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Does optimal iron absorption include vitamin C?
Her blood work shows a hematocrit level of 32, a mean corpuscular volume of 77, a platelet count of 390,000, and a ferritin level of 5.
What would you recommend for iron replacement?
A. FeSO4 325 mg three times a day with vitamin C
B. FeSO4 325 mg daily with vitamin C
C. FeSO4 325 mg every other day
Recommendations and supporting research
I think I would start with choice C, FeSO4 every other day.
Treatment of iron deficiency with oral iron has traditionally been done by giving 150-200 mg of elemental iron (which is equal to three 325 mg tablets of iron sulfate).1 This dosing regimen has considerable gastrointestinal side effects. Recent evidence has shown that iron absorption is diminished the more frequently it is given.
Stoffel and colleagues found that fractional iron absorption was higher in iron-deficient women who were given iron every other day, compared with those who received daily iron.2 They also found that the more frequently iron was administered, the higher the hepcidin levels were, and the lower the iron absorption.
Karacok and colleagues studied every other day iron versus daily iron for the treatment of iron-deficiency anemia of pregnancy.3 A total of 217 women completed randomization and participated in the study, with all women receiving 100 mg of elemental iron, either daily (111) or every other day (106). There was no significant difference in increase in ferritin levels, or hemoglobin increase between the groups. The daily iron group had more gastrointestinal symptoms (41.4%) than the every other day iron group (15.1%) (P < .0057).
Düzen Oflas and colleagues looked at the same question in nonpregnant women with iron deficiency anemia.4 Study patients either received 80 mg iron sulfate twice a day, 80 mg once a day, or 80 mg every other day. There was no statistically significant difference in hemoglobin improvement between groups, but the group that received twice a day dosing of iron had statistically significantly higher ferritin levels than the daily or every other day iron groups. This improvement in ferritin levels came at a cost, though, as 68% of patients in the twice daily iron group had gastrointestinal symptoms, compared with only 10% in the every other day iron group (P < .01).
Vitamin C is often recommended to be taken with iron to promote absorption. The evidence for this practice is scant, and dates back almost 50 years.5,6
Cook and Reddy found there was no significant difference in mean iron absorption among the three dietary periods studied in 12 patients despite a range of mean daily intakes of dietary vitamin C of 51-247 mg/d.7
Hunt and colleagues studied 25 non pregnant, healthy women with low ferritin levels.8 The women’s meals were supplemented with vitamin C (500 mg, three times a day) for 5 of the 10 weeks, in a double-blind, crossover design. Vitamin C supplementation did not lead to a difference in iron absorption, lab indices of iron deficiency, or the biological half-life of iron.
Li and colleagues looked at the effect of vitamin C supplementation on iron levels in women with iron deficiency anemia.9 A total of 440 women were recruited, with 432 completing the trial. Women were randomized to receive iron supplements plus vitamin C or iron supplements only. Their findings were that oral iron supplements alone were equivalent to oral iron supplements plus vitamin C in improving hemoglobin recovery and iron absorption.
Bottom line
Less frequent administration of iron supplements (every other day) is as effective as more frequent administration, with less GI symptoms. Also, adding vitamin C does not appear to improve absorption of iron supplements.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. 1. Fairbanks VF and Beutler E. Iron deficiency, in “Williams Textbook of Hematology, 6th ed.” (New York: McGraw-Hill, 2001).
2. Stoffel N et al. Lancet Haematology. 2017;4: e524-33.
3. Karakoc G et al. J Matern Fetal Neonatal Med. 2021 Apr 18:1-5
4. Düzen Oflas N et al. Intern Med J. 2020 Jul;50(7):854-8
5. Cook JD and Monsen ER. Am J Clin Nutr. 1977;30:235-41.
6. Hallberg L etal. Hum Nutr Appl Nutr. 1986;40: 97-113.
7. Cook JD and Reddy M. Am J Clin Nutr. 2001;73:93-8.
8. Hunt JR et al. Am J Clin Nutr. 1994 Jun;59(6):1381-5.
9. Li N et al. JAMA Netw Open. 2020 Nov 2;3(11):e2023644.
Her blood work shows a hematocrit level of 32, a mean corpuscular volume of 77, a platelet count of 390,000, and a ferritin level of 5.
What would you recommend for iron replacement?
A. FeSO4 325 mg three times a day with vitamin C
B. FeSO4 325 mg daily with vitamin C
C. FeSO4 325 mg every other day
Recommendations and supporting research
I think I would start with choice C, FeSO4 every other day.
Treatment of iron deficiency with oral iron has traditionally been done by giving 150-200 mg of elemental iron (which is equal to three 325 mg tablets of iron sulfate).1 This dosing regimen has considerable gastrointestinal side effects. Recent evidence has shown that iron absorption is diminished the more frequently it is given.
Stoffel and colleagues found that fractional iron absorption was higher in iron-deficient women who were given iron every other day, compared with those who received daily iron.2 They also found that the more frequently iron was administered, the higher the hepcidin levels were, and the lower the iron absorption.
Karacok and colleagues studied every other day iron versus daily iron for the treatment of iron-deficiency anemia of pregnancy.3 A total of 217 women completed randomization and participated in the study, with all women receiving 100 mg of elemental iron, either daily (111) or every other day (106). There was no significant difference in increase in ferritin levels, or hemoglobin increase between the groups. The daily iron group had more gastrointestinal symptoms (41.4%) than the every other day iron group (15.1%) (P < .0057).
Düzen Oflas and colleagues looked at the same question in nonpregnant women with iron deficiency anemia.4 Study patients either received 80 mg iron sulfate twice a day, 80 mg once a day, or 80 mg every other day. There was no statistically significant difference in hemoglobin improvement between groups, but the group that received twice a day dosing of iron had statistically significantly higher ferritin levels than the daily or every other day iron groups. This improvement in ferritin levels came at a cost, though, as 68% of patients in the twice daily iron group had gastrointestinal symptoms, compared with only 10% in the every other day iron group (P < .01).
Vitamin C is often recommended to be taken with iron to promote absorption. The evidence for this practice is scant, and dates back almost 50 years.5,6
Cook and Reddy found there was no significant difference in mean iron absorption among the three dietary periods studied in 12 patients despite a range of mean daily intakes of dietary vitamin C of 51-247 mg/d.7
Hunt and colleagues studied 25 non pregnant, healthy women with low ferritin levels.8 The women’s meals were supplemented with vitamin C (500 mg, three times a day) for 5 of the 10 weeks, in a double-blind, crossover design. Vitamin C supplementation did not lead to a difference in iron absorption, lab indices of iron deficiency, or the biological half-life of iron.
Li and colleagues looked at the effect of vitamin C supplementation on iron levels in women with iron deficiency anemia.9 A total of 440 women were recruited, with 432 completing the trial. Women were randomized to receive iron supplements plus vitamin C or iron supplements only. Their findings were that oral iron supplements alone were equivalent to oral iron supplements plus vitamin C in improving hemoglobin recovery and iron absorption.
Bottom line
Less frequent administration of iron supplements (every other day) is as effective as more frequent administration, with less GI symptoms. Also, adding vitamin C does not appear to improve absorption of iron supplements.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. 1. Fairbanks VF and Beutler E. Iron deficiency, in “Williams Textbook of Hematology, 6th ed.” (New York: McGraw-Hill, 2001).
2. Stoffel N et al. Lancet Haematology. 2017;4: e524-33.
3. Karakoc G et al. J Matern Fetal Neonatal Med. 2021 Apr 18:1-5
4. Düzen Oflas N et al. Intern Med J. 2020 Jul;50(7):854-8
5. Cook JD and Monsen ER. Am J Clin Nutr. 1977;30:235-41.
6. Hallberg L etal. Hum Nutr Appl Nutr. 1986;40: 97-113.
7. Cook JD and Reddy M. Am J Clin Nutr. 2001;73:93-8.
8. Hunt JR et al. Am J Clin Nutr. 1994 Jun;59(6):1381-5.
9. Li N et al. JAMA Netw Open. 2020 Nov 2;3(11):e2023644.
Her blood work shows a hematocrit level of 32, a mean corpuscular volume of 77, a platelet count of 390,000, and a ferritin level of 5.
What would you recommend for iron replacement?
A. FeSO4 325 mg three times a day with vitamin C
B. FeSO4 325 mg daily with vitamin C
C. FeSO4 325 mg every other day
Recommendations and supporting research
I think I would start with choice C, FeSO4 every other day.
Treatment of iron deficiency with oral iron has traditionally been done by giving 150-200 mg of elemental iron (which is equal to three 325 mg tablets of iron sulfate).1 This dosing regimen has considerable gastrointestinal side effects. Recent evidence has shown that iron absorption is diminished the more frequently it is given.
Stoffel and colleagues found that fractional iron absorption was higher in iron-deficient women who were given iron every other day, compared with those who received daily iron.2 They also found that the more frequently iron was administered, the higher the hepcidin levels were, and the lower the iron absorption.
Karacok and colleagues studied every other day iron versus daily iron for the treatment of iron-deficiency anemia of pregnancy.3 A total of 217 women completed randomization and participated in the study, with all women receiving 100 mg of elemental iron, either daily (111) or every other day (106). There was no significant difference in increase in ferritin levels, or hemoglobin increase between the groups. The daily iron group had more gastrointestinal symptoms (41.4%) than the every other day iron group (15.1%) (P < .0057).
Düzen Oflas and colleagues looked at the same question in nonpregnant women with iron deficiency anemia.4 Study patients either received 80 mg iron sulfate twice a day, 80 mg once a day, or 80 mg every other day. There was no statistically significant difference in hemoglobin improvement between groups, but the group that received twice a day dosing of iron had statistically significantly higher ferritin levels than the daily or every other day iron groups. This improvement in ferritin levels came at a cost, though, as 68% of patients in the twice daily iron group had gastrointestinal symptoms, compared with only 10% in the every other day iron group (P < .01).
Vitamin C is often recommended to be taken with iron to promote absorption. The evidence for this practice is scant, and dates back almost 50 years.5,6
Cook and Reddy found there was no significant difference in mean iron absorption among the three dietary periods studied in 12 patients despite a range of mean daily intakes of dietary vitamin C of 51-247 mg/d.7
Hunt and colleagues studied 25 non pregnant, healthy women with low ferritin levels.8 The women’s meals were supplemented with vitamin C (500 mg, three times a day) for 5 of the 10 weeks, in a double-blind, crossover design. Vitamin C supplementation did not lead to a difference in iron absorption, lab indices of iron deficiency, or the biological half-life of iron.
Li and colleagues looked at the effect of vitamin C supplementation on iron levels in women with iron deficiency anemia.9 A total of 440 women were recruited, with 432 completing the trial. Women were randomized to receive iron supplements plus vitamin C or iron supplements only. Their findings were that oral iron supplements alone were equivalent to oral iron supplements plus vitamin C in improving hemoglobin recovery and iron absorption.
Bottom line
Less frequent administration of iron supplements (every other day) is as effective as more frequent administration, with less GI symptoms. Also, adding vitamin C does not appear to improve absorption of iron supplements.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].
