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FDA approves first gene therapy for hemophilia A
Valoctocogene roxaparvovec, a one-time, single-dose IV infusion, is the first gene therapy approved in the United States for severe hemophilia A and will cost around $2.9 million. BioMarin has said the price tag reflects “the possibility of freedom from years” of infusions, which come to about $800,000 each year.
However, last December, the Institute for Clinical and Economic Review (ICER) set the upper bounds for the gene therapy at about $1.96 million. The extent to which the gene therapy will provide freedom from infusions, for how long, and in which patients are not completely understood.
Hemophilia A is caused by a mutation in the gene that produces a protein called coagulation factor VIII, which is essential for blood clotting. Valoctocogene roxaparvovec delivers a functional gene to liver cells via an adeno-associated virus serotype 5; the gene instructs the cells to make the missing clotting factor.
“Adults with severe hemophilia A face a lifelong burden, with frequent infusions and a high risk of health complications, including uncontrolled bleeding and irreversible joint damage,” Steven Pipe, MD, professor of pediatrics and pathology at the University of Michigan, Ann Arbor, and an investigator for the phase 3 study that led to the approval, said in a statement. The approval of valoctocogene roxaparvovec “has the potential to transform the way we treat adults based on years of bleed control following a single, one-time infusion.”
About 6,500 U.S. adults live with severe hemophilia A, and BioMarin said it anticipates approximately 2,500 will be eligible to receive the gene therapy following the approval. The U.S. indication is limited to patients without a history of factor VIII inhibitors and without detectable antibodies to the adeno-associated virus serotype 5.
Last August, the European Medicines Agency authorized the gene therapy for use in Europe, but according to Forbes and PharmaPhorum, uptake in Europe has been delayed because of reimbursement issues, given the cost of treatment and clinical uncertainties.
Data to date, however, are promising for most patients. Approval was based on BioMarin’s open-label, single-arm GENEr8-1 study in 134 men with severe congenital hemophilia A. Patients received a single infusion of 6 x 1013 vector genomes per kilogram.
Among the 132 patients available for 2-year evaluation, median factor VIII activity was in the range for mild hemophilia (6%-39% of normal) with an 84.5% reduction in bleeding events from baseline.
More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.
Overall, at 2 years, only 4.5% of patients had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease, and 26.5% had activity in the normal range above 40 IU/dL.
Trial investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.
Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion. All patients developed antibodies to the virus delivery vector, precluding retreatment.
Elevated alanine aminotransferase levels were the most common adverse event, occurring in 88.8% of patients, who were treated with immunosuppressants for a median of 33 weeks. Elevations persisted at 2 years in 29% of patients.
The other most common adverse events were headache (38.1%), nausea (37.3%), and increases in aspartate aminotransferase (35.1%).
A version of this article first appeared on Medscape.com.
Valoctocogene roxaparvovec, a one-time, single-dose IV infusion, is the first gene therapy approved in the United States for severe hemophilia A and will cost around $2.9 million. BioMarin has said the price tag reflects “the possibility of freedom from years” of infusions, which come to about $800,000 each year.
However, last December, the Institute for Clinical and Economic Review (ICER) set the upper bounds for the gene therapy at about $1.96 million. The extent to which the gene therapy will provide freedom from infusions, for how long, and in which patients are not completely understood.
Hemophilia A is caused by a mutation in the gene that produces a protein called coagulation factor VIII, which is essential for blood clotting. Valoctocogene roxaparvovec delivers a functional gene to liver cells via an adeno-associated virus serotype 5; the gene instructs the cells to make the missing clotting factor.
“Adults with severe hemophilia A face a lifelong burden, with frequent infusions and a high risk of health complications, including uncontrolled bleeding and irreversible joint damage,” Steven Pipe, MD, professor of pediatrics and pathology at the University of Michigan, Ann Arbor, and an investigator for the phase 3 study that led to the approval, said in a statement. The approval of valoctocogene roxaparvovec “has the potential to transform the way we treat adults based on years of bleed control following a single, one-time infusion.”
About 6,500 U.S. adults live with severe hemophilia A, and BioMarin said it anticipates approximately 2,500 will be eligible to receive the gene therapy following the approval. The U.S. indication is limited to patients without a history of factor VIII inhibitors and without detectable antibodies to the adeno-associated virus serotype 5.
Last August, the European Medicines Agency authorized the gene therapy for use in Europe, but according to Forbes and PharmaPhorum, uptake in Europe has been delayed because of reimbursement issues, given the cost of treatment and clinical uncertainties.
Data to date, however, are promising for most patients. Approval was based on BioMarin’s open-label, single-arm GENEr8-1 study in 134 men with severe congenital hemophilia A. Patients received a single infusion of 6 x 1013 vector genomes per kilogram.
Among the 132 patients available for 2-year evaluation, median factor VIII activity was in the range for mild hemophilia (6%-39% of normal) with an 84.5% reduction in bleeding events from baseline.
More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.
Overall, at 2 years, only 4.5% of patients had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease, and 26.5% had activity in the normal range above 40 IU/dL.
Trial investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.
Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion. All patients developed antibodies to the virus delivery vector, precluding retreatment.
Elevated alanine aminotransferase levels were the most common adverse event, occurring in 88.8% of patients, who were treated with immunosuppressants for a median of 33 weeks. Elevations persisted at 2 years in 29% of patients.
The other most common adverse events were headache (38.1%), nausea (37.3%), and increases in aspartate aminotransferase (35.1%).
A version of this article first appeared on Medscape.com.
Valoctocogene roxaparvovec, a one-time, single-dose IV infusion, is the first gene therapy approved in the United States for severe hemophilia A and will cost around $2.9 million. BioMarin has said the price tag reflects “the possibility of freedom from years” of infusions, which come to about $800,000 each year.
However, last December, the Institute for Clinical and Economic Review (ICER) set the upper bounds for the gene therapy at about $1.96 million. The extent to which the gene therapy will provide freedom from infusions, for how long, and in which patients are not completely understood.
Hemophilia A is caused by a mutation in the gene that produces a protein called coagulation factor VIII, which is essential for blood clotting. Valoctocogene roxaparvovec delivers a functional gene to liver cells via an adeno-associated virus serotype 5; the gene instructs the cells to make the missing clotting factor.
“Adults with severe hemophilia A face a lifelong burden, with frequent infusions and a high risk of health complications, including uncontrolled bleeding and irreversible joint damage,” Steven Pipe, MD, professor of pediatrics and pathology at the University of Michigan, Ann Arbor, and an investigator for the phase 3 study that led to the approval, said in a statement. The approval of valoctocogene roxaparvovec “has the potential to transform the way we treat adults based on years of bleed control following a single, one-time infusion.”
About 6,500 U.S. adults live with severe hemophilia A, and BioMarin said it anticipates approximately 2,500 will be eligible to receive the gene therapy following the approval. The U.S. indication is limited to patients without a history of factor VIII inhibitors and without detectable antibodies to the adeno-associated virus serotype 5.
Last August, the European Medicines Agency authorized the gene therapy for use in Europe, but according to Forbes and PharmaPhorum, uptake in Europe has been delayed because of reimbursement issues, given the cost of treatment and clinical uncertainties.
Data to date, however, are promising for most patients. Approval was based on BioMarin’s open-label, single-arm GENEr8-1 study in 134 men with severe congenital hemophilia A. Patients received a single infusion of 6 x 1013 vector genomes per kilogram.
Among the 132 patients available for 2-year evaluation, median factor VIII activity was in the range for mild hemophilia (6%-39% of normal) with an 84.5% reduction in bleeding events from baseline.
More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.
Overall, at 2 years, only 4.5% of patients had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease, and 26.5% had activity in the normal range above 40 IU/dL.
Trial investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.
Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion. All patients developed antibodies to the virus delivery vector, precluding retreatment.
Elevated alanine aminotransferase levels were the most common adverse event, occurring in 88.8% of patients, who were treated with immunosuppressants for a median of 33 weeks. Elevations persisted at 2 years in 29% of patients.
The other most common adverse events were headache (38.1%), nausea (37.3%), and increases in aspartate aminotransferase (35.1%).
A version of this article first appeared on Medscape.com.
Guide explains nonsurgical management of major hemorrhage
A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.
Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.
“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”
The guide was published in the Canadian Medical Association Journal.
Fast care essential
The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.
Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.
Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”
Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.
“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
Administer TXA quickly
The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.
Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.
An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.
“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”
TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.
TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”
Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
‘Optimal recommendations’
Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”
The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”
“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.
“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”
No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.
Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.
“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”
The guide was published in the Canadian Medical Association Journal.
Fast care essential
The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.
Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.
Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”
Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.
“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
Administer TXA quickly
The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.
Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.
An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.
“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”
TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.
TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”
Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
‘Optimal recommendations’
Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”
The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”
“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.
“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”
No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A new guide offers recommendations for the nonsurgical management of major hemorrhage, which is a challenging clinical problem.
Major hemorrhage is a significant cause of death and can occur in a myriad of clinical settings.
“In Ontario, we’ve been collecting quality metrics on major hemorrhages to try and make sure that a higher percentage of patients gets the best possible care when they are experiencing significant bleeding,” author Jeannie Callum, MD, professor and director of transfusion medicine at Kingston (Ont.) Health Sciences Centre and Queen’s University, also in Kingston, said in an interview. “There were some gaps, so this is our effort to get open, clear information out to the emergency doctors, intensive care unit doctors, the surgeons, and everyone else involved in managing major hemorrhage, to help close these gaps.”
The guide was published in the Canadian Medical Association Journal.
Fast care essential
The guide aims to provide answers, based on the latest research, to questions such as when to activate a massive hemorrhage protocol (MHP), which patients should receive tranexamic acid (TXA), which blood products should be transfused before laboratory results are available, how to monitor the effects of blood transfusion, and when fibrinogen concentrate or prothrombin complex concentrate should be given.
Not all recommendations will be followed, Dr. Callum said, especially in rural hospitals with limited resources. But the guide is adaptable, and rural hospitals can create protocols that are customized to their unique circumstances.
Care must be “perfect and fast” in the first hour of major injury, said Dr. Callum. “You need to get a proclotting drug in that first hour if you have a traumatic or postpartum bleed. You have to make sure your clotting factors never fail you throughout your resuscitation. You have to be fast with the transfusion. You have to monitor for the complications of the transfusion, electrolyte disturbances, and the patient’s temperature dropping. It’s a complicated situation that needs a multidisciplinary team.”
Bleeding affects everybody in medicine, from family doctors in smaller institutions who work in emergency departments to obstetricians and surgeons, she added.
“For people under the age of 45, trauma is the most common cause of death. When people die of trauma, they die of bleeding. So many people experience these extreme bleeds. We believe that some of them might be preventable with faster, more standardized, more aggressive care. That’s why we wrote this review,” said Dr. Callum.
Administer TXA quickly
The first recommendation is to ensure that every hospital has a massive hemorrhage protocol. Such a protocol is vital for the emergency department, operating room, and obstetric unit. “Making sure you’ve got a protocol that is updated every 3 years and adjusted to the local hospital context is essential,” said Dr. Callum.
Smaller hospitals will have to adjust their protocols according to the capabilities of their sites. “Some smaller hospitals do not have platelets in stock and get their platelets from another hospital, so you need to adjust your protocol to what you are able to do. Not every hospital can control bleeding in a trauma patient, so your protocol would be to stabilize and call a helicopter. Make sure all of this is detailed so that implementing it becomes automatic,” said Dr. Callum.
An MHP should be activated for patients with uncontrolled hemorrhage who meet the clinical criteria of the local hospital and are expected to need blood product support and red blood cells.
“Lots of people bleed, but not everybody is bleeding enough that they need a code transfusion,” said Dr. Callum. Most patients with gastrointestinal bleeds caused by NSAID use can be managed with uncrossed matched blood from the local blood bank. “But in patients who need the full code transfusion because they are going to need plasma, clotting factor replacement, and many other drugs, that is when the MHP should be activated. Don’t activate it when you don’t need it, because doing so activates the whole hospital and diverts care away from other patients.”
TXA should be administered as soon as possible after onset of hemorrhage in most patients, with the exception of gastrointestinal hemorrhage, where a benefit has not been shown.
TXA has been a major advance in treating massive bleeding, Dr. Callum said. “TXA was invented by a Japanese husband-and-wife research team. We know that it reduces the death rate in trauma and in postpartum hemorrhage, and it reduces the chance of major bleeding with major surgical procedures. We give it routinely in surgical procedures. If a patient gets TXA within 60 minutes of injury, it dramatically reduces the death rate. And it costs $10 per patient. It’s cheap, it’s easy, it has no side effects. It’s just amazing.”
