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‘Time is blood’: Researchers devise shortcut to AHA diagnosis
“A simple algorithm for unexplained bleeding might be helpful to emergency department physicians and other frontline workers to improve recognition of the disease,” said Amar Kelkar, MD, a fellow at the Dana-Farber Cancer Institute, Boston, and corresponding author of “Time is blood: The impact of diagnostic delays on acquired hemophilia A,” a report that appeared in the journal Cureus.
According to Dr. Kelkar, AHA is an autoimmune disease caused by the formation of autoantibodies against factor VIII (FVIII). “Classically, patients present with various forms of bleeding symptoms, including extensive bruising, spontaneous prolonged or persistent bleeding, and blood in the urine. These symptoms are usually accompanied by a prolonged activated partial thromboplastin time (aPTT) test,” he said in an interview. “While this is a rare diagnosis to be seen in primary, critical, or emergency care, it’s a disease that most hematologists should have seen and managed before.”
For the new study, researchers retrospectively tracked patients with AHA at the OSF Healthcare System in Illinois from 2010 to 2017. They focused on six patients (mean age, 79.5; male = 5). Cancer was considered a cause in four cases, and autoimmune disease in one. The sixth case was idiopathic. Five of the six patients died, with all but one death related to bleeding.
The researchers note that they saw more cases than expected (6 per 2.1 million vs. an estimated incidence of 1.48 per 1 million per year), although they attributed this high incidence to the population being made up of older hospitalized patients. In fact, Dr. Kelkar said, researchers believe this is an undercount reflecting diagnostic misses.
The median time to diagnosis was 14 days, the authors report, reflecting other studies that have also shown delays. Pseudo-thrombosis and preexisting anticoagulant therapy likely contribute to the diagnostic delays, they write.
In their new report, the authors developed an algorithm to speed diagnosis.
“The initial step is the identification of a patient with new, unexplained bleeding,” they write. “In the setting of unexplained bleeding, a detailed clinical history, including medication use, along with a thorough physical examination is critical. Prompt primary laboratory testing should include a complete blood count, a metabolic panel including creatinine and bilirubin, and coagulation testing including aPTT and prothrombin time with international normalized ratio (PT/INR). A resulting isolated aPTT elevation will initiate subsequent steps. Early inpatient hematology consultation is recommended.”
The authors add: “An important point to highlight is that we recommend concurrently ordering an aPTT mixing study and a factor VIII activity (FVIII:C) once a prolonged aPTT is confirmed. This may decrease the time to initiate treatment and improve patient outcomes. If the mixing study result is abnormal with low FVIII:C, hemostatic treatment could be initiated with concurrent confirmatory Bethesda assay or anti-FVIII ELISA, preventing further delay in patient recovery and hopefully reducing potential complications. If there is limited availability of specialty testing or prolonged delays in getting test results, such as for FVIII:C, or an inability to confirm a diagnosis at any stage of the algorithm, transferring the patient to a higher level of care with these laboratory and hematology services should be strongly considered.”
The authors also note that “when the diagnostic delay is greater than 1 month, there will be a significant increase in the days that the patient is required to be on hemostatic therapy, compared to diagnosis before 1 month (23.8 ± 13 vs. 7.6 ± 5.7 days, respectively; P = .003).”
The algorithm is meant to be widely available, Dr. Kelkar said. “That is why we targeted an open-source, general medicine journal like Cureus.”
Jerome Teitel, MD, a hematologist with St. Michael’s Hospital in Toronto, said in an interview that the algorithm “might be a useful guide for initial investigation at community hospitals.”
However, he recommended against emphasizing the use of mixing studies. They are “often ambiguous and just delay ordering the definitive tests (FVIII activity and inhibitor assay), which will need to be done regardless,” he said. “The most important message should be that patients with AHA should be referred to, or at least comanaged with, a hematologist who has specific experience and expertise in the field, and who will likely have access to specialized coagulation tests with short turnaround times.”
Another hematologist, George M. Rodgers III, MD, of the University of Utah, Salt Lake City, said in an interview that the algorithm is appropriate for the evaluation of possible AHA. “Patients with the disorder who present with minor bleeding are not evaluated with high priority by physicians,” he said. “Patients with bleeding and a prolonged PTT should be taken very seriously because AHA patients can develop spontaneous fatal bleeding.”
No study funding is reported. The authors, Dr. Teitel, and Dr. Rodgers report no relevant disclosures.
“A simple algorithm for unexplained bleeding might be helpful to emergency department physicians and other frontline workers to improve recognition of the disease,” said Amar Kelkar, MD, a fellow at the Dana-Farber Cancer Institute, Boston, and corresponding author of “Time is blood: The impact of diagnostic delays on acquired hemophilia A,” a report that appeared in the journal Cureus.
According to Dr. Kelkar, AHA is an autoimmune disease caused by the formation of autoantibodies against factor VIII (FVIII). “Classically, patients present with various forms of bleeding symptoms, including extensive bruising, spontaneous prolonged or persistent bleeding, and blood in the urine. These symptoms are usually accompanied by a prolonged activated partial thromboplastin time (aPTT) test,” he said in an interview. “While this is a rare diagnosis to be seen in primary, critical, or emergency care, it’s a disease that most hematologists should have seen and managed before.”
For the new study, researchers retrospectively tracked patients with AHA at the OSF Healthcare System in Illinois from 2010 to 2017. They focused on six patients (mean age, 79.5; male = 5). Cancer was considered a cause in four cases, and autoimmune disease in one. The sixth case was idiopathic. Five of the six patients died, with all but one death related to bleeding.
The researchers note that they saw more cases than expected (6 per 2.1 million vs. an estimated incidence of 1.48 per 1 million per year), although they attributed this high incidence to the population being made up of older hospitalized patients. In fact, Dr. Kelkar said, researchers believe this is an undercount reflecting diagnostic misses.
