sunlight. In this study, 38 patients treated with afamelanotide spent a median total of 6 hours, compared with 0.75 hours among the remaining 36 who were taking a placebo.
The most common side effects include implant site reaction, nausea, and oropharyngeal pain. The implant should be administered only by trained professionals. Because afamelanotide may cause skin darkening, it’s recommended that patients should undergo twice-yearly skin examinations. Patients are also encouraged to maintain sun protection measures to help prevent phototoxic reactions.
“Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible,” said Julie Beitz, MD, director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III in the FDA release.
The Food and Drug Administration has approved , a rare condition that causes extremely painful reactions when skin is exposed to light, according to an FDA announcement.
This is the first treatment approved to help patients with this condition increase their exposure to light, according to the release.
Afamelanotide, administered in a subcutaneous implant, is a melanocortin-1 receptor (MC1-R) agonist, which “increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources,” the release says.
Approval is based on a pair of parallel-group clinical trials that compared the number of hours spent in sunlight in the treatment and placebo groups. The first trial enrolled 93 patients; 48 received afamelanotide. The treated patients spent a median of 61 hours in total over 180 days in direct sunlight between 10 a.m. and 6 p.m. on days with no pain, compared with 41 hours for patients taking placebo.
The second trial assessed the total number of hours over 270 days spent outdoors between 10 a.m. and 3 p.m. on days with no pain for which “most of the day” was spent in direct sunlight. In this study, 38 patients treated with afamelanotide spent a median total of 6 hours, compared with 0.75 hours among the remaining 36 who were taking a placebo.
The most common side effects include implant site reaction, nausea, and oropharyngeal pain. The implant should be administered only by trained professionals. Because afamelanotide may cause skin darkening, it’s recommended that patients should undergo twice-yearly skin examinations. Patients are also encouraged to maintain sun protection measures to help prevent phototoxic reactions.
“Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible,” said Julie Beitz, MD, director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III in the FDA release.
Too few pregnant women receive both influenza and Tdap vaccines
according to a Morbidity and Mortality Weekly Report published by the Centers for Disease Control and Prevention.
The CDC recommends that all pregnant women receive the Tdap vaccine, preferably between 27 and 36 weeks’ gestation. The flu vaccine is recommended for all women at any point in pregnancy if the pregnancy falls within flu season. Women do not need a second flu shot if they received the vaccine before pregnancy in the same influenza season. Both vaccines provide protection to infants after birth.
“Clinicians caring for women who are pregnant have a huge role in helping women understand risks and benefits and the value of vaccines,” Anne Schuchat, MD, principal deputy director of the CDC, Atlanta, said in a telebriefing about the new report. “A lot of women are worried about taking any extra medicine or getting shots during pregnancy, and clinicians can let them know about the large data available showing the safety of the vaccine as well as the effectiveness. We also think it’s important to let people know about the risk of not vaccinating.”
Pregnant women are at higher risk for influenza complications and represent a disproportionate number of flu-related hospitalizations. From the 2010-2011 to 2017-2018 influenza seasons, 24%-34% of influenza hospitalizations each season were pregnant women aged 15-44, yet only 9% of women in this age group are pregnant at any point each year, according to the report.
Similarly, infants under 6 months have the greatest risk of hospitalization from influenza, and half of pertussis hospitalizations and 69% of pertussis deaths occur in infants under 2 months old. But a fetus receives protective maternal antibodies from flu and pertussis vaccines about 2 weeks after the mother is vaccinated.
Influenza hospitalization is 40% lower among pregnant women vaccinated against flu and 72% lower in infants under 6 months who received maternal influenza antibodies during gestation. Similarly, Tdap vaccination during the third trimester of pregnancy reduces pertussis infection risk by 78% and pertussis hospitalization by 91% in infants under 2 months.
“Infant protection can motivate pregnant women to receive recommended vaccines, and intention to vaccinate is higher among women who perceive more serious consequences of influenza or pertussis disease for their own or their infant’s health,” Megan C. Lindley, MPH, of the CDC’s Immunization Services Division, and colleagues wrote in the MMWR report.
In March-April 2019, Ms. Lindley and associates conducted an Internet survey about flu and Tdap immunizations among women aged 18-49 who had been pregnant at any point since August 1, 2018. A total of 2,626 women completed the survey of 2,762 invitations (95% response rate).
Among 817 women who knew their Tdap status during pregnancy, 55% received the Tdap vaccine. Among 2,097 women who reported a pregnancy between October 2018 and January 2019, 54% received the flu vaccine before or during pregnancy.
But many women received one vaccine without the other: 65% of women surveyed had not received both vaccines during pregnancy. Higher immunization rates occurred among women whose clinicians recommended the vaccines: 66% received a flu shot and 71% received Tdap.
“We’re learning a lot about improved communication between clinicians and patients. One thing we suggest is to begin the conversations early.” Dr Schuchat said. “If you begin talking early in the pregnancy about the things you’ll be looking forward to and provide information, by the time it is flu season or it is that third trimester, they’re prepared to make a good choice.”
Most women surveyed (75%) said their providers did offer a flu or Tdap vaccine in the office or a referral for one. Yet more than 30% of these women did not get the recommended vaccine.
The most common reason for not getting the Tdap during pregnancy, cited by 38% of women who didn’t receive it, was not knowing about the recommendation. Those who did not receive flu vaccination, however, cited concerns about effectiveness (18%) or safety for the baby (16%). A similar proportion of women cited safety concerns for not getting the Tdap (17%).
Sharing information early and engaging respectfully with patients are key to successful provider recommendations, Dr Schuchat said.
“It’s really important for clinicians to begin by listening to women, asking, ‘Can I answer your questions? What are the concerns that you have?’ ” she said. “We find that, when a clinician validates a patient’s concerns and really shows that they’re listening, they can build trust and respect.”
Providers’ sharing their personal experience can help as well, Dr Schuchat added. Clinicians can let patients know if they themselves, or their partner, received the vaccines during pregnancy.
Rates for turning down vaccines were higher for black women: 47% received the flu vaccine after a recommendation, compared with 69% of white women. Among those receiving a Tdap recommendation, 53% of black women accepted it, compared with 77% of white women and 66% of Latina women. The authors noted a past study showing black adults had a higher distrust of flu vaccination, their doctor, and CDC information than white adults.
“Differential effects of provider vaccination offers or referrals might also be explained by less patient-centered provider communication with black patients,” Ms. Lindley and associates wrote.
SOURCE: Lindley MC. MMWR Morb Mortal Wkly Rep. 2019 Oct 8. doi: 10.15585/mmwr.mm6840e1.
according to a Morbidity and Mortality Weekly Report published by the Centers for Disease Control and Prevention.
The CDC recommends that all pregnant women receive the Tdap vaccine, preferably between 27 and 36 weeks’ gestation. The flu vaccine is recommended for all women at any point in pregnancy if the pregnancy falls within flu season. Women do not need a second flu shot if they received the vaccine before pregnancy in the same influenza season. Both vaccines provide protection to infants after birth.
“Clinicians caring for women who are pregnant have a huge role in helping women understand risks and benefits and the value of vaccines,” Anne Schuchat, MD, principal deputy director of the CDC, Atlanta, said in a telebriefing about the new report. “A lot of women are worried about taking any extra medicine or getting shots during pregnancy, and clinicians can let them know about the large data available showing the safety of the vaccine as well as the effectiveness. We also think it’s important to let people know about the risk of not vaccinating.”