Future research must address several unanswered questions, said Dr. Callum. These questions include whether prehospital transfusion improves patient outcomes, whether whole blood has a role in the early management of major hemorrhage, and what role factor concentrates play in patients with major bleeding.
‘Optimal recommendations’
Commenting on the document, Bourke Tillmann, MD, PhD, trauma team leader at Sunnybrook Health Sciences Centre and the Ross Tilley Burn Center in Toronto, said: “Overall, I think it is a good overview of MHPs as an approach to major hemorrhage.”
The review also is timely, since Ontario released its MHP guidelines in 2021, he added. “I would have liked to see more about the treatment aspects than just an overview of an MHP. But if you are the person overseeing the emergency department or running the blood bank, these protocols are incredibly useful and incredibly important.”
“This report is a nice and thoughtful overview of best practices in many areas, especially trauma, and makes recommendations that are optimal, although they are not necessarily practical in all centers,” Eric L. Legome, MD, professor and chair of emergency medicine at Mount Sinai West and Mount Sinai Morningside, New York, said in an interview.
“If you’re in a small rural hospital with one lab technician, trying to do all of these things, it will not be possible. These are optimal recommendations that people can use to the best of their ability, but they are not standard of care, because some places will not be able to provide this level of care,” he added. “This paper provides practical, reasonable advice that should be looked at as you are trying to implement transfusion policies and processes, with the understanding that it is not necessarily applicable or practical for very small hospitals in very rural centers that might not have access to these types of products and tools, but it’s a reasonable and nicely written paper.”
No outside funding for the guideline was reported. Dr. Callum has received research funding from Canadian Blood Services and Octapharma. She sits on the nominating committee with the Association for the Advancement of Blood & Biotherapies and on the data safety monitoring boards for the Tranexamic Acid for Subdural Hematoma trial and the Fibrinogen Replacement in Trauma trial. Dr. Tillmann and Dr. Legome reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM THE CANADIAN MEDICAL ASSOCIATION JOURNAL
Focus of new ASH VTE guidelines: Thrombophilia testing
according to new clinical practice guidelines released by the American Society of Hematology. Individuals with a family history of VTE and high-risk thrombophilia, and those with VTE at unusual body sites should also be tested, the guidelines panel agreed.
“These guidelines will potentially change practice – we know that providers and patients will make a shared treatment decision and we wanted to outline specific scenarios to guide that decision,” panel cochair and first author Saskia Middeldorp, MD, PhD, explained in a press release announcing the publication of the guidelines in Blood Advances.
Dr. Middeldorp is a professor of medicine and head of the department of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands.
The guidelines are the latest in an ASH series of VTE-related guidelines. ASH convened a multidisciplinary panel with clinical and methodological expertise to develop the guidelines, which were subject to public comment, and they “provide recommendations informed by case-based approaches and modeling to ensure the medical community can better diagnose and treat thrombophilia and people with the condition can make the best decisions for their care,” the press release explains.
Thrombophilia affects an estimated 10% of the population. Testing for the clotting disorder can be costly, and the use of testing to help guide treatment decisions is controversial.
“For decades there has been dispute about thrombophilia testing,” Dr. Middeldorp said. “We created a model about whether and when it would be useful to test for thrombophilia, and based on the model, we suggest it can be appropriate in [the specified] situations.
The panel agreed on 23 recommendations regarding thrombophilia testing and management. Most are based on “very low certainty” in the evidence because of modeling assumptions.
However, the panel agreed on a strong recommendation against testing the general population before starting combined oral contraceptives (COC), and a conditional recommendation for thrombophilia testing in:
- Patients with VTE associated with nonsurgical major transient or hormonal risk factors
- Patients with cerebral or splanchnic venous thrombosis in settings where anticoagulation would otherwise be discontinued
- Individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance related to the use of COC or hormone therapy
- Pregnant women with a family history of high-risk thrombophilia types
- Patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE
“In all other instances, we suggest not testing for thrombophilia,” said Dr. Middeldorp.
The ASH guidelines largely mirror those of existing guidelines from a number of other organizations, but the recommendation in favor of testing for thrombophilia in patients with VTE provoked by a nonsurgical major transient risk factor or associated with COCs, hormone therapy, pregnancy or postpartum is new and “may cause considerable discussion, as many currently view these VTE episodes as provoked and are generally inclined to use short-term anticoagulation for such patients,” the guideline authors wrote.
“It is important to note, however, that most guidelines or guidance statements on thrombophilia testing did not distinguish between major and minor provoking risk factors, which current science suggests is appropriate,” they added.
Another novel recommendation is the suggestion to test for hereditary thrombophilia to guide the use of thromboprophylaxis during systemic treatment in ambulatory patients with cancer who are at low or intermediate risk for VTE and who have a family history of VTE.
“This new recommendation should be seen as a new application of an established risk stratification approach,” they said.
Additional research is urgently needed, particularly “large implementation studies comparing the impact, in terms of outcomes rates, among management strategies involving or not involving thrombophilia testing,” they noted.
The guideline was wholly funded by ASH. Dr. Middeldorp reported having no conflicts of interest.
according to new clinical practice guidelines released by the American Society of Hematology. Individuals with a family history of VTE and high-risk thrombophilia, and those with VTE at unusual body sites should also be tested, the guidelines panel agreed.
“These guidelines will potentially change practice – we know that providers and patients will make a shared treatment decision and we wanted to outline specific scenarios to guide that decision,” panel cochair and first author Saskia Middeldorp, MD, PhD, explained in a press release announcing the publication of the guidelines in Blood Advances.
Dr. Middeldorp is a professor of medicine and head of the department of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands.
The guidelines are the latest in an ASH series of VTE-related guidelines. ASH convened a multidisciplinary panel with clinical and methodological expertise to develop the guidelines, which were subject to public comment, and they “provide recommendations informed by case-based approaches and modeling to ensure the medical community can better diagnose and treat thrombophilia and people with the condition can make the best decisions for their care,” the press release explains.
Thrombophilia affects an estimated 10% of the population. Testing for the clotting disorder can be costly, and the use of testing to help guide treatment decisions is controversial.
“For decades there has been dispute about thrombophilia testing,” Dr. Middeldorp said. “We created a model about whether and when it would be useful to test for thrombophilia, and based on the model, we suggest it can be appropriate in [the specified] situations.
The panel agreed on 23 recommendations regarding thrombophilia testing and management. Most are based on “very low certainty” in the evidence because of modeling assumptions.
However, the panel agreed on a strong recommendation against testing the general population before starting combined oral contraceptives (COC), and a conditional recommendation for thrombophilia testing in:
- Patients with VTE associated with nonsurgical major transient or hormonal risk factors
- Patients with cerebral or splanchnic venous thrombosis in settings where anticoagulation would otherwise be discontinued
- Individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance related to the use of COC or hormone therapy
- Pregnant women with a family history of high-risk thrombophilia types
- Patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE
“In all other instances, we suggest not testing for thrombophilia,” said Dr. Middeldorp.
The ASH guidelines largely mirror those of existing guidelines from a number of other organizations, but the recommendation in favor of testing for thrombophilia in patients with VTE provoked by a nonsurgical major transient risk factor or associated with COCs, hormone therapy, pregnancy or postpartum is new and “may cause considerable discussion, as many currently view these VTE episodes as provoked and are generally inclined to use short-term anticoagulation for such patients,” the guideline authors wrote.
“It is important to note, however, that most guidelines or guidance statements on thrombophilia testing did not distinguish between major and minor provoking risk factors, which current science suggests is appropriate,” they added.
Another novel recommendation is the suggestion to test for hereditary thrombophilia to guide the use of thromboprophylaxis during systemic treatment in ambulatory patients with cancer who are at low or intermediate risk for VTE and who have a family history of VTE.
“This new recommendation should be seen as a new application of an established risk stratification approach,” they said.
Additional research is urgently needed, particularly “large implementation studies comparing the impact, in terms of outcomes rates, among management strategies involving or not involving thrombophilia testing,” they noted.
The guideline was wholly funded by ASH. Dr. Middeldorp reported having no conflicts of interest.
according to new clinical practice guidelines released by the American Society of Hematology. Individuals with a family history of VTE and high-risk thrombophilia, and those with VTE at unusual body sites should also be tested, the guidelines panel agreed.
“These guidelines will potentially change practice – we know that providers and patients will make a shared treatment decision and we wanted to outline specific scenarios to guide that decision,” panel cochair and first author Saskia Middeldorp, MD, PhD, explained in a press release announcing the publication of the guidelines in Blood Advances.
Dr. Middeldorp is a professor of medicine and head of the department of internal medicine at Radboud University Medical Center, Nijmegen, the Netherlands.
The guidelines are the latest in an ASH series of VTE-related guidelines. ASH convened a multidisciplinary panel with clinical and methodological expertise to develop the guidelines, which were subject to public comment, and they “provide recommendations informed by case-based approaches and modeling to ensure the medical community can better diagnose and treat thrombophilia and people with the condition can make the best decisions for their care,” the press release explains.
Thrombophilia affects an estimated 10% of the population. Testing for the clotting disorder can be costly, and the use of testing to help guide treatment decisions is controversial.
“For decades there has been dispute about thrombophilia testing,” Dr. Middeldorp said. “We created a model about whether and when it would be useful to test for thrombophilia, and based on the model, we suggest it can be appropriate in [the specified] situations.
The panel agreed on 23 recommendations regarding thrombophilia testing and management. Most are based on “very low certainty” in the evidence because of modeling assumptions.
However, the panel agreed on a strong recommendation against testing the general population before starting combined oral contraceptives (COC), and a conditional recommendation for thrombophilia testing in:
- Patients with VTE associated with nonsurgical major transient or hormonal risk factors
- Patients with cerebral or splanchnic venous thrombosis in settings where anticoagulation would otherwise be discontinued
- Individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance related to the use of COC or hormone therapy
- Pregnant women with a family history of high-risk thrombophilia types
- Patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE
“In all other instances, we suggest not testing for thrombophilia,” said Dr. Middeldorp.
The ASH guidelines largely mirror those of existing guidelines from a number of other organizations, but the recommendation in favor of testing for thrombophilia in patients with VTE provoked by a nonsurgical major transient risk factor or associated with COCs, hormone therapy, pregnancy or postpartum is new and “may cause considerable discussion, as many currently view these VTE episodes as provoked and are generally inclined to use short-term anticoagulation for such patients,” the guideline authors wrote.
“It is important to note, however, that most guidelines or guidance statements on thrombophilia testing did not distinguish between major and minor provoking risk factors, which current science suggests is appropriate,” they added.
Another novel recommendation is the suggestion to test for hereditary thrombophilia to guide the use of thromboprophylaxis during systemic treatment in ambulatory patients with cancer who are at low or intermediate risk for VTE and who have a family history of VTE.
“This new recommendation should be seen as a new application of an established risk stratification approach,” they said.
Additional research is urgently needed, particularly “large implementation studies comparing the impact, in terms of outcomes rates, among management strategies involving or not involving thrombophilia testing,” they noted.
The guideline was wholly funded by ASH. Dr. Middeldorp reported having no conflicts of interest.
FROM BLOOD ADVANCES
Red-cell donor’s sex does not affect transfusion survival
In a randomized clinical trial with almost 9,000 patients, the adjusted hazard ratio of death among recipients of female donors’ blood, compared with recipients of male donors’ blood, was 0.98. The data contradict the finding of previous observational studies that donor sex is associated with recipient outcomes.
“The key finding was that we actually had a null result,” study author Dean Fergusson, MD, PhD, senior scientist at the Ottawa Hospital Research Institute, said in an interview. “We went in thinking that male donor blood would confer a benefit over female donor blood, and we found that there’s absolutely no difference between the donor sexes on recipient outcomes – mortality and other major secondary outcomes,” Dr. Fergusson added.
The study was published in the New England Journal of Medicine.
Differences ‘don’t matter’
A 2015 article from the National Heart, Lung, and Blood Institute identified a potential effect of donor sex on transfusion recipient survival. Since then, several observational studies have suggested that donor sex may influence survival after transfusion. This research includes two large studies, one from Canada and one from the Netherlands, that reported a heightened risk of death among recipients of red-cell units from female donors or donors who had been pregnant. Other studies, however, yielded conflicting results.