The median time to diagnosis was 14 days, the authors report, reflecting other studies that have also shown delays. Pseudo-thrombosis and preexisting anticoagulant therapy likely contribute to the diagnostic delays, they write.
In their new report, the authors developed an algorithm to speed diagnosis.
“The initial step is the identification of a patient with new, unexplained bleeding,” they write. “In the setting of unexplained bleeding, a detailed clinical history, including medication use, along with a thorough physical examination is critical. Prompt primary laboratory testing should include a complete blood count, a metabolic panel including creatinine and bilirubin, and coagulation testing including aPTT and prothrombin time with international normalized ratio (PT/INR). A resulting isolated aPTT elevation will initiate subsequent steps. Early inpatient hematology consultation is recommended.”
The authors add: “An important point to highlight is that we recommend concurrently ordering an aPTT mixing study and a factor VIII activity (FVIII:C) once a prolonged aPTT is confirmed. This may decrease the time to initiate treatment and improve patient outcomes. If the mixing study result is abnormal with low FVIII:C, hemostatic treatment could be initiated with concurrent confirmatory Bethesda assay or anti-FVIII ELISA, preventing further delay in patient recovery and hopefully reducing potential complications. If there is limited availability of specialty testing or prolonged delays in getting test results, such as for FVIII:C, or an inability to confirm a diagnosis at any stage of the algorithm, transferring the patient to a higher level of care with these laboratory and hematology services should be strongly considered.”
The authors also note that “when the diagnostic delay is greater than 1 month, there will be a significant increase in the days that the patient is required to be on hemostatic therapy, compared to diagnosis before 1 month (23.8 ± 13 vs. 7.6 ± 5.7 days, respectively; P = .003).”
The algorithm is meant to be widely available, Dr. Kelkar said. “That is why we targeted an open-source, general medicine journal like Cureus.”
Jerome Teitel, MD, a hematologist with St. Michael’s Hospital in Toronto, said in an interview that the algorithm “might be a useful guide for initial investigation at community hospitals.”
However, he recommended against emphasizing the use of mixing studies. They are “often ambiguous and just delay ordering the definitive tests (FVIII activity and inhibitor assay), which will need to be done regardless,” he said. “The most important message should be that patients with AHA should be referred to, or at least comanaged with, a hematologist who has specific experience and expertise in the field, and who will likely have access to specialized coagulation tests with short turnaround times.”
Another hematologist, George M. Rodgers III, MD, of the University of Utah, Salt Lake City, said in an interview that the algorithm is appropriate for the evaluation of possible AHA. “Patients with the disorder who present with minor bleeding are not evaluated with high priority by physicians,” he said. “Patients with bleeding and a prolonged PTT should be taken very seriously because AHA patients can develop spontaneous fatal bleeding.”
No study funding is reported. The authors, Dr. Teitel, and Dr. Rodgers report no relevant disclosures.
“A simple algorithm for unexplained bleeding might be helpful to emergency department physicians and other frontline workers to improve recognition of the disease,” said Amar Kelkar, MD, a fellow at the Dana-Farber Cancer Institute, Boston, and corresponding author of “Time is blood: The impact of diagnostic delays on acquired hemophilia A,” a report that appeared in the journal Cureus.
According to Dr. Kelkar, AHA is an autoimmune disease caused by the formation of autoantibodies against factor VIII (FVIII). “Classically, patients present with various forms of bleeding symptoms, including extensive bruising, spontaneous prolonged or persistent bleeding, and blood in the urine. These symptoms are usually accompanied by a prolonged activated partial thromboplastin time (aPTT) test,” he said in an interview. “While this is a rare diagnosis to be seen in primary, critical, or emergency care, it’s a disease that most hematologists should have seen and managed before.”
For the new study, researchers retrospectively tracked patients with AHA at the OSF Healthcare System in Illinois from 2010 to 2017. They focused on six patients (mean age, 79.5; male = 5). Cancer was considered a cause in four cases, and autoimmune disease in one. The sixth case was idiopathic. Five of the six patients died, with all but one death related to bleeding.
The researchers note that they saw more cases than expected (6 per 2.1 million vs. an estimated incidence of 1.48 per 1 million per year), although they attributed this high incidence to the population being made up of older hospitalized patients. In fact, Dr. Kelkar said, researchers believe this is an undercount reflecting diagnostic misses.
The median time to diagnosis was 14 days, the authors report, reflecting other studies that have also shown delays. Pseudo-thrombosis and preexisting anticoagulant therapy likely contribute to the diagnostic delays, they write.
In their new report, the authors developed an algorithm to speed diagnosis.
“The initial step is the identification of a patient with new, unexplained bleeding,” they write. “In the setting of unexplained bleeding, a detailed clinical history, including medication use, along with a thorough physical examination is critical. Prompt primary laboratory testing should include a complete blood count, a metabolic panel including creatinine and bilirubin, and coagulation testing including aPTT and prothrombin time with international normalized ratio (PT/INR). A resulting isolated aPTT elevation will initiate subsequent steps. Early inpatient hematology consultation is recommended.”
The authors add: “An important point to highlight is that we recommend concurrently ordering an aPTT mixing study and a factor VIII activity (FVIII:C) once a prolonged aPTT is confirmed. This may decrease the time to initiate treatment and improve patient outcomes. If the mixing study result is abnormal with low FVIII:C, hemostatic treatment could be initiated with concurrent confirmatory Bethesda assay or anti-FVIII ELISA, preventing further delay in patient recovery and hopefully reducing potential complications. If there is limited availability of specialty testing or prolonged delays in getting test results, such as for FVIII:C, or an inability to confirm a diagnosis at any stage of the algorithm, transferring the patient to a higher level of care with these laboratory and hematology services should be strongly considered.”