Pregnant women are at higher risk for influenza complications and represent a disproportionate number of flu-related hospitalizations. From the 2010-2011 to 2017-2018 influenza seasons, 24%-34% of influenza hospitalizations each season were pregnant women aged 15-44, yet only 9% of women in this age group are pregnant at any point each year, according to the report.
Similarly, infants under 6 months have the greatest risk of hospitalization from influenza, and half of pertussis hospitalizations and 69% of pertussis deaths occur in infants under 2 months old. But a fetus receives protective maternal antibodies from flu and pertussis vaccines about 2 weeks after the mother is vaccinated.
Influenza hospitalization is 40% lower among pregnant women vaccinated against flu and 72% lower in infants under 6 months who received maternal influenza antibodies during gestation. Similarly, Tdap vaccination during the third trimester of pregnancy reduces pertussis infection risk by 78% and pertussis hospitalization by 91% in infants under 2 months.
“Infant protection can motivate pregnant women to receive recommended vaccines, and intention to vaccinate is higher among women who perceive more serious consequences of influenza or pertussis disease for their own or their infant’s health,” Megan C. Lindley, MPH, of the CDC’s Immunization Services Division, and colleagues wrote in the MMWR report.
In March-April 2019, Ms. Lindley and associates conducted an Internet survey about flu and Tdap immunizations among women aged 18-49 who had been pregnant at any point since August 1, 2018. A total of 2,626 women completed the survey of 2,762 invitations (95% response rate).
Among 817 women who knew their Tdap status during pregnancy, 55% received the Tdap vaccine. Among 2,097 women who reported a pregnancy between October 2018 and January 2019, 54% received the flu vaccine before or during pregnancy.
But many women received one vaccine without the other: 65% of women surveyed had not received both vaccines during pregnancy. Higher immunization rates occurred among women whose clinicians recommended the vaccines: 66% received a flu shot and 71% received Tdap.
“We’re learning a lot about improved communication between clinicians and patients. One thing we suggest is to begin the conversations early.” Dr Schuchat said. “If you begin talking early in the pregnancy about the things you’ll be looking forward to and provide information, by the time it is flu season or it is that third trimester, they’re prepared to make a good choice.”
Most women surveyed (75%) said their providers did offer a flu or Tdap vaccine in the office or a referral for one. Yet more than 30% of these women did not get the recommended vaccine.
The most common reason for not getting the Tdap during pregnancy, cited by 38% of women who didn’t receive it, was not knowing about the recommendation. Those who did not receive flu vaccination, however, cited concerns about effectiveness (18%) or safety for the baby (16%). A similar proportion of women cited safety concerns for not getting the Tdap (17%).
Sharing information early and engaging respectfully with patients are key to successful provider recommendations, Dr Schuchat said.
“It’s really important for clinicians to begin by listening to women, asking, ‘Can I answer your questions? What are the concerns that you have?’ ” she said. “We find that, when a clinician validates a patient’s concerns and really shows that they’re listening, they can build trust and respect.”
Providers’ sharing their personal experience can help as well, Dr Schuchat added. Clinicians can let patients know if they themselves, or their partner, received the vaccines during pregnancy.
Rates for turning down vaccines were higher for black women: 47% received the flu vaccine after a recommendation, compared with 69% of white women. Among those receiving a Tdap recommendation, 53% of black women accepted it, compared with 77% of white women and 66% of Latina women. The authors noted a past study showing black adults had a higher distrust of flu vaccination, their doctor, and CDC information than white adults.
“Differential effects of provider vaccination offers or referrals might also be explained by less patient-centered provider communication with black patients,” Ms. Lindley and associates wrote.
SOURCE: Lindley MC. MMWR Morb Mortal Wkly Rep. 2019 Oct 8. doi: 10.15585/mmwr.mm6840e1.
according to a Morbidity and Mortality Weekly Report published by the Centers for Disease Control and Prevention.
The CDC recommends that all pregnant women receive the Tdap vaccine, preferably between 27 and 36 weeks’ gestation. The flu vaccine is recommended for all women at any point in pregnancy if the pregnancy falls within flu season. Women do not need a second flu shot if they received the vaccine before pregnancy in the same influenza season. Both vaccines provide protection to infants after birth.
“Clinicians caring for women who are pregnant have a huge role in helping women understand risks and benefits and the value of vaccines,” Anne Schuchat, MD, principal deputy director of the CDC, Atlanta, said in a telebriefing about the new report. “A lot of women are worried about taking any extra medicine or getting shots during pregnancy, and clinicians can let them know about the large data available showing the safety of the vaccine as well as the effectiveness. We also think it’s important to let people know about the risk of not vaccinating.”
Pregnant women are at higher risk for influenza complications and represent a disproportionate number of flu-related hospitalizations. From the 2010-2011 to 2017-2018 influenza seasons, 24%-34% of influenza hospitalizations each season were pregnant women aged 15-44, yet only 9% of women in this age group are pregnant at any point each year, according to the report.
Similarly, infants under 6 months have the greatest risk of hospitalization from influenza, and half of pertussis hospitalizations and 69% of pertussis deaths occur in infants under 2 months old. But a fetus receives protective maternal antibodies from flu and pertussis vaccines about 2 weeks after the mother is vaccinated.
Influenza hospitalization is 40% lower among pregnant women vaccinated against flu and 72% lower in infants under 6 months who received maternal influenza antibodies during gestation. Similarly, Tdap vaccination during the third trimester of pregnancy reduces pertussis infection risk by 78% and pertussis hospitalization by 91% in infants under 2 months.
“Infant protection can motivate pregnant women to receive recommended vaccines, and intention to vaccinate is higher among women who perceive more serious consequences of influenza or pertussis disease for their own or their infant’s health,” Megan C. Lindley, MPH, of the CDC’s Immunization Services Division, and colleagues wrote in the MMWR report.
In March-April 2019, Ms. Lindley and associates conducted an Internet survey about flu and Tdap immunizations among women aged 18-49 who had been pregnant at any point since August 1, 2018. A total of 2,626 women completed the survey of 2,762 invitations (95% response rate).
Among 817 women who knew their Tdap status during pregnancy, 55% received the Tdap vaccine. Among 2,097 women who reported a pregnancy between October 2018 and January 2019, 54% received the flu vaccine before or during pregnancy.
But many women received one vaccine without the other: 65% of women surveyed had not received both vaccines during pregnancy. Higher immunization rates occurred among women whose clinicians recommended the vaccines: 66% received a flu shot and 71% received Tdap.
“We’re learning a lot about improved communication between clinicians and patients. One thing we suggest is to begin the conversations early.” Dr Schuchat said. “If you begin talking early in the pregnancy about the things you’ll be looking forward to and provide information, by the time it is flu season or it is that third trimester, they’re prepared to make a good choice.”
Most women surveyed (75%) said their providers did offer a flu or Tdap vaccine in the office or a referral for one. Yet more than 30% of these women did not get the recommended vaccine.
The most common reason for not getting the Tdap during pregnancy, cited by 38% of women who didn’t receive it, was not knowing about the recommendation. Those who did not receive flu vaccination, however, cited concerns about effectiveness (18%) or safety for the baby (16%). A similar proportion of women cited safety concerns for not getting the Tdap (17%).
Sharing information early and engaging respectfully with patients are key to successful provider recommendations, Dr Schuchat said.
“It’s really important for clinicians to begin by listening to women, asking, ‘Can I answer your questions? What are the concerns that you have?’ ” she said. “We find that, when a clinician validates a patient’s concerns and really shows that they’re listening, they can build trust and respect.”