References
1. 1. Fairbanks VF and Beutler E. Iron deficiency, in “Williams Textbook of Hematology, 6th ed.” (New York: McGraw-Hill, 2001).
2. Stoffel N et al. Lancet Haematology. 2017;4: e524-33.
3. Karakoc G et al. J Matern Fetal Neonatal Med. 2021 Apr 18:1-5
4. Düzen Oflas N et al. Intern Med J. 2020 Jul;50(7):854-8
5. Cook JD and Monsen ER. Am J Clin Nutr. 1977;30:235-41.
6. Hallberg L etal. Hum Nutr Appl Nutr. 1986;40: 97-113.
7. Cook JD and Reddy M. Am J Clin Nutr. 2001;73:93-8.
8. Hunt JR et al. Am J Clin Nutr. 1994 Jun;59(6):1381-5.
9. Li N et al. JAMA Netw Open. 2020 Nov 2;3(11):e2023644.
Bleeding events tied to higher mortality in patients with factor V inhibition
Coagulation factor V (FV) inhibitor is a rare disease with a mortality rate of nearly 15%. Increased mortality was significantly associated with the incidence of major bleeding, according to a review of PubMed case reports published in Thrombosis Update.
FV autoantibodies are most often detected in patients in the postoperative state, in those who have received a blood transfusion, in patients treated with antibiotics, and in those with immune diseases, according to the online report by Hideo Wada, MD, PhD, of the Mie Prefectural General Medical Center, Yokkaichi, Japan, and colleagues. These patients who acquired immune FV inhibitor (AIFVD) vary widely in symptoms from asymptomatic to mild or severe hemorrhagic manifestations, with some reports of thrombotic complications, the authors added.
Their review assessed the PubMed literature from Jan. 1, 1968, to July 31, 2020, and found 212 case reports on acquired FV deficiency. Of these, 150 cases with confirmed FV inhibitor positivity were included. The 150 reported cases of FV inhibitor were primarily from the United States (n = 48) and Japan (n = 43). The median patient age was 68.0 years, and the female to male ratio of patients was 0.47, according to the authors. The largest associated percentage of underlying conditions were postoperative state (25.3%), idiopathic (18.7%), infection (12.7%) and malignant neoplasms and autoimmune disease, at 7.3% each.
Major bleeds
A total of 73 cases were positive for major bleeding (48.7%) and 30 cases were negative (20.0%), while the rest were undetermined (31.3%). The FV activity was ≤ 28% in all patients with FV inhibitor.
The overall mortality rate was 14.6%, with half of the nonsurvivors dying of major bleeding. The mortality rate was more than twofold higher in the group with major bleeding (23.3% mortality) compared to the group without major bleeding (10.0%), yielding an odds ratio of 2.73 of death because of a major bleed. The most frequent types of fatal bleeding were intracranial bleeding and gastrointestinal bleeding. Of the 20 deaths reported in 135 patients with data, the causes of death were major bleeding (12 patients), infection (6 patients) and thrombosis (2 patients). Remission was observed in three of the nonsurvivors, indicating that even after remission, patients with FV inhibitor might still be susceptible to infection or thrombosis, according to the authors.
“[Major bleeding] should be treated aggressively; however, the best treatment is not clear and even patients in remission should be followed closely due to the risk of death from infection or thrombosis,” the authors concluded.
They reported having no conflicts of interest.
Coagulation factor V (FV) inhibitor is a rare disease with a mortality rate of nearly 15%. Increased mortality was significantly associated with the incidence of major bleeding, according to a review of PubMed case reports published in Thrombosis Update.
FV autoantibodies are most often detected in patients in the postoperative state, in those who have received a blood transfusion, in patients treated with antibiotics, and in those with immune diseases, according to the online report by Hideo Wada, MD, PhD, of the Mie Prefectural General Medical Center, Yokkaichi, Japan, and colleagues. These patients who acquired immune FV inhibitor (AIFVD) vary widely in symptoms from asymptomatic to mild or severe hemorrhagic manifestations, with some reports of thrombotic complications, the authors added.
Their review assessed the PubMed literature from Jan. 1, 1968, to July 31, 2020, and found 212 case reports on acquired FV deficiency. Of these, 150 cases with confirmed FV inhibitor positivity were included. The 150 reported cases of FV inhibitor were primarily from the United States (n = 48) and Japan (n = 43). The median patient age was 68.0 years, and the female to male ratio of patients was 0.47, according to the authors. The largest associated percentage of underlying conditions were postoperative state (25.3%), idiopathic (18.7%), infection (12.7%) and malignant neoplasms and autoimmune disease, at 7.3% each.
Major bleeds
A total of 73 cases were positive for major bleeding (48.7%) and 30 cases were negative (20.0%), while the rest were undetermined (31.3%). The FV activity was ≤ 28% in all patients with FV inhibitor.
The overall mortality rate was 14.6%, with half of the nonsurvivors dying of major bleeding. The mortality rate was more than twofold higher in the group with major bleeding (23.3% mortality) compared to the group without major bleeding (10.0%), yielding an odds ratio of 2.73 of death because of a major bleed. The most frequent types of fatal bleeding were intracranial bleeding and gastrointestinal bleeding. Of the 20 deaths reported in 135 patients with data, the causes of death were major bleeding (12 patients), infection (6 patients) and thrombosis (2 patients). Remission was observed in three of the nonsurvivors, indicating that even after remission, patients with FV inhibitor might still be susceptible to infection or thrombosis, according to the authors.
“[Major bleeding] should be treated aggressively; however, the best treatment is not clear and even patients in remission should be followed closely due to the risk of death from infection or thrombosis,” the authors concluded.
They reported having no conflicts of interest.
Coagulation factor V (FV) inhibitor is a rare disease with a mortality rate of nearly 15%. Increased mortality was significantly associated with the incidence of major bleeding, according to a review of PubMed case reports published in Thrombosis Update.
FV autoantibodies are most often detected in patients in the postoperative state, in those who have received a blood transfusion, in patients treated with antibiotics, and in those with immune diseases, according to the online report by Hideo Wada, MD, PhD, of the Mie Prefectural General Medical Center, Yokkaichi, Japan, and colleagues. These patients who acquired immune FV inhibitor (AIFVD) vary widely in symptoms from asymptomatic to mild or severe hemorrhagic manifestations, with some reports of thrombotic complications, the authors added.
Their review assessed the PubMed literature from Jan. 1, 1968, to July 31, 2020, and found 212 case reports on acquired FV deficiency. Of these, 150 cases with confirmed FV inhibitor positivity were included. The 150 reported cases of FV inhibitor were primarily from the United States (n = 48) and Japan (n = 43). The median patient age was 68.0 years, and the female to male ratio of patients was 0.47, according to the authors. The largest associated percentage of underlying conditions were postoperative state (25.3%), idiopathic (18.7%), infection (12.7%) and malignant neoplasms and autoimmune disease, at 7.3% each.
Major bleeds
A total of 73 cases were positive for major bleeding (48.7%) and 30 cases were negative (20.0%), while the rest were undetermined (31.3%). The FV activity was ≤ 28% in all patients with FV inhibitor.
The overall mortality rate was 14.6%, with half of the nonsurvivors dying of major bleeding. The mortality rate was more than twofold higher in the group with major bleeding (23.3% mortality) compared to the group without major bleeding (10.0%), yielding an odds ratio of 2.73 of death because of a major bleed. The most frequent types of fatal bleeding were intracranial bleeding and gastrointestinal bleeding. Of the 20 deaths reported in 135 patients with data, the causes of death were major bleeding (12 patients), infection (6 patients) and thrombosis (2 patients). Remission was observed in three of the nonsurvivors, indicating that even after remission, patients with FV inhibitor might still be susceptible to infection or thrombosis, according to the authors.
“[Major bleeding] should be treated aggressively; however, the best treatment is not clear and even patients in remission should be followed closely due to the risk of death from infection or thrombosis,” the authors concluded.
They reported having no conflicts of interest.
FROM THROMBOSIS UPDATE
Infusion centers may best EDs for treating sickle cell crises
At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.
“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”
To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.
The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.
The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs.
Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.
The investigators used propensity score methodology to balance patient characteristics in the study groups.
Quick, effective pain reduction is beneficial
The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write.
Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.
The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note.
“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write.
“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.
Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote.
The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study.
“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
Infusion centers are scarce
“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.
“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.”
The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.
“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”
To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.
The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.
The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs.
Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.
The investigators used propensity score methodology to balance patient characteristics in the study groups.
Quick, effective pain reduction is beneficial
The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write.
Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.
The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note.
“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write.
“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.
Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote.
The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study.
“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
Infusion centers are scarce
“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.
“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.”
The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.
“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”
To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.
The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.
The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs.
Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.
The investigators used propensity score methodology to balance patient characteristics in the study groups.
Quick, effective pain reduction is beneficial
The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write.
Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.
The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note.
“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write.
“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.
Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote.
The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study.
“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
Infusion centers are scarce
“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.
“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.”
The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CDC notes sharp declines in breast and cervical cancer screening
The new data come from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a program that provides cancer screening services to women with low income and inadequate health insurance.
The data show that the total number of screenings funded by the NBCCEDP declined by 87% for breast cancer screening and by 84% for cervical cancer screening in April 2020 in comparison with the previous 5-year averages for that month.
The declines in breast cancer screening varied from 84% among Hispanic women to 98% among American Indian/Alaskan Native women. The declines in cervical cancer screening varied from 82% among Black women to 92% among Asian Pacific Islander women.
In April 2020, breast cancer screening declined by 86% in metro areas, 88% in urban areas, and 89% in rural areas in comparison with respective 5-year averages. For cervical cancer screenings, the corresponding declines were 85%, 77%, and 82%.
The findings are consistent with those from studies conducted in insured populations, note the authors, led by the Amy DeGroff, PhD, MPH, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion.
“Prolonged delays in screening related to the COVID-19 pandemic may lead to delayed diagnoses, poor health consequences, and an increase in cancer disparities among women already experiencing health inequities,” the CDC states in a press release.
Women from racial and ethnic minority groups already face a disproportionate burden of cervical and breast cancers in the United States: Black women and Hispanic women have the highest rates of cervical cancer incidence (8.3 and 8.9 per 100,000 women, respectively, vs. 7.3 per 100,000 among White women) and the highest rates of cervical cancer deaths. Black women have the highest rate of breast cancer death (26.9 per 100,000 women, vs. 19.4 per 100,000 among White women), the study authors explain.
Although the volume of screening began to recover in May 2020 – test volumes for breast and cervical cancer were 39% and 40% below the 5-year average by June 2020 – breast cancer screening in rural areas remained 52% below the 5-year average, they report.
The findings were published online June 30 in Preventive Medicine.
“This study highlights a decline in cancer screening among women of racial and ethnic minority groups with low incomes when their access to medical services decreased at the beginning of the pandemic,” Dr. DeGroff comments in the CDC press release.
The findings “reinforce the need to safely maintain routine health care services during the pandemic, especially when the health care environment meets COVID-19 safety guidelines,” she adds.