“The rationale was that female blood, because of biochemical properties, different hormones, exposure to babies and other males, all led to a different product, if you will, and these subtle changes could affect the blood product in terms of shelf life and potency,” said Dr. Fergusson. “That itself would have downstream effects on the recipient.”
The current double-blind study included 8,719 patients who received transfusions from September 2018 to December 2020 at three academic medical centers in Canada. Of this group, 5,190 received male donor blood, and 3,529 received blood from female donors.
The researchers randomly assigned patients in a 60:40 ratio to male and female donor groups. Data collection and follow-up were performed by the Ottawa Hospital Data Warehouse, Canadian Blood Services, and ICES, an independent research institute. Patient characteristics were similar in both trial groups at baseline.
After an average follow-up of 11.2 months, with a maximum follow-up of 29 months, 1,141 patients in the female donor group and 1,712 in the male donor group died. The study found no statistically significant difference in overall survival between the two groups. The unadjusted HR for death, with the male group as the reference, was 0.97, and the adjusted HR was 0.98. The rates of overall survival were 58% and 56.1% in the female and male donor groups, respectively.
The study did not prove that differences in outcome based on donor sex do not exist, said Dr. Fergusson. “But those differences really don’t matter in the recipient.”
The design of the trial itself was unique, Dr. Fergusson said. After patients consented to participate and underwent randomization, the study used routinely collected data from the participating hospitals’ electronic medical records rather than collect data anew for each patient. “That had a profound effect on the efficiency of the trial. We did this trial for a cost of less than $300,000, and typically it would cost $9 million by using high-quality electronic health data.”
The study also evaluated several secondary outcomes. Recipients of female donor blood had twice the incidence of MRSA infection. In addition, an unadjusted subgroup analysis suggested a 10% lower risk of death among male patients assigned to the female donor group, compared with those assigned to the male donor group.
The risk of death was almost three times higher among patients in the female donor group who received units from donors aged 20-29.9 years (HR, 2.93). “The inconsistency of the point estimates across groups and the multiplicity of analyses increase the risk that those findings were due to chance,” according to the authors.
Big data
Commenting on the study, Jeannie Callum, MD, professor and director of transfusion medicine at Queen’s University, Kingston, Ont., said that the use of routinely collected data from the participating hospitals’ electronic medical records was “one of the really great things about this paper.”
This use of Big Data “allows you to do a trial like this with almost 9,000 patients without spending millions and millions of dollars to have people go through charts and record data,” she added.
Dr. Callum also pointed out some of the trial’s limitations. “One of the things that kind of detracts from the study in my mind is that they randomized everybody that was getting a transfusion, but outpatients getting a transfusion have a very low mortality rate. So, you have a group of patients that are never going to have that endpoint being included in the study, and that might’ve diluted the findings.”
About 11.4% of participants received blood from a donor group other than the one to which they had been assigned, and this factor may further dilute the findings, said Dr. Callum. “That’s a difficult thing to avoid.” She noted that a trial in which she is collaborating, called Sex Matters, may answer some of these questions about the use of female versus male donor blood.
The investigators also noted that the findings may not be generalizable to other countries. “Just because we didn’t find something in Canada with our blood production system doesn’t mean that the United States might not find it different, because how they manufacture their red blood cells for transfusion is different than how we do them in Canada,” said Dr. Callum.
Nonetheless, this study shows the potential of using Big Data in medicine. “This is the future of large randomized clinical trials to quickly answer questions,” said Dr. Callum. “In the United States, Canada, and other countries that have these large electronic medical records systems, this kind of trial would be able to be done in other centers.”
The study was funded by the Canadian Institutes of Health Research. Dr. Fergusson and Dr. Callum disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a randomized clinical trial with almost 9,000 patients, the adjusted hazard ratio of death among recipients of female donors’ blood, compared with recipients of male donors’ blood, was 0.98. The data contradict the finding of previous observational studies that donor sex is associated with recipient outcomes.
“The key finding was that we actually had a null result,” study author Dean Fergusson, MD, PhD, senior scientist at the Ottawa Hospital Research Institute, said in an interview. “We went in thinking that male donor blood would confer a benefit over female donor blood, and we found that there’s absolutely no difference between the donor sexes on recipient outcomes – mortality and other major secondary outcomes,” Dr. Fergusson added.
The study was published in the New England Journal of Medicine.
Differences ‘don’t matter’
A 2015 article from the National Heart, Lung, and Blood Institute identified a potential effect of donor sex on transfusion recipient survival. Since then, several observational studies have suggested that donor sex may influence survival after transfusion. This research includes two large studies, one from Canada and one from the Netherlands, that reported a heightened risk of death among recipients of red-cell units from female donors or donors who had been pregnant. Other studies, however, yielded conflicting results.
“The rationale was that female blood, because of biochemical properties, different hormones, exposure to babies and other males, all led to a different product, if you will, and these subtle changes could affect the blood product in terms of shelf life and potency,” said Dr. Fergusson. “That itself would have downstream effects on the recipient.”
The current double-blind study included 8,719 patients who received transfusions from September 2018 to December 2020 at three academic medical centers in Canada. Of this group, 5,190 received male donor blood, and 3,529 received blood from female donors.
The researchers randomly assigned patients in a 60:40 ratio to male and female donor groups. Data collection and follow-up were performed by the Ottawa Hospital Data Warehouse, Canadian Blood Services, and ICES, an independent research institute. Patient characteristics were similar in both trial groups at baseline.
After an average follow-up of 11.2 months, with a maximum follow-up of 29 months, 1,141 patients in the female donor group and 1,712 in the male donor group died. The study found no statistically significant difference in overall survival between the two groups. The unadjusted HR for death, with the male group as the reference, was 0.97, and the adjusted HR was 0.98. The rates of overall survival were 58% and 56.1% in the female and male donor groups, respectively.
The study did not prove that differences in outcome based on donor sex do not exist, said Dr. Fergusson. “But those differences really don’t matter in the recipient.”
The design of the trial itself was unique, Dr. Fergusson said. After patients consented to participate and underwent randomization, the study used routinely collected data from the participating hospitals’ electronic medical records rather than collect data anew for each patient. “That had a profound effect on the efficiency of the trial. We did this trial for a cost of less than $300,000, and typically it would cost $9 million by using high-quality electronic health data.”
The study also evaluated several secondary outcomes. Recipients of female donor blood had twice the incidence of MRSA infection. In addition, an unadjusted subgroup analysis suggested a 10% lower risk of death among male patients assigned to the female donor group, compared with those assigned to the male donor group.
The risk of death was almost three times higher among patients in the female donor group who received units from donors aged 20-29.9 years (HR, 2.93). “The inconsistency of the point estimates across groups and the multiplicity of analyses increase the risk that those findings were due to chance,” according to the authors.
Big data
Commenting on the study, Jeannie Callum, MD, professor and director of transfusion medicine at Queen’s University, Kingston, Ont., said that the use of routinely collected data from the participating hospitals’ electronic medical records was “one of the really great things about this paper.”
This use of Big Data “allows you to do a trial like this with almost 9,000 patients without spending millions and millions of dollars to have people go through charts and record data,” she added.
Dr. Callum also pointed out some of the trial’s limitations. “One of the things that kind of detracts from the study in my mind is that they randomized everybody that was getting a transfusion, but outpatients getting a transfusion have a very low mortality rate. So, you have a group of patients that are never going to have that endpoint being included in the study, and that might’ve diluted the findings.”
About 11.4% of participants received blood from a donor group other than the one to which they had been assigned, and this factor may further dilute the findings, said Dr. Callum. “That’s a difficult thing to avoid.” She noted that a trial in which she is collaborating, called Sex Matters, may answer some of these questions about the use of female versus male donor blood.
The investigators also noted that the findings may not be generalizable to other countries. “Just because we didn’t find something in Canada with our blood production system doesn’t mean that the United States might not find it different, because how they manufacture their red blood cells for transfusion is different than how we do them in Canada,” said Dr. Callum.
Nonetheless, this study shows the potential of using Big Data in medicine. “This is the future of large randomized clinical trials to quickly answer questions,” said Dr. Callum. “In the United States, Canada, and other countries that have these large electronic medical records systems, this kind of trial would be able to be done in other centers.”
The study was funded by the Canadian Institutes of Health Research. Dr. Fergusson and Dr. Callum disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a randomized clinical trial with almost 9,000 patients, the adjusted hazard ratio of death among recipients of female donors’ blood, compared with recipients of male donors’ blood, was 0.98. The data contradict the finding of previous observational studies that donor sex is associated with recipient outcomes.
“The key finding was that we actually had a null result,” study author Dean Fergusson, MD, PhD, senior scientist at the Ottawa Hospital Research Institute, said in an interview. “We went in thinking that male donor blood would confer a benefit over female donor blood, and we found that there’s absolutely no difference between the donor sexes on recipient outcomes – mortality and other major secondary outcomes,” Dr. Fergusson added.
The study was published in the New England Journal of Medicine.
Differences ‘don’t matter’
A 2015 article from the National Heart, Lung, and Blood Institute identified a potential effect of donor sex on transfusion recipient survival. Since then, several observational studies have suggested that donor sex may influence survival after transfusion. This research includes two large studies, one from Canada and one from the Netherlands, that reported a heightened risk of death among recipients of red-cell units from female donors or donors who had been pregnant. Other studies, however, yielded conflicting results.
“The rationale was that female blood, because of biochemical properties, different hormones, exposure to babies and other males, all led to a different product, if you will, and these subtle changes could affect the blood product in terms of shelf life and potency,” said Dr. Fergusson. “That itself would have downstream effects on the recipient.”
The current double-blind study included 8,719 patients who received transfusions from September 2018 to December 2020 at three academic medical centers in Canada. Of this group, 5,190 received male donor blood, and 3,529 received blood from female donors.
The researchers randomly assigned patients in a 60:40 ratio to male and female donor groups. Data collection and follow-up were performed by the Ottawa Hospital Data Warehouse, Canadian Blood Services, and ICES, an independent research institute. Patient characteristics were similar in both trial groups at baseline.
After an average follow-up of 11.2 months, with a maximum follow-up of 29 months, 1,141 patients in the female donor group and 1,712 in the male donor group died. The study found no statistically significant difference in overall survival between the two groups. The unadjusted HR for death, with the male group as the reference, was 0.97, and the adjusted HR was 0.98. The rates of overall survival were 58% and 56.1% in the female and male donor groups, respectively.
The study did not prove that differences in outcome based on donor sex do not exist, said Dr. Fergusson. “But those differences really don’t matter in the recipient.”
The design of the trial itself was unique, Dr. Fergusson said. After patients consented to participate and underwent randomization, the study used routinely collected data from the participating hospitals’ electronic medical records rather than collect data anew for each patient. “That had a profound effect on the efficiency of the trial. We did this trial for a cost of less than $300,000, and typically it would cost $9 million by using high-quality electronic health data.”
The study also evaluated several secondary outcomes. Recipients of female donor blood had twice the incidence of MRSA infection. In addition, an unadjusted subgroup analysis suggested a 10% lower risk of death among male patients assigned to the female donor group, compared with those assigned to the male donor group.
The risk of death was almost three times higher among patients in the female donor group who received units from donors aged 20-29.9 years (HR, 2.93). “The inconsistency of the point estimates across groups and the multiplicity of analyses increase the risk that those findings were due to chance,” according to the authors.
Big data
Commenting on the study, Jeannie Callum, MD, professor and director of transfusion medicine at Queen’s University, Kingston, Ont., said that the use of routinely collected data from the participating hospitals’ electronic medical records was “one of the really great things about this paper.”
This use of Big Data “allows you to do a trial like this with almost 9,000 patients without spending millions and millions of dollars to have people go through charts and record data,” she added.
Dr. Callum also pointed out some of the trial’s limitations. “One of the things that kind of detracts from the study in my mind is that they randomized everybody that was getting a transfusion, but outpatients getting a transfusion have a very low mortality rate. So, you have a group of patients that are never going to have that endpoint being included in the study, and that might’ve diluted the findings.”
About 11.4% of participants received blood from a donor group other than the one to which they had been assigned, and this factor may further dilute the findings, said Dr. Callum. “That’s a difficult thing to avoid.” She noted that a trial in which she is collaborating, called Sex Matters, may answer some of these questions about the use of female versus male donor blood.