Providers’ sharing their personal experience can help as well, Dr Schuchat added. Clinicians can let patients know if they themselves, or their partner, received the vaccines during pregnancy.
Rates for turning down vaccines were higher for black women: 47% received the flu vaccine after a recommendation, compared with 69% of white women. Among those receiving a Tdap recommendation, 53% of black women accepted it, compared with 77% of white women and 66% of Latina women. The authors noted a past study showing black adults had a higher distrust of flu vaccination, their doctor, and CDC information than white adults.
“Differential effects of provider vaccination offers or referrals might also be explained by less patient-centered provider communication with black patients,” Ms. Lindley and associates wrote.
SOURCE: Lindley MC. MMWR Morb Mortal Wkly Rep. 2019 Oct 8. doi: 10.15585/mmwr.mm6840e1.
FROM MMWR TELEBRIEFING
Using AI safely in the clinical setting
Understanding limitations of technology is key
Artificial intelligence (AI) and machine learning (ML) are promoted as the solution to many health care problems, but the area risks becoming technology led – with only secondary consideration to the safe clinical application of the technology, says Robert Challen, PhD.
Dr. Challen, of the University of Exeter (England), is the lead author of a recent paper that examines the short-, medium-, and long-term issues with medical applications of AI. “In the short term, AI systems will effectively function like laboratory screening tests, identifying patients who are at higher risk than others of disease, or who could benefit more from a particular treatment,” Dr. Challen said. “We usually accept that laboratory tests are useful to help make a diagnosis; however, clinicians are aware that they might not always be accurate and interpret their output in the clinical context. AI systems are no different in that they will be a useful tool so long as they are designed with safety in mind and used with a pragmatic attitude to their interpretation.”
The paper also suggests a set of short-and medium-term clinical safety issues that need addressing when bringing these systems from laboratory to bedside.
In the longer term, as more continuously learning and autonomous systems are developed, the safety risks will need to be continuously reevaluated, he added. “Any new technology comes with limitations and understanding those limitations is key to safe use of that technology. In the same way a new screening test has limitations on its sensitivity and specificity that define how it can be used, AL and ML systems have limitations on accuracy and which patients they can be used on,” Dr. Challen said. If hospitalists understand these limitations, they can participate better in their development.
Dr. Challen recommends that hospitalists help the development of AI tools by participating in studies that assess AI applications in the clinical environment. “Try to make sure that where AI research is taking place, there is strong clinical involvement.”
Reference
1. Challen R et al. Artificial intelligence, bias and clinical safety. BMJ Qual Saf. 2019 Jan 12. doi: 10.1136/bmjqs-2018-008370.
Understanding limitations of technology is key
Understanding limitations of technology is key
Artificial intelligence (AI) and machine learning (ML) are promoted as the solution to many health care problems, but the area risks becoming technology led – with only secondary consideration to the safe clinical application of the technology, says Robert Challen, PhD.
Dr. Challen, of the University of Exeter (England), is the lead author of a recent paper that examines the short-, medium-, and long-term issues with medical applications of AI. “In the short term, AI systems will effectively function like laboratory screening tests, identifying patients who are at higher risk than others of disease, or who could benefit more from a particular treatment,” Dr. Challen said. “We usually accept that laboratory tests are useful to help make a diagnosis; however, clinicians are aware that they might not always be accurate and interpret their output in the clinical context. AI systems are no different in that they will be a useful tool so long as they are designed with safety in mind and used with a pragmatic attitude to their interpretation.”
The paper also suggests a set of short-and medium-term clinical safety issues that need addressing when bringing these systems from laboratory to bedside.
In the longer term, as more continuously learning and autonomous systems are developed, the safety risks will need to be continuously reevaluated, he added. “Any new technology comes with limitations and understanding those limitations is key to safe use of that technology. In the same way a new screening test has limitations on its sensitivity and specificity that define how it can be used, AL and ML systems have limitations on accuracy and which patients they can be used on,” Dr. Challen said. If hospitalists understand these limitations, they can participate better in their development.
Dr. Challen recommends that hospitalists help the development of AI tools by participating in studies that assess AI applications in the clinical environment. “Try to make sure that where AI research is taking place, there is strong clinical involvement.”
Reference
1. Challen R et al. Artificial intelligence, bias and clinical safety. BMJ Qual Saf. 2019 Jan 12. doi: 10.1136/bmjqs-2018-008370.
Artificial intelligence (AI) and machine learning (ML) are promoted as the solution to many health care problems, but the area risks becoming technology led – with only secondary consideration to the safe clinical application of the technology, says Robert Challen, PhD.
Dr. Challen, of the University of Exeter (England), is the lead author of a recent paper that examines the short-, medium-, and long-term issues with medical applications of AI. “In the short term, AI systems will effectively function like laboratory screening tests, identifying patients who are at higher risk than others of disease, or who could benefit more from a particular treatment,” Dr. Challen said. “We usually accept that laboratory tests are useful to help make a diagnosis; however, clinicians are aware that they might not always be accurate and interpret their output in the clinical context. AI systems are no different in that they will be a useful tool so long as they are designed with safety in mind and used with a pragmatic attitude to their interpretation.”
The paper also suggests a set of short-and medium-term clinical safety issues that need addressing when bringing these systems from laboratory to bedside.
In the longer term, as more continuously learning and autonomous systems are developed, the safety risks will need to be continuously reevaluated, he added. “Any new technology comes with limitations and understanding those limitations is key to safe use of that technology. In the same way a new screening test has limitations on its sensitivity and specificity that define how it can be used, AL and ML systems have limitations on accuracy and which patients they can be used on,” Dr. Challen said. If hospitalists understand these limitations, they can participate better in their development.
Dr. Challen recommends that hospitalists help the development of AI tools by participating in studies that assess AI applications in the clinical environment. “Try to make sure that where AI research is taking place, there is strong clinical involvement.”
Reference
1. Challen R et al. Artificial intelligence, bias and clinical safety. BMJ Qual Saf. 2019 Jan 12. doi: 10.1136/bmjqs-2018-008370.
Dysregulated sleep is common in children with eosinophilic esophagitis
, Rasintra Siriwat, MD, and colleagues have ascertained.
Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.
The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m2. A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.
Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.
Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).
All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.
“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.
The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).
Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.
“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”
Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.
SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.
, Rasintra Siriwat, MD, and colleagues have ascertained.
Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.
The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m2. A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.
Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.
Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).
All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.
“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.
The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).
Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.
“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”
Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.
SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.
, Rasintra Siriwat, MD, and colleagues have ascertained.
Children with eosinophilic esophagitis (EoE) also were found to have a high prevalence of atopic diseases, including allergic rhinitis and eczema – findings that could be driving the breathing problems, said Dr. Siriwat, a neurology fellow at the Cleveland Clinic, and coauthors.
The retrospective study comprised 81 children with a diagnosis of EoE who were referred to sleep clinics. In this group, 46 of the children had active EoE (having gastrointestinal symptoms, including feeding difficulties, dysphagia, reflux, nausea/vomiting, or epigastric pain at presentation). The other 35 had an EoE diagnosis but no symptoms on presentation and were categorized as having inactive EoE. Most were male (71.6%) and white (92.5%). The mean age in the cohort was 10 years and the mean body mass index for all subjects was 22 kg/m2. A control group of 192 children without an EoE diagnosis who had overnight polysomnography were included in the analysis.