The investigators used NBCCEDP administrative and program data reported to the CDC by awardees – organizations that receive funding to implement the NBCCEDP – to assess the impact of COVID-19 on the number of breast and cervical cancer screening tests administered through the program and the effects of COVID-19 on the availability of screening services and NBCCEDP awardees’ capacity to support partner clinics.
A total of 630,264 breast and 594,566 cervical cancer screening tests were conducted during the review period of January-June 2015-2020.
Despite COVID-related challenges, “a large number of awardees reported flexibility and creative efforts to reach women and support clinics’ resumption of clinical care, including screening, during the COVID-19 pandemic,” the authors write.
“[The] CDC encourages health care professionals to help minimize delays in testing by continuing routine cancer screening for women having symptoms or at high risk for breast or cervical cancer,” Dr. DeGroff commented. “The Early Detection Program can help women overcome barriers to health equity by educating them about the importance of routine screening, addressing their concerns about COVID-19 transmission, and helping them to safely access screening through interventions like patient navigation.”
Future studies will examine the effect of the pandemic on screening during the second half of 2020, when surges of COVID-19 and their timing varied geographically, they note.
A version of this article first appeared on Medscape.com.
The new data come from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a program that provides cancer screening services to women with low income and inadequate health insurance.
The data show that the total number of screenings funded by the NBCCEDP declined by 87% for breast cancer screening and by 84% for cervical cancer screening in April 2020 in comparison with the previous 5-year averages for that month.
The declines in breast cancer screening varied from 84% among Hispanic women to 98% among American Indian/Alaskan Native women. The declines in cervical cancer screening varied from 82% among Black women to 92% among Asian Pacific Islander women.
In April 2020, breast cancer screening declined by 86% in metro areas, 88% in urban areas, and 89% in rural areas in comparison with respective 5-year averages. For cervical cancer screenings, the corresponding declines were 85%, 77%, and 82%.
The findings are consistent with those from studies conducted in insured populations, note the authors, led by the Amy DeGroff, PhD, MPH, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion.
“Prolonged delays in screening related to the COVID-19 pandemic may lead to delayed diagnoses, poor health consequences, and an increase in cancer disparities among women already experiencing health inequities,” the CDC states in a press release.
Women from racial and ethnic minority groups already face a disproportionate burden of cervical and breast cancers in the United States: Black women and Hispanic women have the highest rates of cervical cancer incidence (8.3 and 8.9 per 100,000 women, respectively, vs. 7.3 per 100,000 among White women) and the highest rates of cervical cancer deaths. Black women have the highest rate of breast cancer death (26.9 per 100,000 women, vs. 19.4 per 100,000 among White women), the study authors explain.
Although the volume of screening began to recover in May 2020 – test volumes for breast and cervical cancer were 39% and 40% below the 5-year average by June 2020 – breast cancer screening in rural areas remained 52% below the 5-year average, they report.
The findings were published online June 30 in Preventive Medicine.
“This study highlights a decline in cancer screening among women of racial and ethnic minority groups with low incomes when their access to medical services decreased at the beginning of the pandemic,” Dr. DeGroff comments in the CDC press release.
The findings “reinforce the need to safely maintain routine health care services during the pandemic, especially when the health care environment meets COVID-19 safety guidelines,” she adds.
The investigators used NBCCEDP administrative and program data reported to the CDC by awardees – organizations that receive funding to implement the NBCCEDP – to assess the impact of COVID-19 on the number of breast and cervical cancer screening tests administered through the program and the effects of COVID-19 on the availability of screening services and NBCCEDP awardees’ capacity to support partner clinics.
A total of 630,264 breast and 594,566 cervical cancer screening tests were conducted during the review period of January-June 2015-2020.
Despite COVID-related challenges, “a large number of awardees reported flexibility and creative efforts to reach women and support clinics’ resumption of clinical care, including screening, during the COVID-19 pandemic,” the authors write.
“[The] CDC encourages health care professionals to help minimize delays in testing by continuing routine cancer screening for women having symptoms or at high risk for breast or cervical cancer,” Dr. DeGroff commented. “The Early Detection Program can help women overcome barriers to health equity by educating them about the importance of routine screening, addressing their concerns about COVID-19 transmission, and helping them to safely access screening through interventions like patient navigation.”
Future studies will examine the effect of the pandemic on screening during the second half of 2020, when surges of COVID-19 and their timing varied geographically, they note.
A version of this article first appeared on Medscape.com.
The new data come from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a program that provides cancer screening services to women with low income and inadequate health insurance.
The data show that the total number of screenings funded by the NBCCEDP declined by 87% for breast cancer screening and by 84% for cervical cancer screening in April 2020 in comparison with the previous 5-year averages for that month.
The declines in breast cancer screening varied from 84% among Hispanic women to 98% among American Indian/Alaskan Native women. The declines in cervical cancer screening varied from 82% among Black women to 92% among Asian Pacific Islander women.
In April 2020, breast cancer screening declined by 86% in metro areas, 88% in urban areas, and 89% in rural areas in comparison with respective 5-year averages. For cervical cancer screenings, the corresponding declines were 85%, 77%, and 82%.
The findings are consistent with those from studies conducted in insured populations, note the authors, led by the Amy DeGroff, PhD, MPH, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion.
“Prolonged delays in screening related to the COVID-19 pandemic may lead to delayed diagnoses, poor health consequences, and an increase in cancer disparities among women already experiencing health inequities,” the CDC states in a press release.
Women from racial and ethnic minority groups already face a disproportionate burden of cervical and breast cancers in the United States: Black women and Hispanic women have the highest rates of cervical cancer incidence (8.3 and 8.9 per 100,000 women, respectively, vs. 7.3 per 100,000 among White women) and the highest rates of cervical cancer deaths. Black women have the highest rate of breast cancer death (26.9 per 100,000 women, vs. 19.4 per 100,000 among White women), the study authors explain.
Although the volume of screening began to recover in May 2020 – test volumes for breast and cervical cancer were 39% and 40% below the 5-year average by June 2020 – breast cancer screening in rural areas remained 52% below the 5-year average, they report.
The findings were published online June 30 in Preventive Medicine.
“This study highlights a decline in cancer screening among women of racial and ethnic minority groups with low incomes when their access to medical services decreased at the beginning of the pandemic,” Dr. DeGroff comments in the CDC press release.
The findings “reinforce the need to safely maintain routine health care services during the pandemic, especially when the health care environment meets COVID-19 safety guidelines,” she adds.
The investigators used NBCCEDP administrative and program data reported to the CDC by awardees – organizations that receive funding to implement the NBCCEDP – to assess the impact of COVID-19 on the number of breast and cervical cancer screening tests administered through the program and the effects of COVID-19 on the availability of screening services and NBCCEDP awardees’ capacity to support partner clinics.
A total of 630,264 breast and 594,566 cervical cancer screening tests were conducted during the review period of January-June 2015-2020.
Despite COVID-related challenges, “a large number of awardees reported flexibility and creative efforts to reach women and support clinics’ resumption of clinical care, including screening, during the COVID-19 pandemic,” the authors write.
“[The] CDC encourages health care professionals to help minimize delays in testing by continuing routine cancer screening for women having symptoms or at high risk for breast or cervical cancer,” Dr. DeGroff commented. “The Early Detection Program can help women overcome barriers to health equity by educating them about the importance of routine screening, addressing their concerns about COVID-19 transmission, and helping them to safely access screening through interventions like patient navigation.”
Future studies will examine the effect of the pandemic on screening during the second half of 2020, when surges of COVID-19 and their timing varied geographically, they note.
A version of this article first appeared on Medscape.com.
Reversal agents curb DOAC-related bleeding but deaths still high
Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.
Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).
“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.
The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.
“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.
To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”
More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.
As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.
Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.
The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.
Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.
Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.
The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.
“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”
Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.
“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.
The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”
Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.
Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.
In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.
“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”
No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.
A version of this article first appeared on Medscape.com.
Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.
Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).
“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.
The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.
“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.
To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”
More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.
As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.
Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.
The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.
Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.
Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.
The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.
“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”
Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.
“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.
The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”
Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.
Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.
In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.
“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”
No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.
A version of this article first appeared on Medscape.com.
Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.
Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).
“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.
The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.
“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.
To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”
More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.
As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.
Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.
The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.
Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.
Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.
The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.
“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”
Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.
“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.
The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”
Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.
Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.
In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.
“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”
No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.
A version of this article first appeared on Medscape.com.
First year of life sees initial bleeding episodes in children with von Willebrand disease
To remedy a lack of data on infants and toddlers with von Willebrand disease (VWD), researchers examined data on patients collected from the U.S. Hemophilia Treatment Center Network. They examined birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were younger than 2 years of age.
For these patients, the mean age of diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history of VWD were diagnosed approximately 4 months earlier than those with none (P < .001), according to the report by Brandi Dupervil, DHSC, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, and colleagues.
Approximately 14% of the patients were born preterm and 13% had low birth weight, proportions that were higher than national preterm birth rates (approximately 12% and 8%, respectively). There was no way of knowing from the data whether this was due to the presence of VWD or other factors, according to the report (Blood Adv. 2021;5[8]:2079-86).
Specialized care
The study found that initial bleeding episodes were most commonly oropharyngeal, related to circumcision, or intracranial or extracranial, and that most initial bleeding episodes occurred within the first year of life, according to the researchers.
Overall, there were 274 bleeding episodes among 73 children, including oral/nasal episodes (38 patients experienced 166 episodes), soft tissue hematomas (15 patients experienced 57 episodes), and head injuries, including skull fractures (13 patients experienced 19 episodes), according to the report.
In terms of treatment, among the two-thirds of the patients who had intervention to prevent or treat bleeding, most received either plasma-derived VW factor/factor VIII concentrates or antifibrinolytics.
Overall, the researchers advocated a team approach to treating these children “including genetic counselors throughout the prepartum period who work to increase expectant mothers’ understanding of the risks associated with having a child with VWD.”
They also recommended the input of “adult and pediatric hematologists, obstetrician gynecologists, genetic counselors, nurses, and social workers throughout the pre- and postpartum period who seek to optimize outcomes and disease management.”
The authors reported that they had no competing interests.
To remedy a lack of data on infants and toddlers with von Willebrand disease (VWD), researchers examined data on patients collected from the U.S. Hemophilia Treatment Center Network. They examined birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were younger than 2 years of age.
For these patients, the mean age of diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history of VWD were diagnosed approximately 4 months earlier than those with none (P < .001), according to the report by Brandi Dupervil, DHSC, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, and colleagues.
Approximately 14% of the patients were born preterm and 13% had low birth weight, proportions that were higher than national preterm birth rates (approximately 12% and 8%, respectively). There was no way of knowing from the data whether this was due to the presence of VWD or other factors, according to the report (Blood Adv. 2021;5[8]:2079-86).
Specialized care
The study found that initial bleeding episodes were most commonly oropharyngeal, related to circumcision, or intracranial or extracranial, and that most initial bleeding episodes occurred within the first year of life, according to the researchers.
Overall, there were 274 bleeding episodes among 73 children, including oral/nasal episodes (38 patients experienced 166 episodes), soft tissue hematomas (15 patients experienced 57 episodes), and head injuries, including skull fractures (13 patients experienced 19 episodes), according to the report.