The investigators also noted that the findings may not be generalizable to other countries. “Just because we didn’t find something in Canada with our blood production system doesn’t mean that the United States might not find it different, because how they manufacture their red blood cells for transfusion is different than how we do them in Canada,” said Dr. Callum.
Nonetheless, this study shows the potential of using Big Data in medicine. “This is the future of large randomized clinical trials to quickly answer questions,” said Dr. Callum. “In the United States, Canada, and other countries that have these large electronic medical records systems, this kind of trial would be able to be done in other centers.”
The study was funded by the Canadian Institutes of Health Research. Dr. Fergusson and Dr. Callum disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Hemophilia A gene therapy under FDA review
Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.
The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched – etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.
Both products are comprised of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.
The new clinical data on valoctocogene roxaparvovec, published online in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.
Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand, Johannesburg, South Africa.
However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.
“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.
New questions
Data from the study “will directly inform therapeutic decision-making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.
The study speaks to an ongoing concern about the durability of gene therapy for hemophilia but also raises new questions, she said.
For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated U.S. price tag of around $2.5 million per treatment, “it is not possible [at the moment] to predict where an individual patient may fall within this range,” she writes.
Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.
“This is a unique finding with an undefined cause and long-term safety implications,” Dr. George said.
Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserted.
Study details
The new report followed up on the initial trial in 134 men who were treated with a single infusion of 6 × 1013 vector genomes per kilogram of body weight.
Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%-49% of normal) with an 84.5% reduction in bleeding events from baseline.
More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.
Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease; and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.
Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.
All the subjects developed antibodies to the virus delivery vector, precluding retreatment.
The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Dr. Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. Dr. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. The full list of author disclosures can be found with the original article.
A version of this article first appeared on Medscape.com.
Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.
The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched – etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.
Both products are comprised of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.
The new clinical data on valoctocogene roxaparvovec, published online in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.
Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand, Johannesburg, South Africa.
However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.
“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.
New questions
Data from the study “will directly inform therapeutic decision-making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.
The study speaks to an ongoing concern about the durability of gene therapy for hemophilia but also raises new questions, she said.
For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated U.S. price tag of around $2.5 million per treatment, “it is not possible [at the moment] to predict where an individual patient may fall within this range,” she writes.
Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.
“This is a unique finding with an undefined cause and long-term safety implications,” Dr. George said.
Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserted.
Study details
The new report followed up on the initial trial in 134 men who were treated with a single infusion of 6 × 1013 vector genomes per kilogram of body weight.
Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%-49% of normal) with an 84.5% reduction in bleeding events from baseline.
More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.
Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease; and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.
Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.
All the subjects developed antibodies to the virus delivery vector, precluding retreatment.
The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Dr. Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. Dr. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. The full list of author disclosures can be found with the original article.
A version of this article first appeared on Medscape.com.
Hemophilia A (a deficiency of clotting Factor X) is the most common form of the disease, accounting for about 85% of patients.
The other type is hemophilia B (deficiency of clotting Factor VIII), and a gene therapy for this form of the disease has recently been launched – etranacogene dezaparvovec (Hemgenix), at the enormous price tag of $3.5 million.
Both products are comprised of a one-off intravenous IV infusion that delivers a functional gene via an adeno-associated virus that instructs the body to make the missing clotting factor. The hope is that this one-off infusion will act as a ‘cure’ and that the individual will be freed from life-long prophylaxis and/or treatment.
The new clinical data on valoctocogene roxaparvovec, published online in the New England Journal of Medicine, show that the beneficial effects from the gene are largely durable at 2 years, but they are anticipated to fade with time.
Two years after the one-time infusion, there remained “a significant reduction in the annualized bleeding rates” among 132 men who, at baseline, had severe hemophilia A requiring ongoing factor VIII prophylaxis, said the investigators, led by hematologist Johnny Mahlangu, MBBCh, MMed, of the University of the Witwatersrand, Johannesburg, South Africa.
However, the team predicted that median factor VIII activity would decrease below 10% of normal by year 3 or 5 depending on measurement technique, which would still translate to mild disease with an annualized bleeding rate of less than 1 episode per year.
“Although valoctocogene roxaparvovec may not eliminate bleeding, it potentially provides more consistent protection than factor VIII prophylaxis with less treatment burden,” the team said.
New questions
Data from the study “will directly inform therapeutic decision-making” in Europe, where valoctocogene roxaparvovec is already conditionally approved, and the United States, where it is awaiting approval by the FDA, says Lindsey George, MD, a hematologist and gene therapy specialist at Children’s Hospital of Philadelphia, in an accompanying editorial.
The study speaks to an ongoing concern about the durability of gene therapy for hemophilia but also raises new questions, she said.
For instance, while some patients had normal Factor VIII production and activity at 2 years, activity had dropped substantially in others, including in six men who resumed prophylaxis. “The cause of the decrease in factor VIII expression is an unanswered question,” and despite an anticipated U.S. price tag of around $2.5 million per treatment, “it is not possible [at the moment] to predict where an individual patient may fall within this range,” she writes.
Also, some subjects had elevations in liver aminotransferase levels that lasted for several months, including 2 years after infusion in 29% of subjects. Elevations in liver aminotransferase levels were treated with immune suppression for a median of 33 weeks.
“This is a unique finding with an undefined cause and long-term safety implications,” Dr. George said.
Getting to the bottom of such issues will be necessary for hemophilia gene therapy to fulfill its promise as “a one-time, lifelong, disease-ameliorating” fix for the condition, she asserted.
Study details
The new report followed up on the initial trial in 134 men who were treated with a single infusion of 6 × 1013 vector genomes per kilogram of body weight.
Among the 132 subjects available for 2-year evaluation, median factor VIII activity was in the range of mild hemophilia (6%-49% of normal) with an 84.5% reduction in bleeding events from baseline.
More than 80% of participants had no bleeding events requiring treatment, and there was a 98% reduction from baseline in mean use of exogenous factor VIII.
Overall, at year 2, 4.5% of subjects had factor VIII activity consistent with severe hemophilia A; 9.1% had activity consistent with moderate disease; 59.8% had activity consistent with mild disease; and 26.5% had activity in the normal range above 40 IU/dL. The investigators estimated that the typical half-life of the transgene-derived factor VIII production system is 123 weeks.
Among the six men who resumed prophylaxis, most had fewer bleeding events than when they were on prophylaxis before the infusion, investigators noted.
All the subjects developed antibodies to the virus delivery vector, precluding retreatment.
The work was funded by valoctocogene roxaparvovec maker BioMarin Pharmaceuticals. Several investigators are employees. Others reported ties to BioMarin and other companies; Dr. Mahlangu, for instance, reported research grants from BioMarin, Roche, Novo Nordisk, Pfizer, and others. Dr. George reported a research grant from Asklepios Biopharmaceutical and having a patent licensed to the company. The full list of author disclosures can be found with the original article.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Efanesoctocog alfa treatment: ‘Victory’ over hemophilia A
One injection of efanesoctocog alfa, a factor VIII therapy, resolved almost all bleeding episodes (97%) in the overall patient population, and weekly prophylaxis provided mean factor VIII activity in the normal or near-normal range (> 40 IU/dL) for most of the week.
Efanesoctocog alfa is currently under priority review by the U.S. Food and Drug Administration, and the target action date for the approval decision was set for Tuesday, February 28.
“Currently, [patients] often need to make trade-offs between bleed protection and dosing frequency,” study researcher Angela Weyand, MD, of Michigan Medicine, said in a press release. The current phase 3 XTEND-1 results assessing efanesoctocog alfa demonstrate that “we have the opportunity to provide near normal factor activity levels for an extended period of time (the majority of a week) with a single dose, which is a first for hemophilia A.”
According to the researchers, efanesoctocog alfa is also the first investigational treatment for hemophilia A to surpass the von Willebrand factor half-life ceiling, which imposes a half-life limitation on current factor VIII therapies.
The study, which was funded by drugmakers Sanofi and Sobi, was published online in the New England Journal of Medicine.
Hemophilia A is a rare genetic disorder caused by a lack of blood clotting factor VIII. Normalizing factor VIII levels can help protect patients from spontaneous and traumatic bleeding but maintaining factor VIII levels in the normal (50-150 IU/dL) or close-to-normal range (> 40 to < 50 IU/dL) with currently available factor VIII therapies requires frequent administration, the study authors explained.
In the phase 3, open-label trial, the authors evaluated the efficacy, safety, and pharmacokinetics of efanesoctocog alfa for routine prophylaxis, treatment of bleeding episodes, and perioperative management in previously treated patients with severe hemophilia A.
Patients were 12 years of age or older with endogenous factor VIII activity of less than 1 IU/dL or a genotype known to produce severe hemophilia A. Patients were required to have had at least 150 previous exposure days to recombinant or plasma-derived factor VIII concentrates or cryoprecipitate.
Overall, 133 patients received once-weekly prophylaxis doses of 50 IU per kg of intravenous efanesoctocog alfa for 52 weeks (group A), and 26 patients received on-demand efanesoctocog alfa treatment for 26 weeks, followed by once-weekly prophylaxis with the medication for 26 weeks at the same 50 IU per kg dosage (group B). The primary endpoint was the mean annualized bleeding rate in group A.
Among those in group A, the annualized bleeding rate was 0 (interquartile range, 0-1.04) and the estimated mean annualized bleeding rate was 0.71. Overall, 65% of these patients (86 of 133) had no bleeding episodes and 93% had 0-2 bleeding episodes.
As for spontaneous bleeding, no episodes were reported in 80% of patients in group A (107 of 133) and 85% of patients (22 of 26) during the prophylaxis period in group B.
A total of 362 bleeding events occurred during the study, with most (268 of 362, or 74%) occurring in group B during the on-demand treatment period.
Among those in group A, switching from the prestudy standard of care to efanesoctocog alfa prophylaxis reduced the mean annualized bleeding rate from 2.96 to 0.69, a decrease of 77%. In group B, the mean annualized bleeding rate also decreased when patients switched from on-demand efanesoctocog alfa to prophylaxis (21.42 vs. 0.69).
Scores of physical health, joint health, and pain intensity were significantly improved within the 52 weeks. In patients with target joints at baseline, 100% of the target joints were resolved after at least 12 months of continuous prophylaxis.
In other words, not only did the treatment stop bleeding, but efanesoctocog alfa also improved the overall quality of life for patients, said lead author Annette von Drygalski MD, PharmD, of the University of California, San Diego.
“[Efanesoctocog] alfa’s half-life and clotting factor activity levels truly translated into a number of other patient outcomes,” Dr. von Drygalski told this news organization. “All these reductions in parameters, pain improvement, improvement in joint health, reduction in pain, and of course reduction of infusions really resulted in improved quality of life for most patients, and so that’s remarkable.”
In addition, no patients developed inhibitors to factor VIII and there were no reports of serious allergic reactions, anaphylaxis, or vascular thrombotic events.
Of the 159 patients who received at least one dose of efanesoctocog alfa, 123 (77%) had at least one adverse event that developed or worsened during the treatment period. The most common adverse events were headache, arthralgia, fall, and back pain.
In an accompanying editorial, Cindy Leissinger, MD, called efanesoctocog alfa a “victory” for patients with hemophilia A.
“In a crowded field of transformative therapies for hemophilia, efanesoctocog alfa stands out as a winner – a major therapeutic advance that achieves highly protective factor VIII levels with a once-weekly infusion,” writes Dr. Leissinger, director of the Louisiana Center for Bleeding and Clotting Disorders at Tulane University, New Orleans.
The study was supported by Sanofi and Sobi. Both Dr. von Drygalski and Dr. Leissinger disclosed serving as consultants for Sanofi, among other disclosures. Other authors provided a range of disclosures, including serving as consultants for Sanofi and Sobi.
A version of this article first appeared on Medscape.com.
One injection of efanesoctocog alfa, a factor VIII therapy, resolved almost all bleeding episodes (97%) in the overall patient population, and weekly prophylaxis provided mean factor VIII activity in the normal or near-normal range (> 40 IU/dL) for most of the week.
Efanesoctocog alfa is currently under priority review by the U.S. Food and Drug Administration, and the target action date for the approval decision was set for Tuesday, February 28.
“Currently, [patients] often need to make trade-offs between bleed protection and dosing frequency,” study researcher Angela Weyand, MD, of Michigan Medicine, said in a press release. The current phase 3 XTEND-1 results assessing efanesoctocog alfa demonstrate that “we have the opportunity to provide near normal factor activity levels for an extended period of time (the majority of a week) with a single dose, which is a first for hemophilia A.”