Allergic-type comorbidities were common among those with active EoE, including allergic rhinitis (55.5%), food allergy (39.5%), and eczema (26%). In addition, a quarter had attention-deficit/hyperactivity disorder, 22% an autism spectrum disorder, 21% a neurological disease, and 29% a psychiatric disorder.
Several sleep complaints were common in the entire EoE cohort, including snoring (76.5 %), restless sleep (66.6%), legs jerking or leg discomfort (43.2%), and daytime sleepiness (58%).
All children underwent an overnight polysomnography. Compared with controls, the children with EoE had significantly higher non-REM2 sleep, significantly lower non-REM3 sleep, lower REM, increased periodic leg movement disorder, and increased arousal index.
“Of note, we found a much higher percentage of [periodic leg movement disorder] in active EoE compared to inactive EoE,” the authors said.
The most common sleep diagnosis for the children with EoE was sleep-disordered breathing. Of 62 children with EoE and sleep disordered breathing, 37% had obstructive sleep apnea (OSA). Two patients had central sleep apnea and five had nocturnal hypoventilation. Children with EoE also reported parasomnia symptoms such as sleep talking (35.8%), sleepwalking (16%), bruxism (23.4%), night terrors (28.4%), and nocturnal enuresis (21.2%).
Of the 59 children with leg movement, 20 had periodic limb movement disorder and 5 were diagnosed with restless leg syndrome. Two were diagnosed with narcolepsy and three with hypersomnia. Four children had a circadian rhythm disorder.
“Notably, the majority of children with EoE had symptoms of sleep-disordered breathing, and more than one-third of total subjects were diagnosed with OSA,” the authors noted. “However, most of them were mild-moderate OSA. It should be noted that the prevalence of OSA in the pediatric population is 1%-5% mostly between the ages of 2-8 years, while the mean age of our subjects was 10 years old. The high prevalence of mild-moderate OSA in the EoE population might be explained by the relationship between EoE and atopic disease.”
Dr. Siriwat had no financial disclosures. The study was supported by Cincinnati Children’s Hospital Research Fund.
SOURCE: Siriwat R et al. Sleep Med. 2019 Sep 11. doi: 10.1016/j.sleep.2019.08.018.
FROM SLEEP MEDICINE
Set reasonable expectations for managing refractory rheumatoid arthritis
LAS VEGAS – Rheumatoid arthritis that is difficult to treat may occur in about 10% of patients with the disease. The definition of difficult-to-treat rheumatoid arthritis varies among experts, however, and the reasons for refractoriness are often unknown, said Iain McInnes, MD, PhD, professor of experimental medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow and current president of the European League Against Rheumatism.
There may be an intrinsic refractory disease state, where the disease will manifest despite the use of any existing medications. Patients may have pharmacokinetic refractory disease, which could result from antidrug antibodies. There may be false positives. “It could well be that the patient is sore, but it is not because of the active inflammation,” he said. “It is because of biomechanical disease or pain sensitization. Or it could be that there is osteoarthritis.”
In the end, managing patients with difficult-to-treat rheumatoid arthritis may come down to setting reasonable expectations and addressing practical concerns, such as medication adherence, comorbidities, and adverse drug reactions – “the realpolitik of rheumatological care,” Dr. McInnes said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Defining difficult to treat
In a recently published study, Dr. McInnes and colleagues surveyed rheumatologists about what characterizes difficult-to-treat rheumatoid arthritis (Ann Rheum Dis. 2018 Dec;77[12]:1705-9).
“There was remarkable variation,” Dr. McInnes said. “Should fatigue be involved? Do the types of drugs that you have failed matter? Should a patient’s need for glucocorticoids be part of the definition? ... We did not really find much of a consensus.”
The presence of cardiovascular disease, extra-articular manifestations, infection, malignancy, diabetes mellitus, and other factors add to the challenge. “These are all very familiar problems that you face in your routine practice, whether you are in rheumatology care primarily or whether you are in family practice,” he said.
Although it is difficult to determine how many patients have refractory rheumatoid arthritis, “the rule of thumb is about 10%,” Dr. McInnes said. Using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, researchers estimated that approximately 6% of patients would be refractory to a biologic drug, defined as patients who move on to a third class of biologic therapy (Ann Rheum Dis. 2018 Oct;77[10]:1405-12).
The same study found that, in recent years, patients have cycled through drugs more quickly than they had in the past. Many patients prove difficult to treat within 4 or 5 years, “which is pretty terrifying with a disease whose median age of onset is early 50s, but whose clinics are full of people in their teens, 20s, and 30s,” Dr. McInnes said.
Approaches to treatment
New medications, therapeutic targets, and treatment approaches eventually may help treat or prevent refractory disease. In the meantime, it may be beneficial to “go back to the beginning” when caring for patients with difficult-to-treat rheumatoid arthritis, Dr. McInnes said. “Make absolutely certain that we understand what is going on in that patient. Even just the opportunity to go through the disease course is reassuring for our patients. If nothing else, it tells them that we are listening, paying attention, and we are taking it seriously.”
Physicians may need to recognize the presence of antidrug antibodies. In addition, medication adherence may be a problem. About one-third of patients who are prescribed methotrexate do not take the medication, which may be a difficult topic for them to discuss, he said.
“Detect that inflammation which is there and treat it,” Dr. McInnes said. “And detect that which is not of an inflammatory origin and manage it on its own merits.”
Dr. McInnes is a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galvani, GlaxoSmithKline, Leo Pharma, Novartis, Pfizer, and UCB. He has received grant or research support from AstraZeneca, Bristol-Myers Squibb, Compugen, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Rheumatoid arthritis that is difficult to treat may occur in about 10% of patients with the disease. The definition of difficult-to-treat rheumatoid arthritis varies among experts, however, and the reasons for refractoriness are often unknown, said Iain McInnes, MD, PhD, professor of experimental medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow and current president of the European League Against Rheumatism.
There may be an intrinsic refractory disease state, where the disease will manifest despite the use of any existing medications. Patients may have pharmacokinetic refractory disease, which could result from antidrug antibodies. There may be false positives. “It could well be that the patient is sore, but it is not because of the active inflammation,” he said. “It is because of biomechanical disease or pain sensitization. Or it could be that there is osteoarthritis.”
In the end, managing patients with difficult-to-treat rheumatoid arthritis may come down to setting reasonable expectations and addressing practical concerns, such as medication adherence, comorbidities, and adverse drug reactions – “the realpolitik of rheumatological care,” Dr. McInnes said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Defining difficult to treat
In a recently published study, Dr. McInnes and colleagues surveyed rheumatologists about what characterizes difficult-to-treat rheumatoid arthritis (Ann Rheum Dis. 2018 Dec;77[12]:1705-9).
“There was remarkable variation,” Dr. McInnes said. “Should fatigue be involved? Do the types of drugs that you have failed matter? Should a patient’s need for glucocorticoids be part of the definition? ... We did not really find much of a consensus.”
The presence of cardiovascular disease, extra-articular manifestations, infection, malignancy, diabetes mellitus, and other factors add to the challenge. “These are all very familiar problems that you face in your routine practice, whether you are in rheumatology care primarily or whether you are in family practice,” he said.
Although it is difficult to determine how many patients have refractory rheumatoid arthritis, “the rule of thumb is about 10%,” Dr. McInnes said. Using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, researchers estimated that approximately 6% of patients would be refractory to a biologic drug, defined as patients who move on to a third class of biologic therapy (Ann Rheum Dis. 2018 Oct;77[10]:1405-12).