In terms of treatment, among the two-thirds of the patients who had intervention to prevent or treat bleeding, most received either plasma-derived VW factor/factor VIII concentrates or antifibrinolytics.
Overall, the researchers advocated a team approach to treating these children “including genetic counselors throughout the prepartum period who work to increase expectant mothers’ understanding of the risks associated with having a child with VWD.”
They also recommended the input of “adult and pediatric hematologists, obstetrician gynecologists, genetic counselors, nurses, and social workers throughout the pre- and postpartum period who seek to optimize outcomes and disease management.”
The authors reported that they had no competing interests.
To remedy a lack of data on infants and toddlers with von Willebrand disease (VWD), researchers examined data on patients collected from the U.S. Hemophilia Treatment Center Network. They examined birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were younger than 2 years of age.
For these patients, the mean age of diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history of VWD were diagnosed approximately 4 months earlier than those with none (P < .001), according to the report by Brandi Dupervil, DHSC, of the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, and colleagues.
Approximately 14% of the patients were born preterm and 13% had low birth weight, proportions that were higher than national preterm birth rates (approximately 12% and 8%, respectively). There was no way of knowing from the data whether this was due to the presence of VWD or other factors, according to the report (Blood Adv. 2021;5[8]:2079-86).
Specialized care
The study found that initial bleeding episodes were most commonly oropharyngeal, related to circumcision, or intracranial or extracranial, and that most initial bleeding episodes occurred within the first year of life, according to the researchers.
Overall, there were 274 bleeding episodes among 73 children, including oral/nasal episodes (38 patients experienced 166 episodes), soft tissue hematomas (15 patients experienced 57 episodes), and head injuries, including skull fractures (13 patients experienced 19 episodes), according to the report.
In terms of treatment, among the two-thirds of the patients who had intervention to prevent or treat bleeding, most received either plasma-derived VW factor/factor VIII concentrates or antifibrinolytics.
Overall, the researchers advocated a team approach to treating these children “including genetic counselors throughout the prepartum period who work to increase expectant mothers’ understanding of the risks associated with having a child with VWD.”
They also recommended the input of “adult and pediatric hematologists, obstetrician gynecologists, genetic counselors, nurses, and social workers throughout the pre- and postpartum period who seek to optimize outcomes and disease management.”
The authors reported that they had no competing interests.
FROM BLOOD ADVANCES
Elevated factor VIII troughs can lead to a higher proportion of zero bleeds in hemophilia
Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).
Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.
The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.
The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
Promising results
In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.
“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
Problems remain
In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.
“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.
The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.
Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).
Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.
The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.
The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
Promising results
In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.
“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
Problems remain
In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.
“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.
The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.
Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).
Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.
The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.
The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
Promising results
In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.
“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
Problems remain
In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.
“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.
The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.
FROM BLOOD
Venetoclax shows activity against T-ALL in children
Data from a small retrospective study suggest that venetoclax-based regimens may have activity against relapsed or refractory T-lineage acute lymphoblastic leukemia (T-ALL) in children and young adults.
Among seven patients with T-ALL treated with venetoclax (Venclexta) in combination with chemotherapy, four had complete remissions and one had a CR with incomplete recovery of blood counts (CRi), and all four patients had undetectable minimal residual disease (MRD), reported pediatric hematology/oncology fellow Amber Gibson, MD, and colleagues from the University of Texas MD Anderson Cancer Center Children’s Cancer Hospital in Houston.
“This single-institution retrospective review found that venetoclax was safe and well tolerated in combination chemotherapy regimens, thrombocytopenia and neutropenia were the most common toxicities identified, [and] venetoclax should be considered for patients with refractory T-cell ALL and investigated as up-front therapy for this patient population,” they wrote in the abstract accompanying a poster presentation at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Children with relapsed T-ALL and T-lymphoblastic lymphoma (T-LL) have a dismal prognosis, with a 3-year event-free survival rate less than 10%, according to the researchers.
To see whether venetoclax, an inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2), could improve outcomes for children with ALL, the investigators conducted a retrospective chart review of the safety and efficacy of venetoclax in young patients with relapsed/refractory ALL/LL who received the drug at their center.
They identified 10 patients aged 6-21 years (median, 18), 5 of whom had T-ALL (1 with early T-cell precursor ALL), 2 with T-LL, and 3 with B-lineage ALL (B-ALL).
The median number of prior lines of therapy was 3.5. Three of the 10 patients had received hematopoietic stem cell transplants, and the 3 patients with B-ALL had all received prior CD19-directed chimeric antigen receptor T-cell (CAR T) therapy. One of these patients received a dual CD19/CD22 CAR T product, one received CD19-directed blinotumumab.
There were no new safety signals with venetoclax, no treatment-related deaths, and no deaths within 30 days of starting venetoclax.
All 10 patients had grade 4 thrombocytopenias, 6 had grade 4 neutropenia, 3 had grade 4 febrile neutropenia, 2 had grade 4 anemia, and 1 each had grade 4 sepsis, pneumonia, or coagulopathy.
As noted, there were three CRs and one CRi, all in patients with T-ALL. All four of these patients were MRD negative by flow cytometry at a median of 22 days. The median duration of response was 17.4 months (range, 2-18 months).
At the most recent follow-up five patients were still alive, three without disease, one was still undergoing treatment, and one was alive following an allogeneic HSCT.
Early studies
Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, said that there are early studies exploring the use of venetoclax in infants with ALL.
“Venetoclax is a BCL-2 inhibitor that is pretty well tolerated, but you can also have cytopenias with it,” she said.
She noted that it is not typically used in the frontline setting in pediatric populations, but may be considered for patients with difficult-to-treat disease or for whom the relatively good toxicity profile might be appropriate.
The MD Anderson investigators did not report a funding source. The authors and Dr. Shahani reported no relevant conflicts of interest.
Data from a small retrospective study suggest that venetoclax-based regimens may have activity against relapsed or refractory T-lineage acute lymphoblastic leukemia (T-ALL) in children and young adults.
Among seven patients with T-ALL treated with venetoclax (Venclexta) in combination with chemotherapy, four had complete remissions and one had a CR with incomplete recovery of blood counts (CRi), and all four patients had undetectable minimal residual disease (MRD), reported pediatric hematology/oncology fellow Amber Gibson, MD, and colleagues from the University of Texas MD Anderson Cancer Center Children’s Cancer Hospital in Houston.
“This single-institution retrospective review found that venetoclax was safe and well tolerated in combination chemotherapy regimens, thrombocytopenia and neutropenia were the most common toxicities identified, [and] venetoclax should be considered for patients with refractory T-cell ALL and investigated as up-front therapy for this patient population,” they wrote in the abstract accompanying a poster presentation at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Children with relapsed T-ALL and T-lymphoblastic lymphoma (T-LL) have a dismal prognosis, with a 3-year event-free survival rate less than 10%, according to the researchers.
To see whether venetoclax, an inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2), could improve outcomes for children with ALL, the investigators conducted a retrospective chart review of the safety and efficacy of venetoclax in young patients with relapsed/refractory ALL/LL who received the drug at their center.
They identified 10 patients aged 6-21 years (median, 18), 5 of whom had T-ALL (1 with early T-cell precursor ALL), 2 with T-LL, and 3 with B-lineage ALL (B-ALL).
The median number of prior lines of therapy was 3.5. Three of the 10 patients had received hematopoietic stem cell transplants, and the 3 patients with B-ALL had all received prior CD19-directed chimeric antigen receptor T-cell (CAR T) therapy. One of these patients received a dual CD19/CD22 CAR T product, one received CD19-directed blinotumumab.
There were no new safety signals with venetoclax, no treatment-related deaths, and no deaths within 30 days of starting venetoclax.
All 10 patients had grade 4 thrombocytopenias, 6 had grade 4 neutropenia, 3 had grade 4 febrile neutropenia, 2 had grade 4 anemia, and 1 each had grade 4 sepsis, pneumonia, or coagulopathy.
As noted, there were three CRs and one CRi, all in patients with T-ALL. All four of these patients were MRD negative by flow cytometry at a median of 22 days. The median duration of response was 17.4 months (range, 2-18 months).
At the most recent follow-up five patients were still alive, three without disease, one was still undergoing treatment, and one was alive following an allogeneic HSCT.
Early studies
Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, said that there are early studies exploring the use of venetoclax in infants with ALL.
“Venetoclax is a BCL-2 inhibitor that is pretty well tolerated, but you can also have cytopenias with it,” she said.
She noted that it is not typically used in the frontline setting in pediatric populations, but may be considered for patients with difficult-to-treat disease or for whom the relatively good toxicity profile might be appropriate.
The MD Anderson investigators did not report a funding source. The authors and Dr. Shahani reported no relevant conflicts of interest.
Data from a small retrospective study suggest that venetoclax-based regimens may have activity against relapsed or refractory T-lineage acute lymphoblastic leukemia (T-ALL) in children and young adults.
Among seven patients with T-ALL treated with venetoclax (Venclexta) in combination with chemotherapy, four had complete remissions and one had a CR with incomplete recovery of blood counts (CRi), and all four patients had undetectable minimal residual disease (MRD), reported pediatric hematology/oncology fellow Amber Gibson, MD, and colleagues from the University of Texas MD Anderson Cancer Center Children’s Cancer Hospital in Houston.
“This single-institution retrospective review found that venetoclax was safe and well tolerated in combination chemotherapy regimens, thrombocytopenia and neutropenia were the most common toxicities identified, [and] venetoclax should be considered for patients with refractory T-cell ALL and investigated as up-front therapy for this patient population,” they wrote in the abstract accompanying a poster presentation at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Children with relapsed T-ALL and T-lymphoblastic lymphoma (T-LL) have a dismal prognosis, with a 3-year event-free survival rate less than 10%, according to the researchers.
To see whether venetoclax, an inhibitor of the antiapoptotic protein B-cell lymphoma-2 (BCL-2), could improve outcomes for children with ALL, the investigators conducted a retrospective chart review of the safety and efficacy of venetoclax in young patients with relapsed/refractory ALL/LL who received the drug at their center.
They identified 10 patients aged 6-21 years (median, 18), 5 of whom had T-ALL (1 with early T-cell precursor ALL), 2 with T-LL, and 3 with B-lineage ALL (B-ALL).
The median number of prior lines of therapy was 3.5. Three of the 10 patients had received hematopoietic stem cell transplants, and the 3 patients with B-ALL had all received prior CD19-directed chimeric antigen receptor T-cell (CAR T) therapy. One of these patients received a dual CD19/CD22 CAR T product, one received CD19-directed blinotumumab.
There were no new safety signals with venetoclax, no treatment-related deaths, and no deaths within 30 days of starting venetoclax.
All 10 patients had grade 4 thrombocytopenias, 6 had grade 4 neutropenia, 3 had grade 4 febrile neutropenia, 2 had grade 4 anemia, and 1 each had grade 4 sepsis, pneumonia, or coagulopathy.
As noted, there were three CRs and one CRi, all in patients with T-ALL. All four of these patients were MRD negative by flow cytometry at a median of 22 days. The median duration of response was 17.4 months (range, 2-18 months).