The authors also note that “when the diagnostic delay is greater than 1 month, there will be a significant increase in the days that the patient is required to be on hemostatic therapy, compared to diagnosis before 1 month (23.8 ± 13 vs. 7.6 ± 5.7 days, respectively; P = .003).”
The algorithm is meant to be widely available, Dr. Kelkar said. “That is why we targeted an open-source, general medicine journal like Cureus.”
Jerome Teitel, MD, a hematologist with St. Michael’s Hospital in Toronto, said in an interview that the algorithm “might be a useful guide for initial investigation at community hospitals.”
However, he recommended against emphasizing the use of mixing studies. They are “often ambiguous and just delay ordering the definitive tests (FVIII activity and inhibitor assay), which will need to be done regardless,” he said. “The most important message should be that patients with AHA should be referred to, or at least comanaged with, a hematologist who has specific experience and expertise in the field, and who will likely have access to specialized coagulation tests with short turnaround times.”
Another hematologist, George M. Rodgers III, MD, of the University of Utah, Salt Lake City, said in an interview that the algorithm is appropriate for the evaluation of possible AHA. “Patients with the disorder who present with minor bleeding are not evaluated with high priority by physicians,” he said. “Patients with bleeding and a prolonged PTT should be taken very seriously because AHA patients can develop spontaneous fatal bleeding.”
No study funding is reported. The authors, Dr. Teitel, and Dr. Rodgers report no relevant disclosures.
FROM CUREUS
Anticipation key to tackling perioperative anemia
MANCHESTER, ENGLAND –
Anemia management may include dietary changes, iron supplementation, blood transfusion, perioperative physiological optimization, delay or review of the surgical plan, medication reviews, and greater intraoperative care.
It is quite clear that patients have a better experience if management covers the whole pathway, said lead author of the guidelines, Scarlett McNally, MD, PhD, East Sussex Healthcare NHS Trust, Eastbourne, England.
It’s much better for the patient “if every individual member of staff knows what’s supposed to happen, not just for their bit, but the whole way along,” she said. “Otherwise things go wrong, and people don’t anticipate things early enough.”
The new guidelines, to be published in full later this year by the Centre for Perioperative Care, cover emergency and elective surgery for all ages.
It follows the 2021 publication of a guideline for perioperative diabetes management, and a previous document that covered frailty.
Dr. McNally was presenting the new guidelines on perioperative anemia at the British Society for Haematology 62nd Annual Scientific Meeting.
Although perioperative anemia is a “big issue” in clinical management, “some health care professionals know a lot about one area,” but tend to work in “silos,” Dr. McNally said.
The result is clinicians believe that all other areas are “complex” and opaque, and they “don’t make the simple decisions” that could have a big impact on patient care.
As an example, she said there are already some excellent guidelines out there, but they are not widely read.
One example of a comprehensive guideline, Dr. McNally said, is that issued by the British Society of Gastroenterology. This guideline notes that in cases where a man or a postmenopausal woman has anemia of unknown cause, about 30% of those cases end up having a gastrointestinal cause, and so gastroenterologists are happy to have those patients referred to them.
But Dr. McNally said that she personally, as an orthopedic surgeon, wouldn’t have known what to do with such a patient, and may have referred that person back to primary care to be investigated.
The new guidelines contain algorithms to help staff plan care. Without those, she said, “a lot is resting on the preassessment nurses, but they are having to think about everything else.”
The guidance suggests proactive measures to identify and manage anemia. These include testing for anemia while assessing renal function ahead of a CT scan, or asking patients about their nutrition.
For low-risk patients, it may be enough to give general advice about a good diet and exercise to try to get them through the operation.
However, patients who are high risk (defined as likely to lose > 500 mL or > 10% of blood volume during surgery) need to be identified as such early on, so that early measures can be put in place, as well as a senior review of their care plan.
The guidelines also recommend that operating room staff consider tranexamic acid and other bloodless minimization strategies, and that senior staff give clinical input in cases of functional iron deficiency, a marker of ill health.
To maximize postoperative outcomes, it is suggested that staff work with prehabilitation services and mobilize patients, as symptoms allow.
More importantly, they emphasize the need for shared decision-making about potential surgery, ensuring that the patients understand “Benefits, Risks, Alternatives, and what if we do Nothing (BRAN).”
No funding was declared. One study author declared relationships with the National Institute for Health Research and Pfizer.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND –
Anemia management may include dietary changes, iron supplementation, blood transfusion, perioperative physiological optimization, delay or review of the surgical plan, medication reviews, and greater intraoperative care.
It is quite clear that patients have a better experience if management covers the whole pathway, said lead author of the guidelines, Scarlett McNally, MD, PhD, East Sussex Healthcare NHS Trust, Eastbourne, England.
It’s much better for the patient “if every individual member of staff knows what’s supposed to happen, not just for their bit, but the whole way along,” she said. “Otherwise things go wrong, and people don’t anticipate things early enough.”
The new guidelines, to be published in full later this year by the Centre for Perioperative Care, cover emergency and elective surgery for all ages.
It follows the 2021 publication of a guideline for perioperative diabetes management, and a previous document that covered frailty.
Dr. McNally was presenting the new guidelines on perioperative anemia at the British Society for Haematology 62nd Annual Scientific Meeting.
Although perioperative anemia is a “big issue” in clinical management, “some health care professionals know a lot about one area,” but tend to work in “silos,” Dr. McNally said.
The result is clinicians believe that all other areas are “complex” and opaque, and they “don’t make the simple decisions” that could have a big impact on patient care.
As an example, she said there are already some excellent guidelines out there, but they are not widely read.
One example of a comprehensive guideline, Dr. McNally said, is that issued by the British Society of Gastroenterology. This guideline notes that in cases where a man or a postmenopausal woman has anemia of unknown cause, about 30% of those cases end up having a gastrointestinal cause, and so gastroenterologists are happy to have those patients referred to them.