According to the researchers, efanesoctocog alfa is also the first investigational treatment for hemophilia A to surpass the von Willebrand factor half-life ceiling, which imposes a half-life limitation on current factor VIII therapies.
The study, which was funded by drugmakers Sanofi and Sobi, was published online in the New England Journal of Medicine.
Hemophilia A is a rare genetic disorder caused by a lack of blood clotting factor VIII. Normalizing factor VIII levels can help protect patients from spontaneous and traumatic bleeding but maintaining factor VIII levels in the normal (50-150 IU/dL) or close-to-normal range (> 40 to < 50 IU/dL) with currently available factor VIII therapies requires frequent administration, the study authors explained.
In the phase 3, open-label trial, the authors evaluated the efficacy, safety, and pharmacokinetics of efanesoctocog alfa for routine prophylaxis, treatment of bleeding episodes, and perioperative management in previously treated patients with severe hemophilia A.
Patients were 12 years of age or older with endogenous factor VIII activity of less than 1 IU/dL or a genotype known to produce severe hemophilia A. Patients were required to have had at least 150 previous exposure days to recombinant or plasma-derived factor VIII concentrates or cryoprecipitate.
Overall, 133 patients received once-weekly prophylaxis doses of 50 IU per kg of intravenous efanesoctocog alfa for 52 weeks (group A), and 26 patients received on-demand efanesoctocog alfa treatment for 26 weeks, followed by once-weekly prophylaxis with the medication for 26 weeks at the same 50 IU per kg dosage (group B). The primary endpoint was the mean annualized bleeding rate in group A.
Among those in group A, the annualized bleeding rate was 0 (interquartile range, 0-1.04) and the estimated mean annualized bleeding rate was 0.71. Overall, 65% of these patients (86 of 133) had no bleeding episodes and 93% had 0-2 bleeding episodes.
As for spontaneous bleeding, no episodes were reported in 80% of patients in group A (107 of 133) and 85% of patients (22 of 26) during the prophylaxis period in group B.
A total of 362 bleeding events occurred during the study, with most (268 of 362, or 74%) occurring in group B during the on-demand treatment period.
Among those in group A, switching from the prestudy standard of care to efanesoctocog alfa prophylaxis reduced the mean annualized bleeding rate from 2.96 to 0.69, a decrease of 77%. In group B, the mean annualized bleeding rate also decreased when patients switched from on-demand efanesoctocog alfa to prophylaxis (21.42 vs. 0.69).
Scores of physical health, joint health, and pain intensity were significantly improved within the 52 weeks. In patients with target joints at baseline, 100% of the target joints were resolved after at least 12 months of continuous prophylaxis.
In other words, not only did the treatment stop bleeding, but efanesoctocog alfa also improved the overall quality of life for patients, said lead author Annette von Drygalski MD, PharmD, of the University of California, San Diego.
“[Efanesoctocog] alfa’s half-life and clotting factor activity levels truly translated into a number of other patient outcomes,” Dr. von Drygalski told this news organization. “All these reductions in parameters, pain improvement, improvement in joint health, reduction in pain, and of course reduction of infusions really resulted in improved quality of life for most patients, and so that’s remarkable.”
In addition, no patients developed inhibitors to factor VIII and there were no reports of serious allergic reactions, anaphylaxis, or vascular thrombotic events.
Of the 159 patients who received at least one dose of efanesoctocog alfa, 123 (77%) had at least one adverse event that developed or worsened during the treatment period. The most common adverse events were headache, arthralgia, fall, and back pain.
In an accompanying editorial, Cindy Leissinger, MD, called efanesoctocog alfa a “victory” for patients with hemophilia A.
“In a crowded field of transformative therapies for hemophilia, efanesoctocog alfa stands out as a winner – a major therapeutic advance that achieves highly protective factor VIII levels with a once-weekly infusion,” writes Dr. Leissinger, director of the Louisiana Center for Bleeding and Clotting Disorders at Tulane University, New Orleans.
The study was supported by Sanofi and Sobi. Both Dr. von Drygalski and Dr. Leissinger disclosed serving as consultants for Sanofi, among other disclosures. Other authors provided a range of disclosures, including serving as consultants for Sanofi and Sobi.
A version of this article first appeared on Medscape.com.
One injection of efanesoctocog alfa, a factor VIII therapy, resolved almost all bleeding episodes (97%) in the overall patient population, and weekly prophylaxis provided mean factor VIII activity in the normal or near-normal range (> 40 IU/dL) for most of the week.
Efanesoctocog alfa is currently under priority review by the U.S. Food and Drug Administration, and the target action date for the approval decision was set for Tuesday, February 28.
“Currently, [patients] often need to make trade-offs between bleed protection and dosing frequency,” study researcher Angela Weyand, MD, of Michigan Medicine, said in a press release. The current phase 3 XTEND-1 results assessing efanesoctocog alfa demonstrate that “we have the opportunity to provide near normal factor activity levels for an extended period of time (the majority of a week) with a single dose, which is a first for hemophilia A.”
According to the researchers, efanesoctocog alfa is also the first investigational treatment for hemophilia A to surpass the von Willebrand factor half-life ceiling, which imposes a half-life limitation on current factor VIII therapies.
The study, which was funded by drugmakers Sanofi and Sobi, was published online in the New England Journal of Medicine.
Hemophilia A is a rare genetic disorder caused by a lack of blood clotting factor VIII. Normalizing factor VIII levels can help protect patients from spontaneous and traumatic bleeding but maintaining factor VIII levels in the normal (50-150 IU/dL) or close-to-normal range (> 40 to < 50 IU/dL) with currently available factor VIII therapies requires frequent administration, the study authors explained.
In the phase 3, open-label trial, the authors evaluated the efficacy, safety, and pharmacokinetics of efanesoctocog alfa for routine prophylaxis, treatment of bleeding episodes, and perioperative management in previously treated patients with severe hemophilia A.
Patients were 12 years of age or older with endogenous factor VIII activity of less than 1 IU/dL or a genotype known to produce severe hemophilia A. Patients were required to have had at least 150 previous exposure days to recombinant or plasma-derived factor VIII concentrates or cryoprecipitate.
Overall, 133 patients received once-weekly prophylaxis doses of 50 IU per kg of intravenous efanesoctocog alfa for 52 weeks (group A), and 26 patients received on-demand efanesoctocog alfa treatment for 26 weeks, followed by once-weekly prophylaxis with the medication for 26 weeks at the same 50 IU per kg dosage (group B). The primary endpoint was the mean annualized bleeding rate in group A.
Among those in group A, the annualized bleeding rate was 0 (interquartile range, 0-1.04) and the estimated mean annualized bleeding rate was 0.71. Overall, 65% of these patients (86 of 133) had no bleeding episodes and 93% had 0-2 bleeding episodes.
As for spontaneous bleeding, no episodes were reported in 80% of patients in group A (107 of 133) and 85% of patients (22 of 26) during the prophylaxis period in group B.
A total of 362 bleeding events occurred during the study, with most (268 of 362, or 74%) occurring in group B during the on-demand treatment period.
Among those in group A, switching from the prestudy standard of care to efanesoctocog alfa prophylaxis reduced the mean annualized bleeding rate from 2.96 to 0.69, a decrease of 77%. In group B, the mean annualized bleeding rate also decreased when patients switched from on-demand efanesoctocog alfa to prophylaxis (21.42 vs. 0.69).
Scores of physical health, joint health, and pain intensity were significantly improved within the 52 weeks. In patients with target joints at baseline, 100% of the target joints were resolved after at least 12 months of continuous prophylaxis.
In other words, not only did the treatment stop bleeding, but efanesoctocog alfa also improved the overall quality of life for patients, said lead author Annette von Drygalski MD, PharmD, of the University of California, San Diego.
“[Efanesoctocog] alfa’s half-life and clotting factor activity levels truly translated into a number of other patient outcomes,” Dr. von Drygalski told this news organization. “All these reductions in parameters, pain improvement, improvement in joint health, reduction in pain, and of course reduction of infusions really resulted in improved quality of life for most patients, and so that’s remarkable.”
In addition, no patients developed inhibitors to factor VIII and there were no reports of serious allergic reactions, anaphylaxis, or vascular thrombotic events.
Of the 159 patients who received at least one dose of efanesoctocog alfa, 123 (77%) had at least one adverse event that developed or worsened during the treatment period. The most common adverse events were headache, arthralgia, fall, and back pain.
In an accompanying editorial, Cindy Leissinger, MD, called efanesoctocog alfa a “victory” for patients with hemophilia A.
“In a crowded field of transformative therapies for hemophilia, efanesoctocog alfa stands out as a winner – a major therapeutic advance that achieves highly protective factor VIII levels with a once-weekly infusion,” writes Dr. Leissinger, director of the Louisiana Center for Bleeding and Clotting Disorders at Tulane University, New Orleans.
The study was supported by Sanofi and Sobi. Both Dr. von Drygalski and Dr. Leissinger disclosed serving as consultants for Sanofi, among other disclosures. Other authors provided a range of disclosures, including serving as consultants for Sanofi and Sobi.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Europe approves first gene therapy for hemophilia B
The approval means that the product will now be available in all the countries of the European Union as well as the European Economic Area.
The gene therapy was approved in the United States in November 2022. It was launched with a price tag of $3.5 million, making it the most expensive treatment to date.
The treatment comprises a one-time infusion of a functional gene that acts as a blueprint for coagulation factor IX, a protein important for blood clotting, stated the manufacturer, CSL.
People living with hemophilia B currently require lifelong treatment of intravenous infusions of factor IX to maintain sufficient levels, which can have a significant impact on their quality of life and well-being, the company explained in its press release.
The approval was based on findings from the pivotal HOPE-B trial, a single-arm, open-label study of 54 men who relied on factor IX replacement therapy; first results from this trial were reported at the 2020 annual meeting of the American Society of Hematology.
The results showed that patients with hemophilia B treated with the gene therapy demonstrated stable and durable increases in mean factor IX activity (with a mean factor IX activity of 36.9%), which led to an adjusted annualized bleeding rate reduction of 64%.
After receiving the gene therapy, 96% of patients discontinued routine factor IX prophylaxis and mean factor IX consumption was reduced by 97% at 18 months post treatment compared with the lead-in period, the company noted.
“Data from the HOPE-B study demonstrate the potential of Hemgenix to remove the need for routine prophylaxis by providing durable factor IX activity, as well as improved bleeding outcomes and quality of life for people with hemophilia B,” said one of the trialists, Wolfgang Miesbach, MD, PHD, head of coagulation disorders at the Comprehensive Care Center, University Hospital of Frankfurt, Germany.
This European approval “marks an important step forward in the treatment of hemophilia B, which could be transformative for people who are debilitated by bleeds into their muscles, joints, and internal organs, alleviating the burden of lifelong intravenous infusions of factor IX products,” Dr. Miesbach said in the company press release.
A version of this article first appeared on Medscape.com.
The approval means that the product will now be available in all the countries of the European Union as well as the European Economic Area.
The gene therapy was approved in the United States in November 2022. It was launched with a price tag of $3.5 million, making it the most expensive treatment to date.
The treatment comprises a one-time infusion of a functional gene that acts as a blueprint for coagulation factor IX, a protein important for blood clotting, stated the manufacturer, CSL.
People living with hemophilia B currently require lifelong treatment of intravenous infusions of factor IX to maintain sufficient levels, which can have a significant impact on their quality of life and well-being, the company explained in its press release.
The approval was based on findings from the pivotal HOPE-B trial, a single-arm, open-label study of 54 men who relied on factor IX replacement therapy; first results from this trial were reported at the 2020 annual meeting of the American Society of Hematology.
The results showed that patients with hemophilia B treated with the gene therapy demonstrated stable and durable increases in mean factor IX activity (with a mean factor IX activity of 36.9%), which led to an adjusted annualized bleeding rate reduction of 64%.
After receiving the gene therapy, 96% of patients discontinued routine factor IX prophylaxis and mean factor IX consumption was reduced by 97% at 18 months post treatment compared with the lead-in period, the company noted.
“Data from the HOPE-B study demonstrate the potential of Hemgenix to remove the need for routine prophylaxis by providing durable factor IX activity, as well as improved bleeding outcomes and quality of life for people with hemophilia B,” said one of the trialists, Wolfgang Miesbach, MD, PHD, head of coagulation disorders at the Comprehensive Care Center, University Hospital of Frankfurt, Germany.