At the most recent follow-up five patients were still alive, three without disease, one was still undergoing treatment, and one was alive following an allogeneic HSCT.
Early studies
Shilpa Shahani, MD, a pediatric oncologist and assistant clinical professor of pediatrics at City of Hope in Duarte, Calif., who was not involved in the study, said that there are early studies exploring the use of venetoclax in infants with ALL.
“Venetoclax is a BCL-2 inhibitor that is pretty well tolerated, but you can also have cytopenias with it,” she said.
She noted that it is not typically used in the frontline setting in pediatric populations, but may be considered for patients with difficult-to-treat disease or for whom the relatively good toxicity profile might be appropriate.
The MD Anderson investigators did not report a funding source. The authors and Dr. Shahani reported no relevant conflicts of interest.
FROM ASPHO 2021
Medical homes a boon to patients with bleeding disorders
As bleeding disorders are increasingly recognized as a national health priority, hematologists are focusing on how the patient-centered medical home – a widely accepted concept in primary care and in some specialties – can improve outcomes and quality life for their patients.
The patient-centered medical home is a model of health care delivery in which patients receive comprehensive, accessible care that is fully integrated across all providers and elements of a healthcare system.1 The concept emerged in the 1960s among pediatricians seeking to better coordinate care for children with complex medical needs. Since then, the patient-centered medical home has become a globally recognized standard – not only in primary care, but also in specialties such as endocrinology, oncology, and geriatric medicine. The movement to establish medical homes for patients with bleeding disorders is more recent and is receiving national attention.
Why a medical home?
The advent of prophylactic therapies for bleeding disorders has vastly improved the outlook for many patients compared to just a few decades ago. However, treatment options remain limited, and patients who have severe disease or complications – such as an inadequate treatment response or the development of inhibitory antibodies to replacement clotting factors – are at risk for recurrent breakthrough bleeding that can lead to synovitis and ultimately culminate in progressive, irreversible joint damage. The resulting pain and limitation of motion greatly compromises patients’ quality of life across physical, psychological, and social domains, undermines their ability to live and work independently, and greatly increases treatment costs.2-4 Family members, too, face high stress and lower quality of life when they struggle to obtain and manage treatment while caring for loved ones with bleeding disorders.5
For patients with bleeding disorders, a patient-centered medical home can help address or surmount these challenges, said Amy Shapiro, MD, medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis, Ind., which was the first hemophilia treatment center in the country to be formally certified as a medical home.
Dr. Shapiro explained that a patient-centered medical home leverages the care of an integrated multidisciplinary team to help optimize therapies and patient outcomes across all domains of life. She sees the medical home concept as a natural fit for patients with bleeding disorders, given the complexity of their needs and the number of specialties involved. “When you have hemophilia, you don’t just need a hematologist to manage your care. You need nurses, physical therapists, and social workers. You need coordinated care for genetic counseling. You also need to coordinate dental hygiene and surgical interventions, if these are required. Patients need nutrition counseling, and they may need assistance with education or career options if too many days are missed from work or school. Patients or their families may need counseling on choosing the right insurance program so they don’t choose a plan that may create more hardships for them because of their chronic disorder.”
Meeting these needs requires the help of an integrated care team, which many individuals with bleeding disorders lack. “If you are just out there in the community and you have medical issues that need to be dealt with, often the individuals themselves have to coordinate their own care, including their medications and their appointments with different specialists,” said Dr. Shapiro. “For example, a care provider may tell a patient that they need a physical therapist and give them some names, and then the patient has to take it from there and not only find the provider, but also determine if their insurance provides coverage.”
A medical home takes a completely different approach, she explained. “At my center, when we say you need a physical therapist, we have a physical therapist on staff. Our therapist provides an assessment and determines the need for ongoing PT and whether that can be done at home with a plan and intermittent oversight, or whether the patient needs a referral, and whether the person the patient is referred to needs education on how to provide PT for someone with hemophilia. A medical home provides all this in one place. It is a place where patients know they will receive either direct services, or support to shepherd their care and outcomes, and oversight of that support as well.”
Few studies have directly assessed the medical home model in the setting of bleeding disorders, but a number have evaluated the impact of integrated care, a more general term for the practice of coordinating multidisciplinary care to improve access and outcomes while eliminating redundancies and unnecessary costs. In a recent systematic review and meta-analysis of 27 nonrandomized studies of patients with hemophilia, integrated care was linked to lower mortality, fewer emergency room visits and hospitalizations, shorter lengths of stay in the hospital, and fewer missed days of school and work.6 Such findings, combined with promising outcomes data from studies of patient-centered medical homes in other disease settings, suggest that the patient-centered medical home can significantly benefit patients with bleeding disorders and their families and caregivers.
Creating a medical home
Establishing a patient-centered medical home can be challenging, involving a plethora of stakeholders and a considerable investment of time, energy, and resources. Organizations such as the National Committee for Quality Assurance and the Accreditation Association for Ambulatory Health Care have formal certification programs to help ensure that an inpatient or outpatient center that calls itself a medical home truly is one.7-8
The certification process requires centers to document activities in areas such as patients’ rights and responsibilities, administration and governance, patient and care team relationships, clinical records and other health information, and quality, comprehensiveness, continuity, and accessibility.7 Achieving certification is rigorous, often requiring centers to document compliance with more than 100 policies, procedures, and standards.
For the Indiana Hemophilia and Thrombosis Center, becoming certified as a medical home “was a multiyear process and an ongoing process,” said Dr. Shapiro. “It involves documentation of quality improvement initiatives, obtaining input from patients to document their satisfaction, and looking at all types of systems within our center and how we integrate care so that all those systems function together. It’s a difficult process, but treatment centers are a medical home for patients with bleeding disorders, and this is an effort to provide some documentation on a national level of how we’re doing everything that we are doing.”
She noted that the process of obtaining medical home certification may require an even higher level of commitment if a bleeding disorder (hemophilia) treatment center is embedded in a university or academic medical center. In this case, more stakeholders are involved, and more hoops may need to be jumped through to implement processes that meet medical home standards while still adhering to any requirements at the organizational level.
Certification programs for patient-centered medical homes are not designed around specific disorders or diseases, but a closer look at their compliance metrics underscores how medical homes can benefit patients with bleeding disorders. For example, to receive medical home certification from the Accreditation Association for Ambulatory Health Care, a center needs to be able to document that patients’ care is not transferred without first making arrangements with a receiving health care provider, that the quality improvement programs are peer-led, and that these programs assess and address diverse measures of clinical performance, cost-effectiveness, and administrative functioning.7-9
Medical homes, the NHPCC, and Healthy People 2030
Creating patient-centered medical homes for patients with bleeding disorders is now a quality improvement objective of the National Hemophilia Program Coordinating Center, or NHPCC. Established in 2012 and funded by the federal Health Resources and Services Administration, the NHPCC partners with the eight regional hemophilia networks and more than 140 federally funded hemophilia treatment centers across the United States to identify gaps, standardize and improve access to care, and share and promote best practices for the treatment and management of blood disorders.10
In the United States, receiving care in a hemophilia treatment center (which, despite its name, typically offers care for other disorders such as von Willebrand disease) has been linked to lower mortality and fewer hospitalizations related to bleeding complications.11 To continue to improve on these outcomes, the NHPCC, regional networks, and hemophilia treatment centers are prioritizing medical homes and ranking their establishments alongside core objectives such as bettering patient and family engagement and improving the transition from pediatric to adult care.12
As part of this quality improvement work, the NHPCC, regional leadership, and hemophilia treatment centers meet regularly to identify needs and priorities, plan programs, and ensure that each center is meeting the goals and objectives set out by its federal grant.13 Such partnerships help improve and integrate care within a coordinated national framework, Dr. Shapiro said. “We all are charged with this same mission,” she added. “That doesn’t mean that every treatment center looks exactly the same, has the same number of staff, or does everything the same way, but we all have the same mission, and we know what that is. That is the work of the NHPCC, to determine and document that and help level and improve care throughout the country.”
The NHPCC also engages other stakeholders, including consumer agencies and professional organizations. Recent achievements have included a first-ever national patient needs assessment, a tandem technical needs assessment of hemophilia treatment centers, an educational outreach program for genetic counselors, a webinar on transitioning care for adolescents, a national survey of the federal 340B Drug Pricing Program, and a survey of minority patients to identify and characterize problems such as language and insurance barriers, the lack of culturally appropriate educational materials on blood disorders, and difficulties getting transportation to treatment centers or educational programs.14
In part because of this advocacy work, the U.S. Department of Health and Human Services recently included hemophilia for the first time in Healthy People, its evidence-based set of decade-long objectives aimed at improving the health of all Americans. In Healthy People 2030, the specific objective for hemophilia is to reduce the proportion of patients with severe disease who experience more than four joint bleeds per year to 13.3% (the current estimate is 16.9%).15
For Healthy People to prioritize hemophilia for the first time alongside much more common conditions such as diabetes and heart disease reflects the challenges of managing bleeding disorders and the efforts by the NHPCC and other stakeholders to raise awareness about current needs. To track progress in meeting the Healthy People 2030 objective, the NHPCC will work with federal partners to analyze patient-level data gathered through the Centers for Disease Control’s Community Counts Registry for Bleeding Disorders Surveillance program, which collects data from hemophilia treatment centers across the United States and includes patients with all levels of disease severity.
“The inclusion of bleeding disorders in Healthy People 2030 is really very significant,” said Dr. Shapiro. “These are disorders that affect less than 200,000 Americans, which is the definition of a rare disease in this context. To have hemophilia considered as a national priority is very important, not only for hemophilia, but also for other rare diseases that may in the future also be considered as being as of national importance in this way.”
References
1. Rodriguez-Saldana J. 2019. The Patient-Centered Medical Home, Primary Care, and Diabetes. In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham.
2. J Comorb. 2011;1:51-59.
3. Eur J Haematol. 2018 Apr;100 Suppl 1:5-13.
4. Blood. 2003;102(7):2358-63.
5. Haemophilia. 2014 Jul;20(4):541-9.
6. Haemophilia. 2016;22(Suppl 3):31-40.
7. AAAHC. Medical Home.
8. NCQA. Patient-centered medical home (PCMH).
9. AAAHC, 2013. Medical Home On-Site Certification Handbook.
10. Centers for Disease Control and Prevention. HTC Population Profile.
11. Blood Transfus. 2014;12 Suppl 3(Suppl 3):e542-e548.
12. American Thrombosis and Hemostasis Network.
13. The Great Lakes Regional Hemophilia Network.
14. American Thrombosis and Hemostasis Network. What the NHPCC does.
15. U.S. Department of Health and Human Services. Healthy People 2030: Blood Disorders.
As bleeding disorders are increasingly recognized as a national health priority, hematologists are focusing on how the patient-centered medical home – a widely accepted concept in primary care and in some specialties – can improve outcomes and quality life for their patients.
The patient-centered medical home is a model of health care delivery in which patients receive comprehensive, accessible care that is fully integrated across all providers and elements of a healthcare system.1 The concept emerged in the 1960s among pediatricians seeking to better coordinate care for children with complex medical needs. Since then, the patient-centered medical home has become a globally recognized standard – not only in primary care, but also in specialties such as endocrinology, oncology, and geriatric medicine. The movement to establish medical homes for patients with bleeding disorders is more recent and is receiving national attention.