But Dr. McNally said that she personally, as an orthopedic surgeon, wouldn’t have known what to do with such a patient, and may have referred that person back to primary care to be investigated.
The new guidelines contain algorithms to help staff plan care. Without those, she said, “a lot is resting on the preassessment nurses, but they are having to think about everything else.”
The guidance suggests proactive measures to identify and manage anemia. These include testing for anemia while assessing renal function ahead of a CT scan, or asking patients about their nutrition.
For low-risk patients, it may be enough to give general advice about a good diet and exercise to try to get them through the operation.
However, patients who are high risk (defined as likely to lose > 500 mL or > 10% of blood volume during surgery) need to be identified as such early on, so that early measures can be put in place, as well as a senior review of their care plan.
The guidelines also recommend that operating room staff consider tranexamic acid and other bloodless minimization strategies, and that senior staff give clinical input in cases of functional iron deficiency, a marker of ill health.
To maximize postoperative outcomes, it is suggested that staff work with prehabilitation services and mobilize patients, as symptoms allow.
More importantly, they emphasize the need for shared decision-making about potential surgery, ensuring that the patients understand “Benefits, Risks, Alternatives, and what if we do Nothing (BRAN).”
No funding was declared. One study author declared relationships with the National Institute for Health Research and Pfizer.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND –
Anemia management may include dietary changes, iron supplementation, blood transfusion, perioperative physiological optimization, delay or review of the surgical plan, medication reviews, and greater intraoperative care.
It is quite clear that patients have a better experience if management covers the whole pathway, said lead author of the guidelines, Scarlett McNally, MD, PhD, East Sussex Healthcare NHS Trust, Eastbourne, England.
It’s much better for the patient “if every individual member of staff knows what’s supposed to happen, not just for their bit, but the whole way along,” she said. “Otherwise things go wrong, and people don’t anticipate things early enough.”
The new guidelines, to be published in full later this year by the Centre for Perioperative Care, cover emergency and elective surgery for all ages.
It follows the 2021 publication of a guideline for perioperative diabetes management, and a previous document that covered frailty.
Dr. McNally was presenting the new guidelines on perioperative anemia at the British Society for Haematology 62nd Annual Scientific Meeting.
Although perioperative anemia is a “big issue” in clinical management, “some health care professionals know a lot about one area,” but tend to work in “silos,” Dr. McNally said.
The result is clinicians believe that all other areas are “complex” and opaque, and they “don’t make the simple decisions” that could have a big impact on patient care.
As an example, she said there are already some excellent guidelines out there, but they are not widely read.
One example of a comprehensive guideline, Dr. McNally said, is that issued by the British Society of Gastroenterology. This guideline notes that in cases where a man or a postmenopausal woman has anemia of unknown cause, about 30% of those cases end up having a gastrointestinal cause, and so gastroenterologists are happy to have those patients referred to them.
But Dr. McNally said that she personally, as an orthopedic surgeon, wouldn’t have known what to do with such a patient, and may have referred that person back to primary care to be investigated.
The new guidelines contain algorithms to help staff plan care. Without those, she said, “a lot is resting on the preassessment nurses, but they are having to think about everything else.”
The guidance suggests proactive measures to identify and manage anemia. These include testing for anemia while assessing renal function ahead of a CT scan, or asking patients about their nutrition.
For low-risk patients, it may be enough to give general advice about a good diet and exercise to try to get them through the operation.
However, patients who are high risk (defined as likely to lose > 500 mL or > 10% of blood volume during surgery) need to be identified as such early on, so that early measures can be put in place, as well as a senior review of their care plan.
The guidelines also recommend that operating room staff consider tranexamic acid and other bloodless minimization strategies, and that senior staff give clinical input in cases of functional iron deficiency, a marker of ill health.
To maximize postoperative outcomes, it is suggested that staff work with prehabilitation services and mobilize patients, as symptoms allow.
More importantly, they emphasize the need for shared decision-making about potential surgery, ensuring that the patients understand “Benefits, Risks, Alternatives, and what if we do Nothing (BRAN).”
No funding was declared. One study author declared relationships with the National Institute for Health Research and Pfizer.
A version of this article first appeared on Medscape.com.
Rapper sings about living with sickle cell disease
MANCHESTER, ENGLAND – A London-based rapper known for his gospel-inspired music has now given a voice to patients with sickle cell disease. He is using one of his music videos to raise awareness and educate health care professionals about living with the condition.
One important aim of the video, he says, is to help educate health care professionals, some of whom have not come across this condition, he explained at a session during the annual meeting of the British Society for Haematology, held recently in Manchester, England.
“It’s kind of frustrating to feel like your safe space, when you’re in front of doctors and nurses and paramedics who are supposed to know what it is and react with treatment, [and they] don’t know what it is,” Mr. Gaspar said.
He recalled an occasion in which he was experiencing a crisis, and his wife called for an ambulance. The paramedics arrived and his wife asked them for “gas and air and morphine, and they were, like, no, we don’t want to give that to him.” She tried to explain that he has sickle cell disease, but the paramedics had not heard of the condition and were suspicious that the request for morphine was a sign of drug addiction.
Mr. Gaspar expressed his frustration over “constantly having to prove that you have something serious enough to need the treatment you are asking for.”
At the meeting, Mr. Gaspar was talking on the stage with hematologist Dr. Stephen Hibbs from Barts Health NHS Trust, London.
Mr. Gaspar explained that it took years before he eventually reached “a point where I understood that it’s something that affects me and affects many other people, and I didn’t want to hide it any more.”
Sickle cell disease, which occurs primarily in people of Afro-Caribbean background, is a taboo subject in his community, Mr. Gaspar elaborated in an interview.
The condition has been associated with a great deal of stigma, with young sufferers traditionally seen as “demonically possessed,” he commented.