The same study found that, in recent years, patients have cycled through drugs more quickly than they had in the past. Many patients prove difficult to treat within 4 or 5 years, “which is pretty terrifying with a disease whose median age of onset is early 50s, but whose clinics are full of people in their teens, 20s, and 30s,” Dr. McInnes said.
Approaches to treatment
New medications, therapeutic targets, and treatment approaches eventually may help treat or prevent refractory disease. In the meantime, it may be beneficial to “go back to the beginning” when caring for patients with difficult-to-treat rheumatoid arthritis, Dr. McInnes said. “Make absolutely certain that we understand what is going on in that patient. Even just the opportunity to go through the disease course is reassuring for our patients. If nothing else, it tells them that we are listening, paying attention, and we are taking it seriously.”
Physicians may need to recognize the presence of antidrug antibodies. In addition, medication adherence may be a problem. About one-third of patients who are prescribed methotrexate do not take the medication, which may be a difficult topic for them to discuss, he said.
“Detect that inflammation which is there and treat it,” Dr. McInnes said. “And detect that which is not of an inflammatory origin and manage it on its own merits.”
Dr. McInnes is a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galvani, GlaxoSmithKline, Leo Pharma, Novartis, Pfizer, and UCB. He has received grant or research support from AstraZeneca, Bristol-Myers Squibb, Compugen, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
Global Academy for Medical Education and this news organization are owned by the same parent company.
LAS VEGAS – Rheumatoid arthritis that is difficult to treat may occur in about 10% of patients with the disease. The definition of difficult-to-treat rheumatoid arthritis varies among experts, however, and the reasons for refractoriness are often unknown, said Iain McInnes, MD, PhD, professor of experimental medicine and director of the Institute of Infection, Immunity and Inflammation at the University of Glasgow and current president of the European League Against Rheumatism.
There may be an intrinsic refractory disease state, where the disease will manifest despite the use of any existing medications. Patients may have pharmacokinetic refractory disease, which could result from antidrug antibodies. There may be false positives. “It could well be that the patient is sore, but it is not because of the active inflammation,” he said. “It is because of biomechanical disease or pain sensitization. Or it could be that there is osteoarthritis.”
In the end, managing patients with difficult-to-treat rheumatoid arthritis may come down to setting reasonable expectations and addressing practical concerns, such as medication adherence, comorbidities, and adverse drug reactions – “the realpolitik of rheumatological care,” Dr. McInnes said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education.
Defining difficult to treat
In a recently published study, Dr. McInnes and colleagues surveyed rheumatologists about what characterizes difficult-to-treat rheumatoid arthritis (Ann Rheum Dis. 2018 Dec;77[12]:1705-9).
“There was remarkable variation,” Dr. McInnes said. “Should fatigue be involved? Do the types of drugs that you have failed matter? Should a patient’s need for glucocorticoids be part of the definition? ... We did not really find much of a consensus.”
The presence of cardiovascular disease, extra-articular manifestations, infection, malignancy, diabetes mellitus, and other factors add to the challenge. “These are all very familiar problems that you face in your routine practice, whether you are in rheumatology care primarily or whether you are in family practice,” he said.
Although it is difficult to determine how many patients have refractory rheumatoid arthritis, “the rule of thumb is about 10%,” Dr. McInnes said. Using data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis, researchers estimated that approximately 6% of patients would be refractory to a biologic drug, defined as patients who move on to a third class of biologic therapy (Ann Rheum Dis. 2018 Oct;77[10]:1405-12).
The same study found that, in recent years, patients have cycled through drugs more quickly than they had in the past. Many patients prove difficult to treat within 4 or 5 years, “which is pretty terrifying with a disease whose median age of onset is early 50s, but whose clinics are full of people in their teens, 20s, and 30s,” Dr. McInnes said.
Approaches to treatment
New medications, therapeutic targets, and treatment approaches eventually may help treat or prevent refractory disease. In the meantime, it may be beneficial to “go back to the beginning” when caring for patients with difficult-to-treat rheumatoid arthritis, Dr. McInnes said. “Make absolutely certain that we understand what is going on in that patient. Even just the opportunity to go through the disease course is reassuring for our patients. If nothing else, it tells them that we are listening, paying attention, and we are taking it seriously.”
Physicians may need to recognize the presence of antidrug antibodies. In addition, medication adherence may be a problem. About one-third of patients who are prescribed methotrexate do not take the medication, which may be a difficult topic for them to discuss, he said.
“Detect that inflammation which is there and treat it,” Dr. McInnes said. “And detect that which is not of an inflammatory origin and manage it on its own merits.”
Dr. McInnes is a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Galvani, GlaxoSmithKline, Leo Pharma, Novartis, Pfizer, and UCB. He has received grant or research support from AstraZeneca, Bristol-Myers Squibb, Compugen, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM PRD 2019
Laparoscopic surgery has short-term advantages for elderly patients with colorectal cancer
Sicheng Zhou, and colleagues wrote in BMC Surgery.
“Laparoscopic surgery showed better results than the open surgery in short-term outcomes,” said Dr. Zhou of the Chinese Academy of Medical Sciences, and coauthors. “[Carcinoembryonic antigen] level, III/IV stage, and perineural invasion were all reliable predictors of overall survival and disease-free survival for the treatment of laparoscopic surgery and open surgery for elderly Chinese patients over 80 years old with colorectal cancer.”
The study comprised 313 patients aged 80 years or older who underwent surgery for colorectal cancer. The group was equally divided between those who had laparoscopic and open surgery. They were matched 1:1, for a total of 93 pairs included. The patients’ mean age was 82 years. Medical comorbidities were present in about 63%. The tumor was more likely to present in the in the rectum and right colon (about 34% each). The next most common disease site was the sigmoid colon (22%).
Most tumors were stage III (58%), and II (about 30%). About 70% were moderately differentiated and 20% poorly differentiated. Carcinoembryonic antigen was greater than 5 ng/mL in about three-fourths of the group, and higher in the reminder.
Surgery duration was somewhat shorter in the open group but not significantly so. However, intraoperative complications were higher in the open group, including transfusion (22.6% vs. 16% and blood loss 50.9 vs. 108 mL). There was a lower occurrence of postoperative complications (10.8% vs. 26.9%) in the laparoscopic group.
Intraoperative complications occurred in only one patient, who was in the laparoscopic group, but perioperative complications were significantly more common in the open group (17.2% vs. 6.5%). In the open group these included wound infection (9.7%), followed by ileus (5.4%), anastomosis leakage (4.3%), and delayed gastric emptying (4.3%). In the laparoscopic group, the most common morbidities were anastomosis leakage (2.2%), ileus (2.2%) and pneumonia (2.2%).
The number of retrieved lymph nodes was also significantly higher in the laparoscopic group (20 vs. 17).
Yet, despite the short-term perioperative advantages of the laparoscopic approach in elderly patients, the 3- and 5-year overall and disease-free survival rates were not significantly different in these groups. The investigators concluded “it is noteworthy that the 3-year and 5-year [overall survival] rates, and 3- year and 5-year [disease-free survival] rates of patients in the laparoscopic group were generally higher than the open group. The 5-year [disease-free survival] rate in the laparoscopic group was even higher than that in the open group by more than 10%. This difference might be due to the difference in the number of dissected lymph nodes between the open group and the laparoscopic group. Hence, although there was no significant difference in survival outcomes between the two surgical methods, the laparoscopic surgery in elderly patients with colorectal cancer might achieve better survival outcomes than the open surgery.”
The authors declared that they had no competing interests. This work was supported by the Beijing Hope Run Special Fund of Cancer Foundation of China and Capital Health Research and Development.