Why a medical home?
The advent of prophylactic therapies for bleeding disorders has vastly improved the outlook for many patients compared to just a few decades ago. However, treatment options remain limited, and patients who have severe disease or complications – such as an inadequate treatment response or the development of inhibitory antibodies to replacement clotting factors – are at risk for recurrent breakthrough bleeding that can lead to synovitis and ultimately culminate in progressive, irreversible joint damage. The resulting pain and limitation of motion greatly compromises patients’ quality of life across physical, psychological, and social domains, undermines their ability to live and work independently, and greatly increases treatment costs.2-4 Family members, too, face high stress and lower quality of life when they struggle to obtain and manage treatment while caring for loved ones with bleeding disorders.5
For patients with bleeding disorders, a patient-centered medical home can help address or surmount these challenges, said Amy Shapiro, MD, medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis, Ind., which was the first hemophilia treatment center in the country to be formally certified as a medical home.
Dr. Shapiro explained that a patient-centered medical home leverages the care of an integrated multidisciplinary team to help optimize therapies and patient outcomes across all domains of life. She sees the medical home concept as a natural fit for patients with bleeding disorders, given the complexity of their needs and the number of specialties involved. “When you have hemophilia, you don’t just need a hematologist to manage your care. You need nurses, physical therapists, and social workers. You need coordinated care for genetic counseling. You also need to coordinate dental hygiene and surgical interventions, if these are required. Patients need nutrition counseling, and they may need assistance with education or career options if too many days are missed from work or school. Patients or their families may need counseling on choosing the right insurance program so they don’t choose a plan that may create more hardships for them because of their chronic disorder.”
Meeting these needs requires the help of an integrated care team, which many individuals with bleeding disorders lack. “If you are just out there in the community and you have medical issues that need to be dealt with, often the individuals themselves have to coordinate their own care, including their medications and their appointments with different specialists,” said Dr. Shapiro. “For example, a care provider may tell a patient that they need a physical therapist and give them some names, and then the patient has to take it from there and not only find the provider, but also determine if their insurance provides coverage.”
A medical home takes a completely different approach, she explained. “At my center, when we say you need a physical therapist, we have a physical therapist on staff. Our therapist provides an assessment and determines the need for ongoing PT and whether that can be done at home with a plan and intermittent oversight, or whether the patient needs a referral, and whether the person the patient is referred to needs education on how to provide PT for someone with hemophilia. A medical home provides all this in one place. It is a place where patients know they will receive either direct services, or support to shepherd their care and outcomes, and oversight of that support as well.”
Few studies have directly assessed the medical home model in the setting of bleeding disorders, but a number have evaluated the impact of integrated care, a more general term for the practice of coordinating multidisciplinary care to improve access and outcomes while eliminating redundancies and unnecessary costs. In a recent systematic review and meta-analysis of 27 nonrandomized studies of patients with hemophilia, integrated care was linked to lower mortality, fewer emergency room visits and hospitalizations, shorter lengths of stay in the hospital, and fewer missed days of school and work.6 Such findings, combined with promising outcomes data from studies of patient-centered medical homes in other disease settings, suggest that the patient-centered medical home can significantly benefit patients with bleeding disorders and their families and caregivers.
Creating a medical home
Establishing a patient-centered medical home can be challenging, involving a plethora of stakeholders and a considerable investment of time, energy, and resources. Organizations such as the National Committee for Quality Assurance and the Accreditation Association for Ambulatory Health Care have formal certification programs to help ensure that an inpatient or outpatient center that calls itself a medical home truly is one.7-8
The certification process requires centers to document activities in areas such as patients’ rights and responsibilities, administration and governance, patient and care team relationships, clinical records and other health information, and quality, comprehensiveness, continuity, and accessibility.7 Achieving certification is rigorous, often requiring centers to document compliance with more than 100 policies, procedures, and standards.
For the Indiana Hemophilia and Thrombosis Center, becoming certified as a medical home “was a multiyear process and an ongoing process,” said Dr. Shapiro. “It involves documentation of quality improvement initiatives, obtaining input from patients to document their satisfaction, and looking at all types of systems within our center and how we integrate care so that all those systems function together. It’s a difficult process, but treatment centers are a medical home for patients with bleeding disorders, and this is an effort to provide some documentation on a national level of how we’re doing everything that we are doing.”
She noted that the process of obtaining medical home certification may require an even higher level of commitment if a bleeding disorder (hemophilia) treatment center is embedded in a university or academic medical center. In this case, more stakeholders are involved, and more hoops may need to be jumped through to implement processes that meet medical home standards while still adhering to any requirements at the organizational level.
Certification programs for patient-centered medical homes are not designed around specific disorders or diseases, but a closer look at their compliance metrics underscores how medical homes can benefit patients with bleeding disorders. For example, to receive medical home certification from the Accreditation Association for Ambulatory Health Care, a center needs to be able to document that patients’ care is not transferred without first making arrangements with a receiving health care provider, that the quality improvement programs are peer-led, and that these programs assess and address diverse measures of clinical performance, cost-effectiveness, and administrative functioning.7-9
Medical homes, the NHPCC, and Healthy People 2030
Creating patient-centered medical homes for patients with bleeding disorders is now a quality improvement objective of the National Hemophilia Program Coordinating Center, or NHPCC. Established in 2012 and funded by the federal Health Resources and Services Administration, the NHPCC partners with the eight regional hemophilia networks and more than 140 federally funded hemophilia treatment centers across the United States to identify gaps, standardize and improve access to care, and share and promote best practices for the treatment and management of blood disorders.10
In the United States, receiving care in a hemophilia treatment center (which, despite its name, typically offers care for other disorders such as von Willebrand disease) has been linked to lower mortality and fewer hospitalizations related to bleeding complications.11 To continue to improve on these outcomes, the NHPCC, regional networks, and hemophilia treatment centers are prioritizing medical homes and ranking their establishments alongside core objectives such as bettering patient and family engagement and improving the transition from pediatric to adult care.12
As part of this quality improvement work, the NHPCC, regional leadership, and hemophilia treatment centers meet regularly to identify needs and priorities, plan programs, and ensure that each center is meeting the goals and objectives set out by its federal grant.13 Such partnerships help improve and integrate care within a coordinated national framework, Dr. Shapiro said. “We all are charged with this same mission,” she added. “That doesn’t mean that every treatment center looks exactly the same, has the same number of staff, or does everything the same way, but we all have the same mission, and we know what that is. That is the work of the NHPCC, to determine and document that and help level and improve care throughout the country.”
The NHPCC also engages other stakeholders, including consumer agencies and professional organizations. Recent achievements have included a first-ever national patient needs assessment, a tandem technical needs assessment of hemophilia treatment centers, an educational outreach program for genetic counselors, a webinar on transitioning care for adolescents, a national survey of the federal 340B Drug Pricing Program, and a survey of minority patients to identify and characterize problems such as language and insurance barriers, the lack of culturally appropriate educational materials on blood disorders, and difficulties getting transportation to treatment centers or educational programs.14
In part because of this advocacy work, the U.S. Department of Health and Human Services recently included hemophilia for the first time in Healthy People, its evidence-based set of decade-long objectives aimed at improving the health of all Americans. In Healthy People 2030, the specific objective for hemophilia is to reduce the proportion of patients with severe disease who experience more than four joint bleeds per year to 13.3% (the current estimate is 16.9%).15
For Healthy People to prioritize hemophilia for the first time alongside much more common conditions such as diabetes and heart disease reflects the challenges of managing bleeding disorders and the efforts by the NHPCC and other stakeholders to raise awareness about current needs. To track progress in meeting the Healthy People 2030 objective, the NHPCC will work with federal partners to analyze patient-level data gathered through the Centers for Disease Control’s Community Counts Registry for Bleeding Disorders Surveillance program, which collects data from hemophilia treatment centers across the United States and includes patients with all levels of disease severity.
“The inclusion of bleeding disorders in Healthy People 2030 is really very significant,” said Dr. Shapiro. “These are disorders that affect less than 200,000 Americans, which is the definition of a rare disease in this context. To have hemophilia considered as a national priority is very important, not only for hemophilia, but also for other rare diseases that may in the future also be considered as being as of national importance in this way.”
References
1. Rodriguez-Saldana J. 2019. The Patient-Centered Medical Home, Primary Care, and Diabetes. In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham.
2. J Comorb. 2011;1:51-59.
3. Eur J Haematol. 2018 Apr;100 Suppl 1:5-13.
4. Blood. 2003;102(7):2358-63.
5. Haemophilia. 2014 Jul;20(4):541-9.
6. Haemophilia. 2016;22(Suppl 3):31-40.
7. AAAHC. Medical Home.
8. NCQA. Patient-centered medical home (PCMH).
9. AAAHC, 2013. Medical Home On-Site Certification Handbook.
10. Centers for Disease Control and Prevention. HTC Population Profile.
11. Blood Transfus. 2014;12 Suppl 3(Suppl 3):e542-e548.
12. American Thrombosis and Hemostasis Network.
13. The Great Lakes Regional Hemophilia Network.
14. American Thrombosis and Hemostasis Network. What the NHPCC does.
15. U.S. Department of Health and Human Services. Healthy People 2030: Blood Disorders.
As bleeding disorders are increasingly recognized as a national health priority, hematologists are focusing on how the patient-centered medical home – a widely accepted concept in primary care and in some specialties – can improve outcomes and quality life for their patients.
The patient-centered medical home is a model of health care delivery in which patients receive comprehensive, accessible care that is fully integrated across all providers and elements of a healthcare system.1 The concept emerged in the 1960s among pediatricians seeking to better coordinate care for children with complex medical needs. Since then, the patient-centered medical home has become a globally recognized standard – not only in primary care, but also in specialties such as endocrinology, oncology, and geriatric medicine. The movement to establish medical homes for patients with bleeding disorders is more recent and is receiving national attention.
Why a medical home?
The advent of prophylactic therapies for bleeding disorders has vastly improved the outlook for many patients compared to just a few decades ago. However, treatment options remain limited, and patients who have severe disease or complications – such as an inadequate treatment response or the development of inhibitory antibodies to replacement clotting factors – are at risk for recurrent breakthrough bleeding that can lead to synovitis and ultimately culminate in progressive, irreversible joint damage. The resulting pain and limitation of motion greatly compromises patients’ quality of life across physical, psychological, and social domains, undermines their ability to live and work independently, and greatly increases treatment costs.2-4 Family members, too, face high stress and lower quality of life when they struggle to obtain and manage treatment while caring for loved ones with bleeding disorders.5
For patients with bleeding disorders, a patient-centered medical home can help address or surmount these challenges, said Amy Shapiro, MD, medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis, Ind., which was the first hemophilia treatment center in the country to be formally certified as a medical home.