“So there was always a shameful aspect around it when it came to African families speaking about it, especially back in Africa.”
But after his parents came to the United Kingdom, he was able to “do his research and understand that it’s just genetics.”
This knowledge, Mr. Gaspar said, “takes away the spiritual aspect” and allows people to “have the conversation about sickle cell with potential partners” and ask them to find out their genotype, which in turn helps to “break down the barriers and the stigma.”
Mr. Gaspar emphasizes that there is much more work still to do.
In the video, he appeals to the Black community to make blood donations.
He said that something that “haunts” him is that currently, only 1% of Black people in the United Kingdom give blood, “so I really want the song to move my community to take a step forward and make that difference.”
He has been in contact with NHS Blood and Transplant, which provides blood and transplantation service to the National Health Service. They “really liked” the song, Mr. Gaspar said, and helped him get access to a hospital ward in University College Hospital, London, for the video.
“I really wanted to make a video that made people uncomfortable when watching it,” he said. It shows him hospitalized for pain and breathlessness and recalling having to use a Zimmer frame at the age of 25.
“This is a side of sickle cell that normally people don’t know,” he said.
Since releasing the song and the video, Mr. Gaspar says he has been contacted by many fellow patients. They have told him that he is now their “voice”; when they are asked how the condition affects them, “they can show someone the Hidden Pain video and say: This is how it feels.”
Clinicians have also approached him, asking if they can show his video to illustrate to patients and their families how having the condition may affect their lives.
Preventable deaths
At the meeting, Dr. Hibbs highlighted the 2021 report No One’s Listening, which was issued by the Sickle Cell Society following an inquiry into avoidable deaths and failures of care for sickle cell patients.
The inquiry, published by an All-Party Parliamentary group, found “serious care failings” in acute services and evidence of attitudes underpinned by racism. There was evidence of substandard care for sickle cell patients who were admitted to general wards or to hospital accident and emergency departments, as well as low awareness of the condition among health care professionals.
The report noted that the care failings have led to patient deaths, some which could have been prevented, and that there have been many “near misses.”
Many patients with sickle cell disease said they are “not being listened to” or are not being understood, especially during that vulnerable period when they are “in a crisis.”
Mr. Gaspar said that the report, and also the deaths, really struck a chord with him and many in his community. “We felt like that was us. ... We’ve all been in that same position where we’ve been misunderstood and not heard by nurses, doctors, or paramedics.”
He emphasized the need for awareness of the condition and the need for timely treatment. Just 3 weeks ago, Mr. Gaspar attended the funeral of one of his friends who is in the Hidden Pain video, a fellow sickle cell disease patient, who died at 30 years of age.
Ignorance about the condition ‘all too common’
The lack of awareness about sickle cell disease, even among health care professionals, is “all too common,” says Dr. Subarna Chakravorty, consultant pediatric hematologist, King’s College Hospital, London.
Even in London, where there is a large Black community and the teaching hospitals have world-class expertise, patients with sickle cell disease are “still facing a lot of problems with knowledge” among health care professionals, she said in an interview.
“Often people are having to speak for their own condition; which is fine, except that sometimes they are not believed,” she commented.
“On the one hand, you rely on the patient to provide information about their disease, and then when you receive it, you don’t do anything about it. So [they’re] between a rock and a hard place.”
Why are sickle cell patients treated in this way?
For Dr. Chakravorty, there is “a lot to be said about racism and disparities” in treating patients “as morphine-seekers, opiate addicts, even in children.”
“So we really need to improve the knowledge and perceptions among nonspecialist staff,” she said, “and even among specialists.”
Mr. Gaspar aims to help with this effort and hopes that his song and video will be useful to health care professionals. Sickle cell disease “needs to be spoken about,” and more doctors and nurses need to “know what it is,” he said.
He said it is a relief to encounter health care professionals who are knowledgeable about his condition. There have been times when he has been “having a crisis at home, calling the ambulance, and the paramedic comes and says: ‘Mr. Gaspar, you have sickle cell...we believe that you usually have gas and air and morphine, is that correct?’”
“That gives me a sense of peace, to know that I don’t have to fight my case or convince someone I have sickle cell, and I need to start treatment. They already know.”
No relevant financial relationships have been disclosed.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND – A London-based rapper known for his gospel-inspired music has now given a voice to patients with sickle cell disease. He is using one of his music videos to raise awareness and educate health care professionals about living with the condition.
One important aim of the video, he says, is to help educate health care professionals, some of whom have not come across this condition, he explained at a session during the annual meeting of the British Society for Haematology, held recently in Manchester, England.
“It’s kind of frustrating to feel like your safe space, when you’re in front of doctors and nurses and paramedics who are supposed to know what it is and react with treatment, [and they] don’t know what it is,” Mr. Gaspar said.
He recalled an occasion in which he was experiencing a crisis, and his wife called for an ambulance. The paramedics arrived and his wife asked them for “gas and air and morphine, and they were, like, no, we don’t want to give that to him.” She tried to explain that he has sickle cell disease, but the paramedics had not heard of the condition and were suspicious that the request for morphine was a sign of drug addiction.
Mr. Gaspar expressed his frustration over “constantly having to prove that you have something serious enough to need the treatment you are asking for.”
At the meeting, Mr. Gaspar was talking on the stage with hematologist Dr. Stephen Hibbs from Barts Health NHS Trust, London.
Mr. Gaspar explained that it took years before he eventually reached “a point where I understood that it’s something that affects me and affects many other people, and I didn’t want to hide it any more.”
Sickle cell disease, which occurs primarily in people of Afro-Caribbean background, is a taboo subject in his community, Mr. Gaspar elaborated in an interview.
The condition has been associated with a great deal of stigma, with young sufferers traditionally seen as “demonically possessed,” he commented.
“So there was always a shameful aspect around it when it came to African families speaking about it, especially back in Africa.”