This European approval “marks an important step forward in the treatment of hemophilia B, which could be transformative for people who are debilitated by bleeds into their muscles, joints, and internal organs, alleviating the burden of lifelong intravenous infusions of factor IX products,” Dr. Miesbach said in the company press release.
A version of this article first appeared on Medscape.com.
The approval means that the product will now be available in all the countries of the European Union as well as the European Economic Area.
The gene therapy was approved in the United States in November 2022. It was launched with a price tag of $3.5 million, making it the most expensive treatment to date.
The treatment comprises a one-time infusion of a functional gene that acts as a blueprint for coagulation factor IX, a protein important for blood clotting, stated the manufacturer, CSL.
People living with hemophilia B currently require lifelong treatment of intravenous infusions of factor IX to maintain sufficient levels, which can have a significant impact on their quality of life and well-being, the company explained in its press release.
The approval was based on findings from the pivotal HOPE-B trial, a single-arm, open-label study of 54 men who relied on factor IX replacement therapy; first results from this trial were reported at the 2020 annual meeting of the American Society of Hematology.
The results showed that patients with hemophilia B treated with the gene therapy demonstrated stable and durable increases in mean factor IX activity (with a mean factor IX activity of 36.9%), which led to an adjusted annualized bleeding rate reduction of 64%.
After receiving the gene therapy, 96% of patients discontinued routine factor IX prophylaxis and mean factor IX consumption was reduced by 97% at 18 months post treatment compared with the lead-in period, the company noted.
“Data from the HOPE-B study demonstrate the potential of Hemgenix to remove the need for routine prophylaxis by providing durable factor IX activity, as well as improved bleeding outcomes and quality of life for people with hemophilia B,” said one of the trialists, Wolfgang Miesbach, MD, PHD, head of coagulation disorders at the Comprehensive Care Center, University Hospital of Frankfurt, Germany.
This European approval “marks an important step forward in the treatment of hemophilia B, which could be transformative for people who are debilitated by bleeds into their muscles, joints, and internal organs, alleviating the burden of lifelong intravenous infusions of factor IX products,” Dr. Miesbach said in the company press release.
A version of this article first appeared on Medscape.com.
FDA approves once-weekly hemophilia A product
The product is used once a week and is indicated for routine prophylaxis and on-demand treatment to control bleeding episodes, as well as to control bleeding during surgery (perioperative management).
The manufacturer, Sanofi, says that this is “the first and only hemophilia A treatment that delivers normal to near-normal factor activity levels (over 40%) for most of the week with once-weekly dosing, and significantly reduces bleeds compared to prior factor VIII prophylaxis.”
With this product, “we have the opportunity to provide near-normal factor activity levels for an extended period of time (the majority of a week) with a single dose, which is a first for hemophilia A,” said Angela Weyand, MD, of Michigan Medicine, who was involved in the pivotal phase 3 XTEND-1 trial that led to approval.
Results from the XTEND-1 trial were recently published online in The New England Journal of Medicine. The results show that one injection of efanesoctocog alfa, a factor VIII therapy, resolved almost all bleeding episodes (97%) in the overall patient population and weekly prophylaxis provided mean factor VIII activity in the normal or near-normal range (> 40 IU/dL) for most of the week, as previously reported by this news organization.
The researchers noted that the factor VIII therapies that have been available up to now need to be administered frequently.
In an accompanying editorial, Cindy Leissinger, MD, called efanesoctocog alfa a “victory” for patients with hemophilia A.
“In a crowded field of transformative therapies for hemophilia, efanesoctocog alfa stands out as a winner – a major therapeutic advance that achieves highly protective factor VIII levels with a once-weekly infusion,” wrote Dr. Leissinger, director of the Louisiana Center for Bleeding and Clotting Disorders at Tulane University in New Orleans.
Sanofi said that Altuviiio is expected to be commercially available in April 2023. The company said that it will price the product at parity to the annual cost of treating a prophylaxis patient with its Eloctate product (antihemophilic factor [recombinant], Fc fusion protein). Sanofi will provide comprehensive patient support services and resources online and at 1-855-MyALTUVIIIO (855-692-5888).
A version of this article originally appeared on Medscape.com.
The product is used once a week and is indicated for routine prophylaxis and on-demand treatment to control bleeding episodes, as well as to control bleeding during surgery (perioperative management).
The manufacturer, Sanofi, says that this is “the first and only hemophilia A treatment that delivers normal to near-normal factor activity levels (over 40%) for most of the week with once-weekly dosing, and significantly reduces bleeds compared to prior factor VIII prophylaxis.”
With this product, “we have the opportunity to provide near-normal factor activity levels for an extended period of time (the majority of a week) with a single dose, which is a first for hemophilia A,” said Angela Weyand, MD, of Michigan Medicine, who was involved in the pivotal phase 3 XTEND-1 trial that led to approval.
Results from the XTEND-1 trial were recently published online in The New England Journal of Medicine. The results show that one injection of efanesoctocog alfa, a factor VIII therapy, resolved almost all bleeding episodes (97%) in the overall patient population and weekly prophylaxis provided mean factor VIII activity in the normal or near-normal range (> 40 IU/dL) for most of the week, as previously reported by this news organization.
The researchers noted that the factor VIII therapies that have been available up to now need to be administered frequently.
In an accompanying editorial, Cindy Leissinger, MD, called efanesoctocog alfa a “victory” for patients with hemophilia A.
“In a crowded field of transformative therapies for hemophilia, efanesoctocog alfa stands out as a winner – a major therapeutic advance that achieves highly protective factor VIII levels with a once-weekly infusion,” wrote Dr. Leissinger, director of the Louisiana Center for Bleeding and Clotting Disorders at Tulane University in New Orleans.
Sanofi said that Altuviiio is expected to be commercially available in April 2023. The company said that it will price the product at parity to the annual cost of treating a prophylaxis patient with its Eloctate product (antihemophilic factor [recombinant], Fc fusion protein). Sanofi will provide comprehensive patient support services and resources online and at 1-855-MyALTUVIIIO (855-692-5888).
A version of this article originally appeared on Medscape.com.
The product is used once a week and is indicated for routine prophylaxis and on-demand treatment to control bleeding episodes, as well as to control bleeding during surgery (perioperative management).
The manufacturer, Sanofi, says that this is “the first and only hemophilia A treatment that delivers normal to near-normal factor activity levels (over 40%) for most of the week with once-weekly dosing, and significantly reduces bleeds compared to prior factor VIII prophylaxis.”
With this product, “we have the opportunity to provide near-normal factor activity levels for an extended period of time (the majority of a week) with a single dose, which is a first for hemophilia A,” said Angela Weyand, MD, of Michigan Medicine, who was involved in the pivotal phase 3 XTEND-1 trial that led to approval.
Results from the XTEND-1 trial were recently published online in The New England Journal of Medicine. The results show that one injection of efanesoctocog alfa, a factor VIII therapy, resolved almost all bleeding episodes (97%) in the overall patient population and weekly prophylaxis provided mean factor VIII activity in the normal or near-normal range (> 40 IU/dL) for most of the week, as previously reported by this news organization.
The researchers noted that the factor VIII therapies that have been available up to now need to be administered frequently.
In an accompanying editorial, Cindy Leissinger, MD, called efanesoctocog alfa a “victory” for patients with hemophilia A.
“In a crowded field of transformative therapies for hemophilia, efanesoctocog alfa stands out as a winner – a major therapeutic advance that achieves highly protective factor VIII levels with a once-weekly infusion,” wrote Dr. Leissinger, director of the Louisiana Center for Bleeding and Clotting Disorders at Tulane University in New Orleans.
Sanofi said that Altuviiio is expected to be commercially available in April 2023. The company said that it will price the product at parity to the annual cost of treating a prophylaxis patient with its Eloctate product (antihemophilic factor [recombinant], Fc fusion protein). Sanofi will provide comprehensive patient support services and resources online and at 1-855-MyALTUVIIIO (855-692-5888).
A version of this article originally appeared on Medscape.com.
Abnormal bleeding common among youth with joint hypermobility
A small cohort study of pediatric rheumatology patients with generalized joint hypermobility (GJH) who presented to a specialized rheumatology* clinic suggests that many such patients have abnormal bleeding symptoms, in comparison with health control patients.
The study of 81 patients with GJH found that about three quarters had significantly elevated median bleeding scores, but only 12% had been assessed by hematology for bleeding.
“We propose that screening for bleeding symptoms should be integrated into the routine care for all patients with GJH, with hematology referrals for patients with increased bleeding concerns,” wrote a research team led by Nicole E. Kendel, MD, a pediatric hematologist-oncologist at Akron Children’s Hospital in Ohio, in a study published online in Arthritis Care and Research.
“Further studies are needed to understand the mechanism of bleeding, evaluate comorbidities associated with these bleeding symptoms, and potentially allow for tailored pharmacologic therapy,” the authors stated.
Background
Dr. Kendel’s team had reported moderate menstruation-associated limitations in school, social, and physical activities among female adolescents with GJH. “This cohort also experienced nonreproductive bleeding symptoms and demonstrated minimal hemostatic laboratory abnormalities, indicating that this population may be underdiagnosed and subsequently poorly managed,” she said in an interview. “As excessive bleeding symptoms could have a significant impact on overall health and quality of life, we thought it was important to define the incidence and natural course of bleeding symptoms in a more generalized subset of this population.”
Although the investigators hypothesized that there would be a statistically significant increase in bleeding scores, “we were still impressed by the frequency of abnormal scores, particularly when looking at the low percentage of patients [12%] who had previously been referred to hematology,” she said.
Study results
The median age of the study cohort was 13 years (interquartile range, 10-16 years), and 72.8% were female. The mean Beighton score, which measures joint flexibility, was 6.2 (range, 4-9). All participants were seen by rheumatologists and were diagnosed for conditions on the hypermobility spectrum. Those conditions ranged from GJH to hypermobile Ehlers-Danlos syndrome (hEDS).
Abnormal bleeding, as measured by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, was found in 75% (95% confidence interval [CI], 64%-84%). Overall mean and median bleeding scores were 5.2 and 4, respectively; scores ranged from 0 to 16. Abnormal scores of ≥ 3 were observed for patients < 8 years of age, ≥ 4 for men ≥ 18 years of age, and ≥ 6 for women ≥ 18 years of age. These measures were significantly elevated compared with those reported for historical healthy pediatric control persons (P < .001).
The most common hemorrhagic symptom was oral bleeding (74.1%) that occurred with tooth brushing, flossing, tooth loss, or eruption. Others reported easy bruising (59.3%) and bleeding from minor wounds (42%). In terms of procedures, tooth extraction requiring additional packing was reported by 25.9%, and 22.2% reported significant bleeding after otolaryngologic procedures, such as tonsillectomy/adenoidectomy, septoplasty, and nasal turbinate reduction.
Prolonged or heavy menstrual periods were reported by 37.3% of female patients.
Bleeding scores did not differ by biological sex or NSAID use, nor did any correlation emerge between patients’ bleeding and Beighton scores. However, there was a positive correlation with increasing age, a phenomenon observed with other bleeding disorders and in the healthy population, the authors noted.
Of the 10 study participants who had previously undergone hematologic assessment, one had been diagnosed with acquired, heart disease–related von Willebrand disease, and another with mild bleeding disorder.
Severe connective tissue disorders are associated with increased bleeding symptoms in the adult population, Dr. Kendel said, but few studies have assessed bleeding across the GJH spectrum, particularly in children.
Bleeding is thought to be due to modifications of collagen in the blood vessels. “These modifications create mechanical weakness of the vessel wall, as well as defective subendothelial connective tissue supporting those blood vessels,” Dr. Kendel explained. She noted that altered collagen creates defective interactions between collagen and other coagulation factors.
“Even in the presence of a normal laboratory evaluation, GJH can lead to symptoms consistent with a mild bleeding disorder,” she continued. “These symptoms are both preventable and treatable. I’m hopeful more centers will start routinely evaluating for increased bleeding symptoms, with referral to hematology for those with increased bleeding concerns.”
Commenting on the study’s recommendation, Beth S. Gottlieb, MD, chief of the division of pediatric rheumatology at Northwell Health in New Hyde Park, N.Y., who was not involved in the investigation, said a brief questionnaire on bleeding risk is a reasonable addition to a rheumatology office visit.