SOURCE: Zhou S et al. BMC Surg. 2019;19:137. doi: 10.1186/s12893-019-0596-3.
Sicheng Zhou, and colleagues wrote in BMC Surgery.
“Laparoscopic surgery showed better results than the open surgery in short-term outcomes,” said Dr. Zhou of the Chinese Academy of Medical Sciences, and coauthors. “[Carcinoembryonic antigen] level, III/IV stage, and perineural invasion were all reliable predictors of overall survival and disease-free survival for the treatment of laparoscopic surgery and open surgery for elderly Chinese patients over 80 years old with colorectal cancer.”
The study comprised 313 patients aged 80 years or older who underwent surgery for colorectal cancer. The group was equally divided between those who had laparoscopic and open surgery. They were matched 1:1, for a total of 93 pairs included. The patients’ mean age was 82 years. Medical comorbidities were present in about 63%. The tumor was more likely to present in the in the rectum and right colon (about 34% each). The next most common disease site was the sigmoid colon (22%).
Most tumors were stage III (58%), and II (about 30%). About 70% were moderately differentiated and 20% poorly differentiated. Carcinoembryonic antigen was greater than 5 ng/mL in about three-fourths of the group, and higher in the reminder.
Surgery duration was somewhat shorter in the open group but not significantly so. However, intraoperative complications were higher in the open group, including transfusion (22.6% vs. 16% and blood loss 50.9 vs. 108 mL). There was a lower occurrence of postoperative complications (10.8% vs. 26.9%) in the laparoscopic group.
Intraoperative complications occurred in only one patient, who was in the laparoscopic group, but perioperative complications were significantly more common in the open group (17.2% vs. 6.5%). In the open group these included wound infection (9.7%), followed by ileus (5.4%), anastomosis leakage (4.3%), and delayed gastric emptying (4.3%). In the laparoscopic group, the most common morbidities were anastomosis leakage (2.2%), ileus (2.2%) and pneumonia (2.2%).
The number of retrieved lymph nodes was also significantly higher in the laparoscopic group (20 vs. 17).
Yet, despite the short-term perioperative advantages of the laparoscopic approach in elderly patients, the 3- and 5-year overall and disease-free survival rates were not significantly different in these groups. The investigators concluded “it is noteworthy that the 3-year and 5-year [overall survival] rates, and 3- year and 5-year [disease-free survival] rates of patients in the laparoscopic group were generally higher than the open group. The 5-year [disease-free survival] rate in the laparoscopic group was even higher than that in the open group by more than 10%. This difference might be due to the difference in the number of dissected lymph nodes between the open group and the laparoscopic group. Hence, although there was no significant difference in survival outcomes between the two surgical methods, the laparoscopic surgery in elderly patients with colorectal cancer might achieve better survival outcomes than the open surgery.”
The authors declared that they had no competing interests. This work was supported by the Beijing Hope Run Special Fund of Cancer Foundation of China and Capital Health Research and Development.
SOURCE: Zhou S et al. BMC Surg. 2019;19:137. doi: 10.1186/s12893-019-0596-3.
Sicheng Zhou, and colleagues wrote in BMC Surgery.
“Laparoscopic surgery showed better results than the open surgery in short-term outcomes,” said Dr. Zhou of the Chinese Academy of Medical Sciences, and coauthors. “[Carcinoembryonic antigen] level, III/IV stage, and perineural invasion were all reliable predictors of overall survival and disease-free survival for the treatment of laparoscopic surgery and open surgery for elderly Chinese patients over 80 years old with colorectal cancer.”
The study comprised 313 patients aged 80 years or older who underwent surgery for colorectal cancer. The group was equally divided between those who had laparoscopic and open surgery. They were matched 1:1, for a total of 93 pairs included. The patients’ mean age was 82 years. Medical comorbidities were present in about 63%. The tumor was more likely to present in the in the rectum and right colon (about 34% each). The next most common disease site was the sigmoid colon (22%).
Most tumors were stage III (58%), and II (about 30%). About 70% were moderately differentiated and 20% poorly differentiated. Carcinoembryonic antigen was greater than 5 ng/mL in about three-fourths of the group, and higher in the reminder.
Surgery duration was somewhat shorter in the open group but not significantly so. However, intraoperative complications were higher in the open group, including transfusion (22.6% vs. 16% and blood loss 50.9 vs. 108 mL). There was a lower occurrence of postoperative complications (10.8% vs. 26.9%) in the laparoscopic group.
Intraoperative complications occurred in only one patient, who was in the laparoscopic group, but perioperative complications were significantly more common in the open group (17.2% vs. 6.5%). In the open group these included wound infection (9.7%), followed by ileus (5.4%), anastomosis leakage (4.3%), and delayed gastric emptying (4.3%). In the laparoscopic group, the most common morbidities were anastomosis leakage (2.2%), ileus (2.2%) and pneumonia (2.2%).
The number of retrieved lymph nodes was also significantly higher in the laparoscopic group (20 vs. 17).
Yet, despite the short-term perioperative advantages of the laparoscopic approach in elderly patients, the 3- and 5-year overall and disease-free survival rates were not significantly different in these groups. The investigators concluded “it is noteworthy that the 3-year and 5-year [overall survival] rates, and 3- year and 5-year [disease-free survival] rates of patients in the laparoscopic group were generally higher than the open group. The 5-year [disease-free survival] rate in the laparoscopic group was even higher than that in the open group by more than 10%. This difference might be due to the difference in the number of dissected lymph nodes between the open group and the laparoscopic group. Hence, although there was no significant difference in survival outcomes between the two surgical methods, the laparoscopic surgery in elderly patients with colorectal cancer might achieve better survival outcomes than the open surgery.”
The authors declared that they had no competing interests. This work was supported by the Beijing Hope Run Special Fund of Cancer Foundation of China and Capital Health Research and Development.
SOURCE: Zhou S et al. BMC Surg. 2019;19:137. doi: 10.1186/s12893-019-0596-3.
FROM BMC SURGERY
Consider centralized pain in patients with rheumatic disease
Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.
The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.
Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”
Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
A poor relationship between pain and imaging
Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.
This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”
Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
Opioid responsiveness
To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.
Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.
Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).
Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
Diagnosed cases are the “tip of the iceberg”
Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.
Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”
Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”
Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.
The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.
Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”
Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
A poor relationship between pain and imaging
Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.
This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”
Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
Opioid responsiveness
To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.
Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.
Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).
Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
Diagnosed cases are the “tip of the iceberg”
Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.
Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”
Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”
Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.
The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.
Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”
Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
A poor relationship between pain and imaging
Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.
This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”
Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
Opioid responsiveness
To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.
Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.
Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).
Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
Diagnosed cases are the “tip of the iceberg”
Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.
Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”
Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”
Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM PRD 2019
What is the optimal duration of maintenance in myeloma?
SAN FRANCISCO – Should patients with multiple myeloma receive maintenance therapy until progression?
Yvonne A. Efebera, MD, of The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital in Columbus, and Nina Shah, MD, of the University of California San Francisco Health, faced off on this question at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
Dr. Shah said maintenance therapy improves survival in myeloma patients, so it follows that treating them until progression would confer a survival advantage. While Dr. Efebera agreed that maintenance can improve survival, she said the optimal duration of that treatment is unknown.
Treat until progression
Dr. Shah cited studies suggesting that maintenance improves progression-free survival (PFS) and may prolong overall survival (OS) in multiple myeloma.