But after his parents came to the United Kingdom, he was able to “do his research and understand that it’s just genetics.”
This knowledge, Mr. Gaspar said, “takes away the spiritual aspect” and allows people to “have the conversation about sickle cell with potential partners” and ask them to find out their genotype, which in turn helps to “break down the barriers and the stigma.”
Mr. Gaspar emphasizes that there is much more work still to do.
In the video, he appeals to the Black community to make blood donations.
He said that something that “haunts” him is that currently, only 1% of Black people in the United Kingdom give blood, “so I really want the song to move my community to take a step forward and make that difference.”
He has been in contact with NHS Blood and Transplant, which provides blood and transplantation service to the National Health Service. They “really liked” the song, Mr. Gaspar said, and helped him get access to a hospital ward in University College Hospital, London, for the video.
“I really wanted to make a video that made people uncomfortable when watching it,” he said. It shows him hospitalized for pain and breathlessness and recalling having to use a Zimmer frame at the age of 25.
“This is a side of sickle cell that normally people don’t know,” he said.
Since releasing the song and the video, Mr. Gaspar says he has been contacted by many fellow patients. They have told him that he is now their “voice”; when they are asked how the condition affects them, “they can show someone the Hidden Pain video and say: This is how it feels.”
Clinicians have also approached him, asking if they can show his video to illustrate to patients and their families how having the condition may affect their lives.
Preventable deaths
At the meeting, Dr. Hibbs highlighted the 2021 report No One’s Listening, which was issued by the Sickle Cell Society following an inquiry into avoidable deaths and failures of care for sickle cell patients.
The inquiry, published by an All-Party Parliamentary group, found “serious care failings” in acute services and evidence of attitudes underpinned by racism. There was evidence of substandard care for sickle cell patients who were admitted to general wards or to hospital accident and emergency departments, as well as low awareness of the condition among health care professionals.
The report noted that the care failings have led to patient deaths, some which could have been prevented, and that there have been many “near misses.”
Many patients with sickle cell disease said they are “not being listened to” or are not being understood, especially during that vulnerable period when they are “in a crisis.”
Mr. Gaspar said that the report, and also the deaths, really struck a chord with him and many in his community. “We felt like that was us. ... We’ve all been in that same position where we’ve been misunderstood and not heard by nurses, doctors, or paramedics.”
He emphasized the need for awareness of the condition and the need for timely treatment. Just 3 weeks ago, Mr. Gaspar attended the funeral of one of his friends who is in the Hidden Pain video, a fellow sickle cell disease patient, who died at 30 years of age.
Ignorance about the condition ‘all too common’
The lack of awareness about sickle cell disease, even among health care professionals, is “all too common,” says Dr. Subarna Chakravorty, consultant pediatric hematologist, King’s College Hospital, London.
Even in London, where there is a large Black community and the teaching hospitals have world-class expertise, patients with sickle cell disease are “still facing a lot of problems with knowledge” among health care professionals, she said in an interview.
“Often people are having to speak for their own condition; which is fine, except that sometimes they are not believed,” she commented.
“On the one hand, you rely on the patient to provide information about their disease, and then when you receive it, you don’t do anything about it. So [they’re] between a rock and a hard place.”
Why are sickle cell patients treated in this way?
For Dr. Chakravorty, there is “a lot to be said about racism and disparities” in treating patients “as morphine-seekers, opiate addicts, even in children.”
“So we really need to improve the knowledge and perceptions among nonspecialist staff,” she said, “and even among specialists.”
Mr. Gaspar aims to help with this effort and hopes that his song and video will be useful to health care professionals. Sickle cell disease “needs to be spoken about,” and more doctors and nurses need to “know what it is,” he said.
He said it is a relief to encounter health care professionals who are knowledgeable about his condition. There have been times when he has been “having a crisis at home, calling the ambulance, and the paramedic comes and says: ‘Mr. Gaspar, you have sickle cell...we believe that you usually have gas and air and morphine, is that correct?’”
“That gives me a sense of peace, to know that I don’t have to fight my case or convince someone I have sickle cell, and I need to start treatment. They already know.”
No relevant financial relationships have been disclosed.
A version of this article first appeared on Medscape.com.
MANCHESTER, ENGLAND – A London-based rapper known for his gospel-inspired music has now given a voice to patients with sickle cell disease. He is using one of his music videos to raise awareness and educate health care professionals about living with the condition.
One important aim of the video, he says, is to help educate health care professionals, some of whom have not come across this condition, he explained at a session during the annual meeting of the British Society for Haematology, held recently in Manchester, England.
“It’s kind of frustrating to feel like your safe space, when you’re in front of doctors and nurses and paramedics who are supposed to know what it is and react with treatment, [and they] don’t know what it is,” Mr. Gaspar said.
He recalled an occasion in which he was experiencing a crisis, and his wife called for an ambulance. The paramedics arrived and his wife asked them for “gas and air and morphine, and they were, like, no, we don’t want to give that to him.” She tried to explain that he has sickle cell disease, but the paramedics had not heard of the condition and were suspicious that the request for morphine was a sign of drug addiction.
Mr. Gaspar expressed his frustration over “constantly having to prove that you have something serious enough to need the treatment you are asking for.”
At the meeting, Mr. Gaspar was talking on the stage with hematologist Dr. Stephen Hibbs from Barts Health NHS Trust, London.
Mr. Gaspar explained that it took years before he eventually reached “a point where I understood that it’s something that affects me and affects many other people, and I didn’t want to hide it any more.”
Sickle cell disease, which occurs primarily in people of Afro-Caribbean background, is a taboo subject in his community, Mr. Gaspar elaborated in an interview.
The condition has been associated with a great deal of stigma, with young sufferers traditionally seen as “demonically possessed,” he commented.
“So there was always a shameful aspect around it when it came to African families speaking about it, especially back in Africa.”