“Joint hypermobility is very common, but not all affected children meet the criteria for the hypermobile form of hEDS,” she told this news organization. “Screening for bleeding tendency is often done as routine medical history questions. Once a child is identified as hypermobile, these screening questions are usually asked, but utilizing one of the formal bleeding risk questionnaires is not currently routine.”
According to Dr. Gottlieb, it remains unclear whether screening would have a significant impact on children who have been diagnosed with hypermobility. “Most of these children are young and may not yet have a significant history for bleeding tendency,” she said. “Education of families is always important, and it will be essential to educate without adding unnecessary stress. Screening guidelines may be an important tool that is easy to incorporate into routine clinical practice.”
Limitation
The study was limited by selection bias, as patients had all been referred to a specialized rheumatology clinic.
The study was supported by the Clinical and Translational Intramural Funding Program of the Abigail Wexner Research Institute. The authors and Dr. Gottlieb have disclosed no relevant financial relationships.
*Correction, 1/11/2023: An earlier version of this story misstated the type of specialty clinic where patients were first seen.
A version of this article first appeared on Medscape.com.
A small cohort study of pediatric rheumatology patients with generalized joint hypermobility (GJH) who presented to a specialized rheumatology* clinic suggests that many such patients have abnormal bleeding symptoms, in comparison with health control patients.
The study of 81 patients with GJH found that about three quarters had significantly elevated median bleeding scores, but only 12% had been assessed by hematology for bleeding.
“We propose that screening for bleeding symptoms should be integrated into the routine care for all patients with GJH, with hematology referrals for patients with increased bleeding concerns,” wrote a research team led by Nicole E. Kendel, MD, a pediatric hematologist-oncologist at Akron Children’s Hospital in Ohio, in a study published online in Arthritis Care and Research.
“Further studies are needed to understand the mechanism of bleeding, evaluate comorbidities associated with these bleeding symptoms, and potentially allow for tailored pharmacologic therapy,” the authors stated.
Background
Dr. Kendel’s team had reported moderate menstruation-associated limitations in school, social, and physical activities among female adolescents with GJH. “This cohort also experienced nonreproductive bleeding symptoms and demonstrated minimal hemostatic laboratory abnormalities, indicating that this population may be underdiagnosed and subsequently poorly managed,” she said in an interview. “As excessive bleeding symptoms could have a significant impact on overall health and quality of life, we thought it was important to define the incidence and natural course of bleeding symptoms in a more generalized subset of this population.”
Although the investigators hypothesized that there would be a statistically significant increase in bleeding scores, “we were still impressed by the frequency of abnormal scores, particularly when looking at the low percentage of patients [12%] who had previously been referred to hematology,” she said.
Study results
The median age of the study cohort was 13 years (interquartile range, 10-16 years), and 72.8% were female. The mean Beighton score, which measures joint flexibility, was 6.2 (range, 4-9). All participants were seen by rheumatologists and were diagnosed for conditions on the hypermobility spectrum. Those conditions ranged from GJH to hypermobile Ehlers-Danlos syndrome (hEDS).
Abnormal bleeding, as measured by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, was found in 75% (95% confidence interval [CI], 64%-84%). Overall mean and median bleeding scores were 5.2 and 4, respectively; scores ranged from 0 to 16. Abnormal scores of ≥ 3 were observed for patients < 8 years of age, ≥ 4 for men ≥ 18 years of age, and ≥ 6 for women ≥ 18 years of age. These measures were significantly elevated compared with those reported for historical healthy pediatric control persons (P < .001).
The most common hemorrhagic symptom was oral bleeding (74.1%) that occurred with tooth brushing, flossing, tooth loss, or eruption. Others reported easy bruising (59.3%) and bleeding from minor wounds (42%). In terms of procedures, tooth extraction requiring additional packing was reported by 25.9%, and 22.2% reported significant bleeding after otolaryngologic procedures, such as tonsillectomy/adenoidectomy, septoplasty, and nasal turbinate reduction.
Prolonged or heavy menstrual periods were reported by 37.3% of female patients.
Bleeding scores did not differ by biological sex or NSAID use, nor did any correlation emerge between patients’ bleeding and Beighton scores. However, there was a positive correlation with increasing age, a phenomenon observed with other bleeding disorders and in the healthy population, the authors noted.
Of the 10 study participants who had previously undergone hematologic assessment, one had been diagnosed with acquired, heart disease–related von Willebrand disease, and another with mild bleeding disorder.
Severe connective tissue disorders are associated with increased bleeding symptoms in the adult population, Dr. Kendel said, but few studies have assessed bleeding across the GJH spectrum, particularly in children.
Bleeding is thought to be due to modifications of collagen in the blood vessels. “These modifications create mechanical weakness of the vessel wall, as well as defective subendothelial connective tissue supporting those blood vessels,” Dr. Kendel explained. She noted that altered collagen creates defective interactions between collagen and other coagulation factors.
“Even in the presence of a normal laboratory evaluation, GJH can lead to symptoms consistent with a mild bleeding disorder,” she continued. “These symptoms are both preventable and treatable. I’m hopeful more centers will start routinely evaluating for increased bleeding symptoms, with referral to hematology for those with increased bleeding concerns.”
Commenting on the study’s recommendation, Beth S. Gottlieb, MD, chief of the division of pediatric rheumatology at Northwell Health in New Hyde Park, N.Y., who was not involved in the investigation, said a brief questionnaire on bleeding risk is a reasonable addition to a rheumatology office visit.
“Joint hypermobility is very common, but not all affected children meet the criteria for the hypermobile form of hEDS,” she told this news organization. “Screening for bleeding tendency is often done as routine medical history questions. Once a child is identified as hypermobile, these screening questions are usually asked, but utilizing one of the formal bleeding risk questionnaires is not currently routine.”
According to Dr. Gottlieb, it remains unclear whether screening would have a significant impact on children who have been diagnosed with hypermobility. “Most of these children are young and may not yet have a significant history for bleeding tendency,” she said. “Education of families is always important, and it will be essential to educate without adding unnecessary stress. Screening guidelines may be an important tool that is easy to incorporate into routine clinical practice.”
Limitation
The study was limited by selection bias, as patients had all been referred to a specialized rheumatology clinic.
The study was supported by the Clinical and Translational Intramural Funding Program of the Abigail Wexner Research Institute. The authors and Dr. Gottlieb have disclosed no relevant financial relationships.
*Correction, 1/11/2023: An earlier version of this story misstated the type of specialty clinic where patients were first seen.
A version of this article first appeared on Medscape.com.
A small cohort study of pediatric rheumatology patients with generalized joint hypermobility (GJH) who presented to a specialized rheumatology* clinic suggests that many such patients have abnormal bleeding symptoms, in comparison with health control patients.
The study of 81 patients with GJH found that about three quarters had significantly elevated median bleeding scores, but only 12% had been assessed by hematology for bleeding.
“We propose that screening for bleeding symptoms should be integrated into the routine care for all patients with GJH, with hematology referrals for patients with increased bleeding concerns,” wrote a research team led by Nicole E. Kendel, MD, a pediatric hematologist-oncologist at Akron Children’s Hospital in Ohio, in a study published online in Arthritis Care and Research.
“Further studies are needed to understand the mechanism of bleeding, evaluate comorbidities associated with these bleeding symptoms, and potentially allow for tailored pharmacologic therapy,” the authors stated.
Background
Dr. Kendel’s team had reported moderate menstruation-associated limitations in school, social, and physical activities among female adolescents with GJH. “This cohort also experienced nonreproductive bleeding symptoms and demonstrated minimal hemostatic laboratory abnormalities, indicating that this population may be underdiagnosed and subsequently poorly managed,” she said in an interview. “As excessive bleeding symptoms could have a significant impact on overall health and quality of life, we thought it was important to define the incidence and natural course of bleeding symptoms in a more generalized subset of this population.”
Although the investigators hypothesized that there would be a statistically significant increase in bleeding scores, “we were still impressed by the frequency of abnormal scores, particularly when looking at the low percentage of patients [12%] who had previously been referred to hematology,” she said.
Study results
The median age of the study cohort was 13 years (interquartile range, 10-16 years), and 72.8% were female. The mean Beighton score, which measures joint flexibility, was 6.2 (range, 4-9). All participants were seen by rheumatologists and were diagnosed for conditions on the hypermobility spectrum. Those conditions ranged from GJH to hypermobile Ehlers-Danlos syndrome (hEDS).
Abnormal bleeding, as measured by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool, was found in 75% (95% confidence interval [CI], 64%-84%). Overall mean and median bleeding scores were 5.2 and 4, respectively; scores ranged from 0 to 16. Abnormal scores of ≥ 3 were observed for patients < 8 years of age, ≥ 4 for men ≥ 18 years of age, and ≥ 6 for women ≥ 18 years of age. These measures were significantly elevated compared with those reported for historical healthy pediatric control persons (P < .001).
The most common hemorrhagic symptom was oral bleeding (74.1%) that occurred with tooth brushing, flossing, tooth loss, or eruption. Others reported easy bruising (59.3%) and bleeding from minor wounds (42%). In terms of procedures, tooth extraction requiring additional packing was reported by 25.9%, and 22.2% reported significant bleeding after otolaryngologic procedures, such as tonsillectomy/adenoidectomy, septoplasty, and nasal turbinate reduction.
Prolonged or heavy menstrual periods were reported by 37.3% of female patients.
Bleeding scores did not differ by biological sex or NSAID use, nor did any correlation emerge between patients’ bleeding and Beighton scores. However, there was a positive correlation with increasing age, a phenomenon observed with other bleeding disorders and in the healthy population, the authors noted.
Of the 10 study participants who had previously undergone hematologic assessment, one had been diagnosed with acquired, heart disease–related von Willebrand disease, and another with mild bleeding disorder.
Severe connective tissue disorders are associated with increased bleeding symptoms in the adult population, Dr. Kendel said, but few studies have assessed bleeding across the GJH spectrum, particularly in children.
Bleeding is thought to be due to modifications of collagen in the blood vessels. “These modifications create mechanical weakness of the vessel wall, as well as defective subendothelial connective tissue supporting those blood vessels,” Dr. Kendel explained. She noted that altered collagen creates defective interactions between collagen and other coagulation factors.
“Even in the presence of a normal laboratory evaluation, GJH can lead to symptoms consistent with a mild bleeding disorder,” she continued. “These symptoms are both preventable and treatable. I’m hopeful more centers will start routinely evaluating for increased bleeding symptoms, with referral to hematology for those with increased bleeding concerns.”
Commenting on the study’s recommendation, Beth S. Gottlieb, MD, chief of the division of pediatric rheumatology at Northwell Health in New Hyde Park, N.Y., who was not involved in the investigation, said a brief questionnaire on bleeding risk is a reasonable addition to a rheumatology office visit.
“Joint hypermobility is very common, but not all affected children meet the criteria for the hypermobile form of hEDS,” she told this news organization. “Screening for bleeding tendency is often done as routine medical history questions. Once a child is identified as hypermobile, these screening questions are usually asked, but utilizing one of the formal bleeding risk questionnaires is not currently routine.”
According to Dr. Gottlieb, it remains unclear whether screening would have a significant impact on children who have been diagnosed with hypermobility. “Most of these children are young and may not yet have a significant history for bleeding tendency,” she said. “Education of families is always important, and it will be essential to educate without adding unnecessary stress. Screening guidelines may be an important tool that is easy to incorporate into routine clinical practice.”
Limitation
The study was limited by selection bias, as patients had all been referred to a specialized rheumatology clinic.
The study was supported by the Clinical and Translational Intramural Funding Program of the Abigail Wexner Research Institute. The authors and Dr. Gottlieb have disclosed no relevant financial relationships.
*Correction, 1/11/2023: An earlier version of this story misstated the type of specialty clinic where patients were first seen.
A version of this article first appeared on Medscape.com.
FROM ARTHRITIS CARE AND RESEARCH
ITP: Biologic beat placebo, but few patients improved
NEW ORLEANS –
Nevertheless, “efgartigimod demonstrated a strong clinical benefit,” said hematologist/oncologist and study lead author Catherine M. Broome, MD, of Georgetown University, Washington, in an interview about the findings presented at the annual meeting of the American Society of Hematology.
“The data showed statistically significant and clinically meaningful improvement in platelet counts over placebo, a fast and robust platelet count improvement over placebo, and the confirmed ability for every-other-week dosing, as well as a favorable safety and tolerability profile, consistent with previous clinical trials,” she said.