Dr. Shapiro explained that a patient-centered medical home leverages the care of an integrated multidisciplinary team to help optimize therapies and patient outcomes across all domains of life. She sees the medical home concept as a natural fit for patients with bleeding disorders, given the complexity of their needs and the number of specialties involved. “When you have hemophilia, you don’t just need a hematologist to manage your care. You need nurses, physical therapists, and social workers. You need coordinated care for genetic counseling. You also need to coordinate dental hygiene and surgical interventions, if these are required. Patients need nutrition counseling, and they may need assistance with education or career options if too many days are missed from work or school. Patients or their families may need counseling on choosing the right insurance program so they don’t choose a plan that may create more hardships for them because of their chronic disorder.”
Meeting these needs requires the help of an integrated care team, which many individuals with bleeding disorders lack. “If you are just out there in the community and you have medical issues that need to be dealt with, often the individuals themselves have to coordinate their own care, including their medications and their appointments with different specialists,” said Dr. Shapiro. “For example, a care provider may tell a patient that they need a physical therapist and give them some names, and then the patient has to take it from there and not only find the provider, but also determine if their insurance provides coverage.”
A medical home takes a completely different approach, she explained. “At my center, when we say you need a physical therapist, we have a physical therapist on staff. Our therapist provides an assessment and determines the need for ongoing PT and whether that can be done at home with a plan and intermittent oversight, or whether the patient needs a referral, and whether the person the patient is referred to needs education on how to provide PT for someone with hemophilia. A medical home provides all this in one place. It is a place where patients know they will receive either direct services, or support to shepherd their care and outcomes, and oversight of that support as well.”
Few studies have directly assessed the medical home model in the setting of bleeding disorders, but a number have evaluated the impact of integrated care, a more general term for the practice of coordinating multidisciplinary care to improve access and outcomes while eliminating redundancies and unnecessary costs. In a recent systematic review and meta-analysis of 27 nonrandomized studies of patients with hemophilia, integrated care was linked to lower mortality, fewer emergency room visits and hospitalizations, shorter lengths of stay in the hospital, and fewer missed days of school and work.6 Such findings, combined with promising outcomes data from studies of patient-centered medical homes in other disease settings, suggest that the patient-centered medical home can significantly benefit patients with bleeding disorders and their families and caregivers.
Creating a medical home
Establishing a patient-centered medical home can be challenging, involving a plethora of stakeholders and a considerable investment of time, energy, and resources. Organizations such as the National Committee for Quality Assurance and the Accreditation Association for Ambulatory Health Care have formal certification programs to help ensure that an inpatient or outpatient center that calls itself a medical home truly is one.7-8
The certification process requires centers to document activities in areas such as patients’ rights and responsibilities, administration and governance, patient and care team relationships, clinical records and other health information, and quality, comprehensiveness, continuity, and accessibility.7 Achieving certification is rigorous, often requiring centers to document compliance with more than 100 policies, procedures, and standards.
For the Indiana Hemophilia and Thrombosis Center, becoming certified as a medical home “was a multiyear process and an ongoing process,” said Dr. Shapiro. “It involves documentation of quality improvement initiatives, obtaining input from patients to document their satisfaction, and looking at all types of systems within our center and how we integrate care so that all those systems function together. It’s a difficult process, but treatment centers are a medical home for patients with bleeding disorders, and this is an effort to provide some documentation on a national level of how we’re doing everything that we are doing.”
She noted that the process of obtaining medical home certification may require an even higher level of commitment if a bleeding disorder (hemophilia) treatment center is embedded in a university or academic medical center. In this case, more stakeholders are involved, and more hoops may need to be jumped through to implement processes that meet medical home standards while still adhering to any requirements at the organizational level.
Certification programs for patient-centered medical homes are not designed around specific disorders or diseases, but a closer look at their compliance metrics underscores how medical homes can benefit patients with bleeding disorders. For example, to receive medical home certification from the Accreditation Association for Ambulatory Health Care, a center needs to be able to document that patients’ care is not transferred without first making arrangements with a receiving health care provider, that the quality improvement programs are peer-led, and that these programs assess and address diverse measures of clinical performance, cost-effectiveness, and administrative functioning.7-9
Medical homes, the NHPCC, and Healthy People 2030
Creating patient-centered medical homes for patients with bleeding disorders is now a quality improvement objective of the National Hemophilia Program Coordinating Center, or NHPCC. Established in 2012 and funded by the federal Health Resources and Services Administration, the NHPCC partners with the eight regional hemophilia networks and more than 140 federally funded hemophilia treatment centers across the United States to identify gaps, standardize and improve access to care, and share and promote best practices for the treatment and management of blood disorders.10
In the United States, receiving care in a hemophilia treatment center (which, despite its name, typically offers care for other disorders such as von Willebrand disease) has been linked to lower mortality and fewer hospitalizations related to bleeding complications.11 To continue to improve on these outcomes, the NHPCC, regional networks, and hemophilia treatment centers are prioritizing medical homes and ranking their establishments alongside core objectives such as bettering patient and family engagement and improving the transition from pediatric to adult care.12
As part of this quality improvement work, the NHPCC, regional leadership, and hemophilia treatment centers meet regularly to identify needs and priorities, plan programs, and ensure that each center is meeting the goals and objectives set out by its federal grant.13 Such partnerships help improve and integrate care within a coordinated national framework, Dr. Shapiro said. “We all are charged with this same mission,” she added. “That doesn’t mean that every treatment center looks exactly the same, has the same number of staff, or does everything the same way, but we all have the same mission, and we know what that is. That is the work of the NHPCC, to determine and document that and help level and improve care throughout the country.”
The NHPCC also engages other stakeholders, including consumer agencies and professional organizations. Recent achievements have included a first-ever national patient needs assessment, a tandem technical needs assessment of hemophilia treatment centers, an educational outreach program for genetic counselors, a webinar on transitioning care for adolescents, a national survey of the federal 340B Drug Pricing Program, and a survey of minority patients to identify and characterize problems such as language and insurance barriers, the lack of culturally appropriate educational materials on blood disorders, and difficulties getting transportation to treatment centers or educational programs.14
In part because of this advocacy work, the U.S. Department of Health and Human Services recently included hemophilia for the first time in Healthy People, its evidence-based set of decade-long objectives aimed at improving the health of all Americans. In Healthy People 2030, the specific objective for hemophilia is to reduce the proportion of patients with severe disease who experience more than four joint bleeds per year to 13.3% (the current estimate is 16.9%).15
For Healthy People to prioritize hemophilia for the first time alongside much more common conditions such as diabetes and heart disease reflects the challenges of managing bleeding disorders and the efforts by the NHPCC and other stakeholders to raise awareness about current needs. To track progress in meeting the Healthy People 2030 objective, the NHPCC will work with federal partners to analyze patient-level data gathered through the Centers for Disease Control’s Community Counts Registry for Bleeding Disorders Surveillance program, which collects data from hemophilia treatment centers across the United States and includes patients with all levels of disease severity.
“The inclusion of bleeding disorders in Healthy People 2030 is really very significant,” said Dr. Shapiro. “These are disorders that affect less than 200,000 Americans, which is the definition of a rare disease in this context. To have hemophilia considered as a national priority is very important, not only for hemophilia, but also for other rare diseases that may in the future also be considered as being as of national importance in this way.”
References
1. Rodriguez-Saldana J. 2019. The Patient-Centered Medical Home, Primary Care, and Diabetes. In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham.
2. J Comorb. 2011;1:51-59.
3. Eur J Haematol. 2018 Apr;100 Suppl 1:5-13.
4. Blood. 2003;102(7):2358-63.
5. Haemophilia. 2014 Jul;20(4):541-9.
6. Haemophilia. 2016;22(Suppl 3):31-40.
7. AAAHC. Medical Home.
8. NCQA. Patient-centered medical home (PCMH).
9. AAAHC, 2013. Medical Home On-Site Certification Handbook.
10. Centers for Disease Control and Prevention. HTC Population Profile.
11. Blood Transfus. 2014;12 Suppl 3(Suppl 3):e542-e548.
12. American Thrombosis and Hemostasis Network.
13. The Great Lakes Regional Hemophilia Network.
14. American Thrombosis and Hemostasis Network. What the NHPCC does.
15. U.S. Department of Health and Human Services. Healthy People 2030: Blood Disorders.
Sex differences in pediatric B-ALL outcomes persist
Even in the age of intensive therapy and extensive risk stratification, there are small but significant differences in outcomes between boys and girls with B-lineage acute lymphoblastic leukemia (B-ALL).
This finding comes from a review of 10 years of clinical trials by the Children’s Oncology Group (COG), which showed that, among patients with B-ALL, 5-year event-free survival (EFS) and overall survival (OS) were inferior with boys, compared with girls, even when adjusted for prognostic factors, reported Sumit Gupta, MD, PhD, FRCPC, from the Hospital for Sick Children in Toronto.
“Inferior outcomes, although small in absolute terms, continue to exist among boys versus girls despite modern therapy and after adjusting for other risk factors. These persist also despite the longer duration of therapy among boys,” he said in an oral abstract presentation during the annual meeting of the American Society of Pediatric Hematology/Oncology. (Abstract 2025).
Among pediatric patients with T-cell lineage ALL (T-ALL), however, there were no significant sex-based differences in either EFS or OS, he said.
Although survival for children with ALL has continued to improve, previous studies found inferior survival outcomes in boys, and suggested that the difference might be explained by imbalances in risk factors.
To see whether sex-based disparities persist with modern intensive therapy protocols after adjustment for risk factors, and to determine whether there are sex-based differences in toxicities or patterns of treatment failure, Dr. Gupta and colleagues created a cohort of all patients age 1-30 years enrolled in frontline COG trial for B-ALL and T-ALL from 2004 to 2014.
During this period, boys received an extra year of maintenance. Cranial radiation was limited to B-ALL patients with slow treatment responses and central nervous system status 3, signifying definite CNS involvement. Among patients with T-ALL, cranial radiation was given to all intermediate- and high-risk patients.
Sex differences small, but significant
The investigators identified a total of 8,202 patients (4,463 males and 3,739 females) with B-ALL, and 1,562 (1,161 males and 401 females) with T-ALL. Boys were likely to be older (P < .0001), and to have a small but significantly greater likelihood of having unfavorable B-ALL cytogenetics, compared with girls (P = .05).
Boys with B-ALL were less likely to be negative for minimal residual disease (76.1% vs. 78.1%, P = .04), but the opposite was true for those with T-ALL (59% vs. 56.8%, P = .01).
As noted before, among pediatric patients with B-ALL, EFS and OS were both inferior for males, with a hazard ratio for higher EFS rates in girls of 1.19 (P = .001) and a HR for OS of 1.17 (P = .046).
Both EFS and OS were similar between the sexes among patients with T-ALL.
The differences in EFS in patients with B-ALL was attributable to higher CNS relapses among boys (4.2% vs. 2.5%, P < .0001). The CNS relapses occurred at a median of 2.5 years in boys versus 2.1 years in girls, although most relapses occurred during therapy.
There were no differences in cumulative isolated bone marrow relapses, however.
Treatment-related mortality rates were the same, but osteonecrosis rates were significantly lower for boys, with a 5-year cumulative incidence of 5.2% versus 6.7% for girls (P = .001).