But after his parents came to the United Kingdom, he was able to “do his research and understand that it’s just genetics.”
This knowledge, Mr. Gaspar said, “takes away the spiritual aspect” and allows people to “have the conversation about sickle cell with potential partners” and ask them to find out their genotype, which in turn helps to “break down the barriers and the stigma.”
Mr. Gaspar emphasizes that there is much more work still to do.
In the video, he appeals to the Black community to make blood donations.
He said that something that “haunts” him is that currently, only 1% of Black people in the United Kingdom give blood, “so I really want the song to move my community to take a step forward and make that difference.”
He has been in contact with NHS Blood and Transplant, which provides blood and transplantation service to the National Health Service. They “really liked” the song, Mr. Gaspar said, and helped him get access to a hospital ward in University College Hospital, London, for the video.
“I really wanted to make a video that made people uncomfortable when watching it,” he said. It shows him hospitalized for pain and breathlessness and recalling having to use a Zimmer frame at the age of 25.
“This is a side of sickle cell that normally people don’t know,” he said.
Since releasing the song and the video, Mr. Gaspar says he has been contacted by many fellow patients. They have told him that he is now their “voice”; when they are asked how the condition affects them, “they can show someone the Hidden Pain video and say: This is how it feels.”
Clinicians have also approached him, asking if they can show his video to illustrate to patients and their families how having the condition may affect their lives.
Preventable deaths
At the meeting, Dr. Hibbs highlighted the 2021 report No One’s Listening, which was issued by the Sickle Cell Society following an inquiry into avoidable deaths and failures of care for sickle cell patients.
The inquiry, published by an All-Party Parliamentary group, found “serious care failings” in acute services and evidence of attitudes underpinned by racism. There was evidence of substandard care for sickle cell patients who were admitted to general wards or to hospital accident and emergency departments, as well as low awareness of the condition among health care professionals.
The report noted that the care failings have led to patient deaths, some which could have been prevented, and that there have been many “near misses.”
Many patients with sickle cell disease said they are “not being listened to” or are not being understood, especially during that vulnerable period when they are “in a crisis.”
Mr. Gaspar said that the report, and also the deaths, really struck a chord with him and many in his community. “We felt like that was us. ... We’ve all been in that same position where we’ve been misunderstood and not heard by nurses, doctors, or paramedics.”
He emphasized the need for awareness of the condition and the need for timely treatment. Just 3 weeks ago, Mr. Gaspar attended the funeral of one of his friends who is in the Hidden Pain video, a fellow sickle cell disease patient, who died at 30 years of age.
Ignorance about the condition ‘all too common’
The lack of awareness about sickle cell disease, even among health care professionals, is “all too common,” says Dr. Subarna Chakravorty, consultant pediatric hematologist, King’s College Hospital, London.
Even in London, where there is a large Black community and the teaching hospitals have world-class expertise, patients with sickle cell disease are “still facing a lot of problems with knowledge” among health care professionals, she said in an interview.
“Often people are having to speak for their own condition; which is fine, except that sometimes they are not believed,” she commented.
“On the one hand, you rely on the patient to provide information about their disease, and then when you receive it, you don’t do anything about it. So [they’re] between a rock and a hard place.”
Why are sickle cell patients treated in this way?
For Dr. Chakravorty, there is “a lot to be said about racism and disparities” in treating patients “as morphine-seekers, opiate addicts, even in children.”
“So we really need to improve the knowledge and perceptions among nonspecialist staff,” she said, “and even among specialists.”
Mr. Gaspar aims to help with this effort and hopes that his song and video will be useful to health care professionals. Sickle cell disease “needs to be spoken about,” and more doctors and nurses need to “know what it is,” he said.
He said it is a relief to encounter health care professionals who are knowledgeable about his condition. There have been times when he has been “having a crisis at home, calling the ambulance, and the paramedic comes and says: ‘Mr. Gaspar, you have sickle cell...we believe that you usually have gas and air and morphine, is that correct?’”
“That gives me a sense of peace, to know that I don’t have to fight my case or convince someone I have sickle cell, and I need to start treatment. They already know.”
No relevant financial relationships have been disclosed.
A version of this article first appeared on Medscape.com.
Gene therapy for hemophilia A: `Truly transformative and liberating’
Significant results were seen 1 year after receiving a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), investigators from the international GENEr8-1 trial reported in the New England Journal of Medicine.
‘Truly transformative and liberating’
“If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia,” writes Courtney D. Thornburg, from the Hemophilia and Thrombosis Treatment Center at Rady Children’s Hospital, San Diego, in an accompanying editorial.
Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding for coagulation factor VIII. Although rare, it is nevertheless the most common type, affecting about 12 per 100,000. Hemophilia B affects about 3.7 per 100,000.
The current treatment for hemophilia A is prophylactic infusions of factor VIII, often given three times per week.
With the gene therapy, such a patient could avoid at least 150 intravenous infusions of prophylactic factor in the span of a year, and have zero bleeds, Dr. Thornburg noted.
Valoctocogene roxaparvovec is an adeno-associated virus 5-based gene therapy vector that expresses a human factor VIII coding sequence, and is designed to correct the central genetic defect in hemophilia A.
Results from the phase 3 open-label trial show that it was associated with improved endogenous clotting factor production, and also a significant decrease in bleeding.
At 49-52 weeks of follow-up, 132 patients in a modified intention-to-treat analysis had a mean increase in factor VIII activity levels of 41.9 IU/dL (P < .001).
In a subgroup of 112 patients, the mean annualized factor concentrate use at 4 weeks decreased by 98.6%, and annualized rates of treated bleeding declined by 83.8% (P < .001 for both comparisons).
“Valoctocogene roxaparvovec gene transfer for severe hemophilia A provided significant increases in factor VIII activity, with reduced bleeding and factor VIII use for most participants over a period of up to 2 years,” conclude the investigators, led by Margareth C. Ozelo, MD, PhD, from the University of Campinas (Brazil).