In ITP, according to the National Organization for Rare Disorders, “the patient’s immune system tags their own platelets as ‘foreign,’ leading their B lymphocytes and plasma cells to produce self-reactive antiplatelet antibodies that attach to platelet surface.”
The prevalence of ITP among adults in the United States is 9.5 per 100,000, NORD says. Children are also affected, but they usually recover. An estimated 60% of adults recover within 3 years.
Treatment options include corticosteroids and intravenous immunoglobulin.
“There are a relatively large number of current treatments, and they tend to work well for most patients. However, there are a minority of patients who do not respond to or tolerate current therapies and would benefit from new treatment options,” said hematologist Adam C. Cuker, MD, MS, of Penn Medicine, Philadelphia, in an interview. He is chair of ASH’s Committee on Quality.
For the new industry-funded ADVANCE study, researchers recruited patients with long-standing, persistent/chronic ITP (an average of two platelet counts of < 30×109/L).
Subjects were randomized 2:1 to receive 10 mg/kg of efgartigimod weekly – or response-dependent doses after the first 4 weeks – or placebo for 24 weeks. There were 86 patients in the intervention group and 45 in the placebo group. Overall, 60 were male and 71 were female; 107 were under 65; 121 were White and 8 were Asian. Details about the others were not provided.
Subjects were allowed to take several other drugs such as oral corticosteroids, and oral thrombopoietin receptor agonists other than romiplostim.
Per the primary endpoint, 17/78 (21.8%) reached a sustained response, defined as platelet counts ≥ 50×109/L in ≥ four of six visits between weeks 19 and 24 without intercurrent events, such as rescue therapy at week 12 or later. In the placebo group, 2/40 reached this response (5.0%; P = .0316).
“The primary endpoint was a high bar to achieve,” Dr. Broome said. “This was a difficult-to-treat patient population heavily pretreated and refractory to other treatments: 68.6% of patients in the efgartigimod arm had received three or more prior ITP treatments.”
She added that “subgroup analyses – including prior ITP therapy, time since diagnosis, baseline platelet count and age/region demographics – of patients who achieved the primary endpoint all favored efgartigimod over placebo.”
Side effects were extremely common among both the drug and placebo groups, and serious adverse events were common in the placebo group. No deaths were reported.
Efgartigimod, a neonatal Fc receptor blocker, is an extremely expensive drug that is Food and Drug Administration approved for some cases of generalized myasthenia gravis. According to a report in Neurology earlier this year, company statements listed its price as $855,400 a year; the report questioned its cost-effectiveness.
In response to a query about price, Luc Truyen, MD, PhD, chief medical officer of drug manufacturer Argenx, declined to talk about cost – a sensitive topic for pharmaceutical companies. “It is too early to discuss pricing and access as no regulatory submission or discussion has occurred,” Dr. Truyen said.
Penn Medicine’s Dr. Cuker, who is familiar with the study findings, said the primary endpoint results are not very impressive. “That said, it should be borne in mind that the patients enrolled in the trial tended to be heavily pretreated and refractory patients,” he said.
As for adverse effects, he said the drug “appears to be safe and well tolerated. The biggest theoretical concern with this class of drugs is an increased risk of infection due to lowering of IgG levels.”
It would be helpful to have trials that directly compare second-line therapies in ITP, he added. “Unfortunately, no such trials exist, and pharmaceutical companies would not be motivated to conduct them.”
For now, he said, off-label use of efgartigimod “may be reasonable, but only in rare situations where other approved and better established ITP treatments have been exhausted.”
What’s next? According to Dr. Broome, another trial is currently evaluating efgartigimod for the treatment of primary ITP, with top-line data expected in the second half of 2023.
The study was funded by Argenx. Dr. Broome discloses honoraria from Alexion, Argenx, Apellis, and Sano. Dr. Truyen’s disclosures weren’t available. Dr. Cuker has no disclosures.
NEW ORLEANS –
Nevertheless, “efgartigimod demonstrated a strong clinical benefit,” said hematologist/oncologist and study lead author Catherine M. Broome, MD, of Georgetown University, Washington, in an interview about the findings presented at the annual meeting of the American Society of Hematology.
“The data showed statistically significant and clinically meaningful improvement in platelet counts over placebo, a fast and robust platelet count improvement over placebo, and the confirmed ability for every-other-week dosing, as well as a favorable safety and tolerability profile, consistent with previous clinical trials,” she said.
In ITP, according to the National Organization for Rare Disorders, “the patient’s immune system tags their own platelets as ‘foreign,’ leading their B lymphocytes and plasma cells to produce self-reactive antiplatelet antibodies that attach to platelet surface.”
The prevalence of ITP among adults in the United States is 9.5 per 100,000, NORD says. Children are also affected, but they usually recover. An estimated 60% of adults recover within 3 years.
Treatment options include corticosteroids and intravenous immunoglobulin.
“There are a relatively large number of current treatments, and they tend to work well for most patients. However, there are a minority of patients who do not respond to or tolerate current therapies and would benefit from new treatment options,” said hematologist Adam C. Cuker, MD, MS, of Penn Medicine, Philadelphia, in an interview. He is chair of ASH’s Committee on Quality.
For the new industry-funded ADVANCE study, researchers recruited patients with long-standing, persistent/chronic ITP (an average of two platelet counts of < 30×109/L).
Subjects were randomized 2:1 to receive 10 mg/kg of efgartigimod weekly – or response-dependent doses after the first 4 weeks – or placebo for 24 weeks. There were 86 patients in the intervention group and 45 in the placebo group. Overall, 60 were male and 71 were female; 107 were under 65; 121 were White and 8 were Asian. Details about the others were not provided.
Subjects were allowed to take several other drugs such as oral corticosteroids, and oral thrombopoietin receptor agonists other than romiplostim.
Per the primary endpoint, 17/78 (21.8%) reached a sustained response, defined as platelet counts ≥ 50×109/L in ≥ four of six visits between weeks 19 and 24 without intercurrent events, such as rescue therapy at week 12 or later. In the placebo group, 2/40 reached this response (5.0%; P = .0316).
“The primary endpoint was a high bar to achieve,” Dr. Broome said. “This was a difficult-to-treat patient population heavily pretreated and refractory to other treatments: 68.6% of patients in the efgartigimod arm had received three or more prior ITP treatments.”
She added that “subgroup analyses – including prior ITP therapy, time since diagnosis, baseline platelet count and age/region demographics – of patients who achieved the primary endpoint all favored efgartigimod over placebo.”
Side effects were extremely common among both the drug and placebo groups, and serious adverse events were common in the placebo group. No deaths were reported.
Efgartigimod, a neonatal Fc receptor blocker, is an extremely expensive drug that is Food and Drug Administration approved for some cases of generalized myasthenia gravis. According to a report in Neurology earlier this year, company statements listed its price as $855,400 a year; the report questioned its cost-effectiveness.
In response to a query about price, Luc Truyen, MD, PhD, chief medical officer of drug manufacturer Argenx, declined to talk about cost – a sensitive topic for pharmaceutical companies. “It is too early to discuss pricing and access as no regulatory submission or discussion has occurred,” Dr. Truyen said.
Penn Medicine’s Dr. Cuker, who is familiar with the study findings, said the primary endpoint results are not very impressive. “That said, it should be borne in mind that the patients enrolled in the trial tended to be heavily pretreated and refractory patients,” he said.
As for adverse effects, he said the drug “appears to be safe and well tolerated. The biggest theoretical concern with this class of drugs is an increased risk of infection due to lowering of IgG levels.”
It would be helpful to have trials that directly compare second-line therapies in ITP, he added. “Unfortunately, no such trials exist, and pharmaceutical companies would not be motivated to conduct them.”
For now, he said, off-label use of efgartigimod “may be reasonable, but only in rare situations where other approved and better established ITP treatments have been exhausted.”
What’s next? According to Dr. Broome, another trial is currently evaluating efgartigimod for the treatment of primary ITP, with top-line data expected in the second half of 2023.
The study was funded by Argenx. Dr. Broome discloses honoraria from Alexion, Argenx, Apellis, and Sano. Dr. Truyen’s disclosures weren’t available. Dr. Cuker has no disclosures.
NEW ORLEANS –
Nevertheless, “efgartigimod demonstrated a strong clinical benefit,” said hematologist/oncologist and study lead author Catherine M. Broome, MD, of Georgetown University, Washington, in an interview about the findings presented at the annual meeting of the American Society of Hematology.
“The data showed statistically significant and clinically meaningful improvement in platelet counts over placebo, a fast and robust platelet count improvement over placebo, and the confirmed ability for every-other-week dosing, as well as a favorable safety and tolerability profile, consistent with previous clinical trials,” she said.
In ITP, according to the National Organization for Rare Disorders, “the patient’s immune system tags their own platelets as ‘foreign,’ leading their B lymphocytes and plasma cells to produce self-reactive antiplatelet antibodies that attach to platelet surface.”
The prevalence of ITP among adults in the United States is 9.5 per 100,000, NORD says. Children are also affected, but they usually recover. An estimated 60% of adults recover within 3 years.
Treatment options include corticosteroids and intravenous immunoglobulin.
“There are a relatively large number of current treatments, and they tend to work well for most patients. However, there are a minority of patients who do not respond to or tolerate current therapies and would benefit from new treatment options,” said hematologist Adam C. Cuker, MD, MS, of Penn Medicine, Philadelphia, in an interview. He is chair of ASH’s Committee on Quality.
For the new industry-funded ADVANCE study, researchers recruited patients with long-standing, persistent/chronic ITP (an average of two platelet counts of < 30×109/L).
Subjects were randomized 2:1 to receive 10 mg/kg of efgartigimod weekly – or response-dependent doses after the first 4 weeks – or placebo for 24 weeks. There were 86 patients in the intervention group and 45 in the placebo group. Overall, 60 were male and 71 were female; 107 were under 65; 121 were White and 8 were Asian. Details about the others were not provided.
Subjects were allowed to take several other drugs such as oral corticosteroids, and oral thrombopoietin receptor agonists other than romiplostim.
Per the primary endpoint, 17/78 (21.8%) reached a sustained response, defined as platelet counts ≥ 50×109/L in ≥ four of six visits between weeks 19 and 24 without intercurrent events, such as rescue therapy at week 12 or later. In the placebo group, 2/40 reached this response (5.0%; P = .0316).
“The primary endpoint was a high bar to achieve,” Dr. Broome said. “This was a difficult-to-treat patient population heavily pretreated and refractory to other treatments: 68.6% of patients in the efgartigimod arm had received three or more prior ITP treatments.”
She added that “subgroup analyses – including prior ITP therapy, time since diagnosis, baseline platelet count and age/region demographics – of patients who achieved the primary endpoint all favored efgartigimod over placebo.”
Side effects were extremely common among both the drug and placebo groups, and serious adverse events were common in the placebo group. No deaths were reported.
Efgartigimod, a neonatal Fc receptor blocker, is an extremely expensive drug that is Food and Drug Administration approved for some cases of generalized myasthenia gravis. According to a report in Neurology earlier this year, company statements listed its price as $855,400 a year; the report questioned its cost-effectiveness.
In response to a query about price, Luc Truyen, MD, PhD, chief medical officer of drug manufacturer Argenx, declined to talk about cost – a sensitive topic for pharmaceutical companies. “It is too early to discuss pricing and access as no regulatory submission or discussion has occurred,” Dr. Truyen said.
Penn Medicine’s Dr. Cuker, who is familiar with the study findings, said the primary endpoint results are not very impressive. “That said, it should be borne in mind that the patients enrolled in the trial tended to be heavily pretreated and refractory patients,” he said.
As for adverse effects, he said the drug “appears to be safe and well tolerated. The biggest theoretical concern with this class of drugs is an increased risk of infection due to lowering of IgG levels.”
It would be helpful to have trials that directly compare second-line therapies in ITP, he added. “Unfortunately, no such trials exist, and pharmaceutical companies would not be motivated to conduct them.”
For now, he said, off-label use of efgartigimod “may be reasonable, but only in rare situations where other approved and better established ITP treatments have been exhausted.”
What’s next? According to Dr. Broome, another trial is currently evaluating efgartigimod for the treatment of primary ITP, with top-line data expected in the second half of 2023.
The study was funded by Argenx. Dr. Broome discloses honoraria from Alexion, Argenx, Apellis, and Sano. Dr. Truyen’s disclosures weren’t available. Dr. Cuker has no disclosures.
AT ASH 2022