A meta-analysis of data from the IFM 2005-02, CALGB 100104, and GIMEMA RV-MM-PI-209 trials showed that lenalidomide maintenance prolonged PFS and OS. The median PFS was 52.8 months in patients who received maintenance and 23.5 months in those who received placebo or observation (hazard ratio [HR], 0.48). At a median follow-up of 79.5 months, the median OS was not reached for the maintenance group and was 86.0 months for the no-maintenance group (HR, 0.75; P = .001; J Clin Oncol. 2017 Oct 10;35[29]:3279-89).
In the Myeloma XI trial, maintenance improved PFS, but not OS, in both transplant-eligible and ineligible patients. Overall, the median PFS was 39 months in the lenalidomide maintenance arm and 20 months in the observation arm (P less than .0001). Among transplant-eligible patients, the median PFS was 57 months and 30 months, respectively (P less than .0001). Among transplant-ineligible patients, the median PFS was 26 months and 11 months, respectively (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:57-73).
These data suggest maintenance can improve survival, “but the question is, how long should we have therapy,” Dr. Shah said. “No one has looked at this in a prospective manner, so we really have to look at our retrospective data.”
One study suggested a longer duration of lenalidomide maintenance improves PFS. The HR for progression or death was 0.39 for patients who received maintenance for 12-24 months, compared with those who received maintenance for less than 12 months. The HR was 0.13 for patients who received maintenance for more than 24 months, compared with less than 12 months (Leuk Lymphoma. 2019 Feb;60[2]:511-4).
Dr. Shah also cited a pooled analysis of three phase 3 trials suggesting that continuous therapy is superior to fixed-duration therapy in patients with newly diagnosed myeloma. The median PFS was 32 months with continuous therapy and 16 months with fixed-duration therapy (P less than .001). The 4-year OS was 69% and 60%, respectively (P = .003; J Clin Oncol. 2015 Oct 20;33[30]:3459-66).
These data suggest that “continuous therapy, more therapy, has a survival advantage,” Dr. Shah said.
Don’t treat until progression
Dr. Efebera also discussed data from studies showing that lenalidomide maintenance can prolong survival in multiple myeloma. However, she said, it’s unclear how long maintenance should last.
Different durations of maintenance have proved effective in different trials. In the CALGB 100104 trial, the median duration of maintenance was 31 months (Lancet Haematol. 2017 Sep;4[9]:e431-e442). In the meta-analysis of the CALGB, IFM, and GIMEMA trials, the median duration was 22 months. And in Myeloma XI, the median duration was 18 months.
As there is no randomized trial comparing different durations of maintenance, Dr. Efebera proposed that researchers conduct one. She said this “perfect study” would involve induction with an immunomodulatory agent, a proteasome inhibitor, dexamethasone, and perhaps an anti-CD38 therapy. Transplant-eligible patients would receive four cycles of induction before transplant. Transplant-ineligible patients would receive eight cycles of induction. Then, all patients would be randomized to lenalidomide maintenance for 3 years, 5 years, or 7-10 years.
Until a trial like this reveals the optimal duration of maintenance, we cannot conclude that treating patients until progression is better, Dr. Efebera said.
She added that maintenance has been shown to have detrimental effects, and these should be taken into consideration. For instance, neutropenia, other hematologic adverse events, and second primary malignancies have been shown to be more common among patients who receive lenalidomide maintenance (N Engl J Med. 2012; 366:1782-91).
The cost of maintenance is another factor to consider. Researchers analyzed data from the CALGB 100104 and IFM 2005-02 trials to compare the cost of lenalidomide maintenance with no maintenance. In the CALGB 100104 trial, patients who received lenalidomide maintenance had 5.72 quality-adjusted life years (QALYs), and those who received no maintenance had 4.61 QALYs. The incremental cost-utility ratio (ICUR) was more than 277,000 euros per QALY.
In the IFM2005-02 trial, patients in the lenalidomide group had 5.13 QALYs, and those who didn’t receive maintenance had 4.98 QALYs. The ICUR was more than 1.5 million euros per QALY. The researchers said the high ICURs and budgetary impact add “uncertainty about the maximum prudent duration of the treatment” (Bone Marrow Transplant. 2019 May 31. doi: 10.1038/s41409-019-0574-5).
Dr. Efebera reported relationships with Akcea Therapeutics, Janssen, and Takeda. Dr. Shah reported having no relevant financial relationships.
SAN FRANCISCO – Should patients with multiple myeloma receive maintenance therapy until progression?
Yvonne A. Efebera, MD, of The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital in Columbus, and Nina Shah, MD, of the University of California San Francisco Health, faced off on this question at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
Dr. Shah said maintenance therapy improves survival in myeloma patients, so it follows that treating them until progression would confer a survival advantage. While Dr. Efebera agreed that maintenance can improve survival, she said the optimal duration of that treatment is unknown.
Treat until progression
Dr. Shah cited studies suggesting that maintenance improves progression-free survival (PFS) and may prolong overall survival (OS) in multiple myeloma.
A meta-analysis of data from the IFM 2005-02, CALGB 100104, and GIMEMA RV-MM-PI-209 trials showed that lenalidomide maintenance prolonged PFS and OS. The median PFS was 52.8 months in patients who received maintenance and 23.5 months in those who received placebo or observation (hazard ratio [HR], 0.48). At a median follow-up of 79.5 months, the median OS was not reached for the maintenance group and was 86.0 months for the no-maintenance group (HR, 0.75; P = .001; J Clin Oncol. 2017 Oct 10;35[29]:3279-89).
In the Myeloma XI trial, maintenance improved PFS, but not OS, in both transplant-eligible and ineligible patients. Overall, the median PFS was 39 months in the lenalidomide maintenance arm and 20 months in the observation arm (P less than .0001). Among transplant-eligible patients, the median PFS was 57 months and 30 months, respectively (P less than .0001). Among transplant-ineligible patients, the median PFS was 26 months and 11 months, respectively (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:57-73).
These data suggest maintenance can improve survival, “but the question is, how long should we have therapy,” Dr. Shah said. “No one has looked at this in a prospective manner, so we really have to look at our retrospective data.”
One study suggested a longer duration of lenalidomide maintenance improves PFS. The HR for progression or death was 0.39 for patients who received maintenance for 12-24 months, compared with those who received maintenance for less than 12 months. The HR was 0.13 for patients who received maintenance for more than 24 months, compared with less than 12 months (Leuk Lymphoma. 2019 Feb;60[2]:511-4).
Dr. Shah also cited a pooled analysis of three phase 3 trials suggesting that continuous therapy is superior to fixed-duration therapy in patients with newly diagnosed myeloma. The median PFS was 32 months with continuous therapy and 16 months with fixed-duration therapy (P less than .001). The 4-year OS was 69% and 60%, respectively (P = .003; J Clin Oncol. 2015 Oct 20;33[30]:3459-66).
These data suggest that “continuous therapy, more therapy, has a survival advantage,” Dr. Shah said.
Don’t treat until progression
Dr. Efebera also discussed data from studies showing that lenalidomide maintenance can prolong survival in multiple myeloma. However, she said, it’s unclear how long maintenance should last.
Different durations of maintenance have proved effective in different trials. In the CALGB 100104 trial, the median duration of maintenance was 31 months (Lancet Haematol. 2017 Sep;4[9]:e431-e442). In the meta-analysis of the CALGB, IFM, and GIMEMA trials, the median duration was 22 months. And in Myeloma XI, the median duration was 18 months.