Possible explanations
Dr. Gupta noted that the inferior outcomes among boys may be attributable to extramedullary relapses among patients with B-ALL.
In addition, the lack of sex-based differences in T-ALL may be caused in part by the increased use of CNS radiation in this population. Previous studies in which CNS radiation was omitted showed an increase in CNS relapsed rates among boys but not girls, he pointed out.
“This does imply that in the more recent generation of T-lineage ALL treatment trials that we’ll need to monitor sex-based differences in outcome, as fewer and fewer patients with T-ALL disease received cranial radiation in these more recent trials and in contemporary therapy,” he said.
One possible mechanism for sex-based outcome differences might be differences in steroid metabolism, as suggested by the higher osteonecrosis rate among girls, he added.
In the question-and-answer following the presentation, William G. Woods, MD, from Emory University, Atlanta, asked what role testicular relapse played in outcomes.
Dr. Gupta replied that the investigators had considered that the excess risk for extramedullary relapse in boys might be accounted for by testicular relapse, but “when you take away testicular relapse from those numbers and really just concentrate on CNS, it’s still that substantial difference when you’re talking about B-lineage disease.”
In patients with T-ALL as well, CNS relapse was more common in boys after controlling for testicular relapse, he said.
Another audience member asked whether the data suggest a benefit to treating boys with CNS-penetrating drugs such as dexamethasone or high-dose methotrexate,
Dr. Gupta said that it’s still uncertain whether it is clinically sound to subject a boy with otherwise–standard-risk disease to more intensive high-risk therapy, given the relatively small absolute differences in outcomes between the sexes.
The study was supported by grants from the National Cancer Institute and the St. Baldrick’s Foundation. Dr. Gupta, Dr. Woods, and Dr. Meret had no relevant conflicts of interest to report.
Even in the age of intensive therapy and extensive risk stratification, there are small but significant differences in outcomes between boys and girls with B-lineage acute lymphoblastic leukemia (B-ALL).
This finding comes from a review of 10 years of clinical trials by the Children’s Oncology Group (COG), which showed that, among patients with B-ALL, 5-year event-free survival (EFS) and overall survival (OS) were inferior with boys, compared with girls, even when adjusted for prognostic factors, reported Sumit Gupta, MD, PhD, FRCPC, from the Hospital for Sick Children in Toronto.
“Inferior outcomes, although small in absolute terms, continue to exist among boys versus girls despite modern therapy and after adjusting for other risk factors. These persist also despite the longer duration of therapy among boys,” he said in an oral abstract presentation during the annual meeting of the American Society of Pediatric Hematology/Oncology. (Abstract 2025).
Among pediatric patients with T-cell lineage ALL (T-ALL), however, there were no significant sex-based differences in either EFS or OS, he said.
Although survival for children with ALL has continued to improve, previous studies found inferior survival outcomes in boys, and suggested that the difference might be explained by imbalances in risk factors.
To see whether sex-based disparities persist with modern intensive therapy protocols after adjustment for risk factors, and to determine whether there are sex-based differences in toxicities or patterns of treatment failure, Dr. Gupta and colleagues created a cohort of all patients age 1-30 years enrolled in frontline COG trial for B-ALL and T-ALL from 2004 to 2014.
During this period, boys received an extra year of maintenance. Cranial radiation was limited to B-ALL patients with slow treatment responses and central nervous system status 3, signifying definite CNS involvement. Among patients with T-ALL, cranial radiation was given to all intermediate- and high-risk patients.
Sex differences small, but significant
The investigators identified a total of 8,202 patients (4,463 males and 3,739 females) with B-ALL, and 1,562 (1,161 males and 401 females) with T-ALL. Boys were likely to be older (P < .0001), and to have a small but significantly greater likelihood of having unfavorable B-ALL cytogenetics, compared with girls (P = .05).
Boys with B-ALL were less likely to be negative for minimal residual disease (76.1% vs. 78.1%, P = .04), but the opposite was true for those with T-ALL (59% vs. 56.8%, P = .01).
As noted before, among pediatric patients with B-ALL, EFS and OS were both inferior for males, with a hazard ratio for higher EFS rates in girls of 1.19 (P = .001) and a HR for OS of 1.17 (P = .046).
Both EFS and OS were similar between the sexes among patients with T-ALL.
The differences in EFS in patients with B-ALL was attributable to higher CNS relapses among boys (4.2% vs. 2.5%, P < .0001). The CNS relapses occurred at a median of 2.5 years in boys versus 2.1 years in girls, although most relapses occurred during therapy.
There were no differences in cumulative isolated bone marrow relapses, however.
Treatment-related mortality rates were the same, but osteonecrosis rates were significantly lower for boys, with a 5-year cumulative incidence of 5.2% versus 6.7% for girls (P = .001).
Possible explanations
Dr. Gupta noted that the inferior outcomes among boys may be attributable to extramedullary relapses among patients with B-ALL.
In addition, the lack of sex-based differences in T-ALL may be caused in part by the increased use of CNS radiation in this population. Previous studies in which CNS radiation was omitted showed an increase in CNS relapsed rates among boys but not girls, he pointed out.
“This does imply that in the more recent generation of T-lineage ALL treatment trials that we’ll need to monitor sex-based differences in outcome, as fewer and fewer patients with T-ALL disease received cranial radiation in these more recent trials and in contemporary therapy,” he said.
One possible mechanism for sex-based outcome differences might be differences in steroid metabolism, as suggested by the higher osteonecrosis rate among girls, he added.
In the question-and-answer following the presentation, William G. Woods, MD, from Emory University, Atlanta, asked what role testicular relapse played in outcomes.
Dr. Gupta replied that the investigators had considered that the excess risk for extramedullary relapse in boys might be accounted for by testicular relapse, but “when you take away testicular relapse from those numbers and really just concentrate on CNS, it’s still that substantial difference when you’re talking about B-lineage disease.”
In patients with T-ALL as well, CNS relapse was more common in boys after controlling for testicular relapse, he said.
Another audience member asked whether the data suggest a benefit to treating boys with CNS-penetrating drugs such as dexamethasone or high-dose methotrexate,
Dr. Gupta said that it’s still uncertain whether it is clinically sound to subject a boy with otherwise–standard-risk disease to more intensive high-risk therapy, given the relatively small absolute differences in outcomes between the sexes.
The study was supported by grants from the National Cancer Institute and the St. Baldrick’s Foundation. Dr. Gupta, Dr. Woods, and Dr. Meret had no relevant conflicts of interest to report.
Even in the age of intensive therapy and extensive risk stratification, there are small but significant differences in outcomes between boys and girls with B-lineage acute lymphoblastic leukemia (B-ALL).
This finding comes from a review of 10 years of clinical trials by the Children’s Oncology Group (COG), which showed that, among patients with B-ALL, 5-year event-free survival (EFS) and overall survival (OS) were inferior with boys, compared with girls, even when adjusted for prognostic factors, reported Sumit Gupta, MD, PhD, FRCPC, from the Hospital for Sick Children in Toronto.
“Inferior outcomes, although small in absolute terms, continue to exist among boys versus girls despite modern therapy and after adjusting for other risk factors. These persist also despite the longer duration of therapy among boys,” he said in an oral abstract presentation during the annual meeting of the American Society of Pediatric Hematology/Oncology. (Abstract 2025).
Among pediatric patients with T-cell lineage ALL (T-ALL), however, there were no significant sex-based differences in either EFS or OS, he said.
Although survival for children with ALL has continued to improve, previous studies found inferior survival outcomes in boys, and suggested that the difference might be explained by imbalances in risk factors.
To see whether sex-based disparities persist with modern intensive therapy protocols after adjustment for risk factors, and to determine whether there are sex-based differences in toxicities or patterns of treatment failure, Dr. Gupta and colleagues created a cohort of all patients age 1-30 years enrolled in frontline COG trial for B-ALL and T-ALL from 2004 to 2014.
During this period, boys received an extra year of maintenance. Cranial radiation was limited to B-ALL patients with slow treatment responses and central nervous system status 3, signifying definite CNS involvement. Among patients with T-ALL, cranial radiation was given to all intermediate- and high-risk patients.
Sex differences small, but significant
The investigators identified a total of 8,202 patients (4,463 males and 3,739 females) with B-ALL, and 1,562 (1,161 males and 401 females) with T-ALL. Boys were likely to be older (P < .0001), and to have a small but significantly greater likelihood of having unfavorable B-ALL cytogenetics, compared with girls (P = .05).
Boys with B-ALL were less likely to be negative for minimal residual disease (76.1% vs. 78.1%, P = .04), but the opposite was true for those with T-ALL (59% vs. 56.8%, P = .01).
As noted before, among pediatric patients with B-ALL, EFS and OS were both inferior for males, with a hazard ratio for higher EFS rates in girls of 1.19 (P = .001) and a HR for OS of 1.17 (P = .046).
Both EFS and OS were similar between the sexes among patients with T-ALL.
The differences in EFS in patients with B-ALL was attributable to higher CNS relapses among boys (4.2% vs. 2.5%, P < .0001). The CNS relapses occurred at a median of 2.5 years in boys versus 2.1 years in girls, although most relapses occurred during therapy.
There were no differences in cumulative isolated bone marrow relapses, however.
Treatment-related mortality rates were the same, but osteonecrosis rates were significantly lower for boys, with a 5-year cumulative incidence of 5.2% versus 6.7% for girls (P = .001).
Possible explanations
Dr. Gupta noted that the inferior outcomes among boys may be attributable to extramedullary relapses among patients with B-ALL.
In addition, the lack of sex-based differences in T-ALL may be caused in part by the increased use of CNS radiation in this population. Previous studies in which CNS radiation was omitted showed an increase in CNS relapsed rates among boys but not girls, he pointed out.
“This does imply that in the more recent generation of T-lineage ALL treatment trials that we’ll need to monitor sex-based differences in outcome, as fewer and fewer patients with T-ALL disease received cranial radiation in these more recent trials and in contemporary therapy,” he said.
One possible mechanism for sex-based outcome differences might be differences in steroid metabolism, as suggested by the higher osteonecrosis rate among girls, he added.
In the question-and-answer following the presentation, William G. Woods, MD, from Emory University, Atlanta, asked what role testicular relapse played in outcomes.
Dr. Gupta replied that the investigators had considered that the excess risk for extramedullary relapse in boys might be accounted for by testicular relapse, but “when you take away testicular relapse from those numbers and really just concentrate on CNS, it’s still that substantial difference when you’re talking about B-lineage disease.”
In patients with T-ALL as well, CNS relapse was more common in boys after controlling for testicular relapse, he said.
Another audience member asked whether the data suggest a benefit to treating boys with CNS-penetrating drugs such as dexamethasone or high-dose methotrexate,
Dr. Gupta said that it’s still uncertain whether it is clinically sound to subject a boy with otherwise–standard-risk disease to more intensive high-risk therapy, given the relatively small absolute differences in outcomes between the sexes.
The study was supported by grants from the National Cancer Institute and the St. Baldrick’s Foundation. Dr. Gupta, Dr. Woods, and Dr. Meret had no relevant conflicts of interest to report.
FROM ASPHO 2021