As there is no randomized trial comparing different durations of maintenance, Dr. Efebera proposed that researchers conduct one. She said this “perfect study” would involve induction with an immunomodulatory agent, a proteasome inhibitor, dexamethasone, and perhaps an anti-CD38 therapy. Transplant-eligible patients would receive four cycles of induction before transplant. Transplant-ineligible patients would receive eight cycles of induction. Then, all patients would be randomized to lenalidomide maintenance for 3 years, 5 years, or 7-10 years.
Until a trial like this reveals the optimal duration of maintenance, we cannot conclude that treating patients until progression is better, Dr. Efebera said.
She added that maintenance has been shown to have detrimental effects, and these should be taken into consideration. For instance, neutropenia, other hematologic adverse events, and second primary malignancies have been shown to be more common among patients who receive lenalidomide maintenance (N Engl J Med. 2012; 366:1782-91).
The cost of maintenance is another factor to consider. Researchers analyzed data from the CALGB 100104 and IFM 2005-02 trials to compare the cost of lenalidomide maintenance with no maintenance. In the CALGB 100104 trial, patients who received lenalidomide maintenance had 5.72 quality-adjusted life years (QALYs), and those who received no maintenance had 4.61 QALYs. The incremental cost-utility ratio (ICUR) was more than 277,000 euros per QALY.
In the IFM2005-02 trial, patients in the lenalidomide group had 5.13 QALYs, and those who didn’t receive maintenance had 4.98 QALYs. The ICUR was more than 1.5 million euros per QALY. The researchers said the high ICURs and budgetary impact add “uncertainty about the maximum prudent duration of the treatment” (Bone Marrow Transplant. 2019 May 31. doi: 10.1038/s41409-019-0574-5).
Dr. Efebera reported relationships with Akcea Therapeutics, Janssen, and Takeda. Dr. Shah reported having no relevant financial relationships.
SAN FRANCISCO – Should patients with multiple myeloma receive maintenance therapy until progression?
Yvonne A. Efebera, MD, of The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital in Columbus, and Nina Shah, MD, of the University of California San Francisco Health, faced off on this question at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
Dr. Shah said maintenance therapy improves survival in myeloma patients, so it follows that treating them until progression would confer a survival advantage. While Dr. Efebera agreed that maintenance can improve survival, she said the optimal duration of that treatment is unknown.
Treat until progression
Dr. Shah cited studies suggesting that maintenance improves progression-free survival (PFS) and may prolong overall survival (OS) in multiple myeloma.
A meta-analysis of data from the IFM 2005-02, CALGB 100104, and GIMEMA RV-MM-PI-209 trials showed that lenalidomide maintenance prolonged PFS and OS. The median PFS was 52.8 months in patients who received maintenance and 23.5 months in those who received placebo or observation (hazard ratio [HR], 0.48). At a median follow-up of 79.5 months, the median OS was not reached for the maintenance group and was 86.0 months for the no-maintenance group (HR, 0.75; P = .001; J Clin Oncol. 2017 Oct 10;35[29]:3279-89).
In the Myeloma XI trial, maintenance improved PFS, but not OS, in both transplant-eligible and ineligible patients. Overall, the median PFS was 39 months in the lenalidomide maintenance arm and 20 months in the observation arm (P less than .0001). Among transplant-eligible patients, the median PFS was 57 months and 30 months, respectively (P less than .0001). Among transplant-ineligible patients, the median PFS was 26 months and 11 months, respectively (P less than .0001; Lancet Oncol. 2019 Jan;20[1]:57-73).
These data suggest maintenance can improve survival, “but the question is, how long should we have therapy,” Dr. Shah said. “No one has looked at this in a prospective manner, so we really have to look at our retrospective data.”
One study suggested a longer duration of lenalidomide maintenance improves PFS. The HR for progression or death was 0.39 for patients who received maintenance for 12-24 months, compared with those who received maintenance for less than 12 months. The HR was 0.13 for patients who received maintenance for more than 24 months, compared with less than 12 months (Leuk Lymphoma. 2019 Feb;60[2]:511-4).
Dr. Shah also cited a pooled analysis of three phase 3 trials suggesting that continuous therapy is superior to fixed-duration therapy in patients with newly diagnosed myeloma. The median PFS was 32 months with continuous therapy and 16 months with fixed-duration therapy (P less than .001). The 4-year OS was 69% and 60%, respectively (P = .003; J Clin Oncol. 2015 Oct 20;33[30]:3459-66).
These data suggest that “continuous therapy, more therapy, has a survival advantage,” Dr. Shah said.
Don’t treat until progression
Dr. Efebera also discussed data from studies showing that lenalidomide maintenance can prolong survival in multiple myeloma. However, she said, it’s unclear how long maintenance should last.
Different durations of maintenance have proved effective in different trials. In the CALGB 100104 trial, the median duration of maintenance was 31 months (Lancet Haematol. 2017 Sep;4[9]:e431-e442). In the meta-analysis of the CALGB, IFM, and GIMEMA trials, the median duration was 22 months. And in Myeloma XI, the median duration was 18 months.
As there is no randomized trial comparing different durations of maintenance, Dr. Efebera proposed that researchers conduct one. She said this “perfect study” would involve induction with an immunomodulatory agent, a proteasome inhibitor, dexamethasone, and perhaps an anti-CD38 therapy. Transplant-eligible patients would receive four cycles of induction before transplant. Transplant-ineligible patients would receive eight cycles of induction. Then, all patients would be randomized to lenalidomide maintenance for 3 years, 5 years, or 7-10 years.
Until a trial like this reveals the optimal duration of maintenance, we cannot conclude that treating patients until progression is better, Dr. Efebera said.
She added that maintenance has been shown to have detrimental effects, and these should be taken into consideration. For instance, neutropenia, other hematologic adverse events, and second primary malignancies have been shown to be more common among patients who receive lenalidomide maintenance (N Engl J Med. 2012; 366:1782-91).
The cost of maintenance is another factor to consider. Researchers analyzed data from the CALGB 100104 and IFM 2005-02 trials to compare the cost of lenalidomide maintenance with no maintenance. In the CALGB 100104 trial, patients who received lenalidomide maintenance had 5.72 quality-adjusted life years (QALYs), and those who received no maintenance had 4.61 QALYs. The incremental cost-utility ratio (ICUR) was more than 277,000 euros per QALY.
In the IFM2005-02 trial, patients in the lenalidomide group had 5.13 QALYs, and those who didn’t receive maintenance had 4.98 QALYs. The ICUR was more than 1.5 million euros per QALY. The researchers said the high ICURs and budgetary impact add “uncertainty about the maximum prudent duration of the treatment” (Bone Marrow Transplant. 2019 May 31. doi: 10.1038/s41409-019-0574-5).
Dr. Efebera reported relationships with Akcea Therapeutics, Janssen, and Takeda. Dr. Shah reported having no relevant financial relationships.
EXPERT ANALYSIS FROM NCCN HEMATOLOGIC MALIGNANCIES
Atezolizumab plus chemo gives slight PFS edge in mUC
BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.
Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.
“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.
Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.
IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.
The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.
As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.
At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).
An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.
A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).
The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.
Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.
Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.
Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.
“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.
But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.
“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.
He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”
The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.
BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.
Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.
“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.
Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.
IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.
The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.
As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.
At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).
An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.
A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).
The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.
Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.
Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.
Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.
“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.
But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.
“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.
He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”
The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.
BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.
Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.
“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.
Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.
IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.
The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.
As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.
At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).
An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.
A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).
The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.
Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.
Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.
Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.
“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.
But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.
“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.
He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”
The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.
REPORTING FROM ESMO 2019