“We are very enthusiastic about the results of this phase 3 clinical trial,” Dr. Ozelo commented to this news organization.
“It is important to recognize the clinical benefit achieved so far with treatment. During the first year, 90% of study participants had either zero treated bleeds or fewer treated bleeds post infusion than with factor VIII prophylaxis,” she said. “In addition, most of the study participants, including those from the phase 1/2 clinical trial, in the 5-year follow-up remain free of the use of additional prophylactic treatments.”
One issue that remains unanswered is how long the effects may last.
Valoctocogene roxaparvovec is a one-time infusion, she explained. “At least for now, redosing with the same AAV vector is not an option due to the immune response induced.”
“The durability of therapeutic response is one of the critical issues involving this new treatment for hemophilia. Currently, we cannot predict how long the transgene expression will last,” she added.
In the study, Dr. Ozelo and colleagues noted that “expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible.”
Editorialist Dr. Thornburg touched on this point in an interview with this news organization.
Complete elimination of factor VIII replacement therapy is an ambitious goal, but gene therapy could obviate the need for prophylaxis in a substantial proportion of patients, she said. “Any increase of about 3%-5% in endogenous factor VIII production would eliminate the need for regular preventive treatments, either with regular factor or nonfactor replacements.
“How long that will be sustained is an open question,” she added. “With hemophilia B [factor IX deficiency] we have longer-term data showing quite good sustainability of the treatment, but I think it’s still an open question for hemophilia A.”
Dr. Thornburg also noted that further studies are needed to find similar therapies to benefit women and children with hemophilia, as well as for patients with factor VIII inhibitors, those with immunity to adenoviral vectors, and patients with hemophilia and concomitant liver disease or HIV infection.
GENEr8-1 study details and results
The trial was conducted in men 18 and older with severe congenital hemophilia A who had received prophylaxis with factor VIII concentrates for at least 1 year and were negative for factor VIII inhibitors.
The patient sample included 20 men enrolled directly, and 110 participants in a prospective noninterventional study of bleeding episodes, factor VIII infusions, and patient-reported outcomes in individuals with severe hemophilia A.
Participants received one infusion of valoctocogene roxaparvovec, at a dose of 6x1013 vector genomes per kilogram of body weight.
They remained on factor VIII prophylaxis for 4 weeks after the infusion of the gene therapy product, but after that factor VIII was used on an as-needed basis.
A total of 134 patients received an infusion and were included in the safety analysis. Two patients who were HIV positive were excluded from the modified intention-to-treat efficacy analysis.
As noted above, the trial met its primary efficacy endpoint of change from baseline in factor VIII activity 49-52 weeks after infusion, and the secondary endpoints of change from baseline to after week 4 in annualized use of factor VIII concentrate and the annualized number of treated bleeding episodes.
The most common adverse event was an elevation in alanine aminotransferase levels, the investigators noted.
These elevations in ALT levels, which have also been seen with gene therapy for hemophilia B, occurred in 85.8% of patients and could be safely managed with immunosuppressants, the authors commented.
Other common adverse events were headache, nausea, and elevations in aspartate aminotransferase levels, each occurring in slightly more than one third of patients.
“Overall, the risk-benefit profile appears favorable,” the team commented.
The study was supported by BioMarin Pharmaceutical. Dr. Ozelo disclosed grant support from the company. Dr. Thornburg disclosed serving as a consultant to BioMarin and others.
A version of this article first appeared on Medscape.com.
Significant results were seen 1 year after receiving a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), investigators from the international GENEr8-1 trial reported in the New England Journal of Medicine.
‘Truly transformative and liberating’
“If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia,” writes Courtney D. Thornburg, from the Hemophilia and Thrombosis Treatment Center at Rady Children’s Hospital, San Diego, in an accompanying editorial.
Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding for coagulation factor VIII. Although rare, it is nevertheless the most common type, affecting about 12 per 100,000. Hemophilia B affects about 3.7 per 100,000.
The current treatment for hemophilia A is prophylactic infusions of factor VIII, often given three times per week.
With the gene therapy, such a patient could avoid at least 150 intravenous infusions of prophylactic factor in the span of a year, and have zero bleeds, Dr. Thornburg noted.
Valoctocogene roxaparvovec is an adeno-associated virus 5-based gene therapy vector that expresses a human factor VIII coding sequence, and is designed to correct the central genetic defect in hemophilia A.
Results from the phase 3 open-label trial show that it was associated with improved endogenous clotting factor production, and also a significant decrease in bleeding.
At 49-52 weeks of follow-up, 132 patients in a modified intention-to-treat analysis had a mean increase in factor VIII activity levels of 41.9 IU/dL (P < .001).
In a subgroup of 112 patients, the mean annualized factor concentrate use at 4 weeks decreased by 98.6%, and annualized rates of treated bleeding declined by 83.8% (P < .001 for both comparisons).
“Valoctocogene roxaparvovec gene transfer for severe hemophilia A provided significant increases in factor VIII activity, with reduced bleeding and factor VIII use for most participants over a period of up to 2 years,” conclude the investigators, led by Margareth C. Ozelo, MD, PhD, from the University of Campinas (Brazil).
“We are very enthusiastic about the results of this phase 3 clinical trial,” Dr. Ozelo commented to this news organization.
“It is important to recognize the clinical benefit achieved so far with treatment. During the first year, 90% of study participants had either zero treated bleeds or fewer treated bleeds post infusion than with factor VIII prophylaxis,” she said. “In addition, most of the study participants, including those from the phase 1/2 clinical trial, in the 5-year follow-up remain free of the use of additional prophylactic treatments.”
One issue that remains unanswered is how long the effects may last.
Valoctocogene roxaparvovec is a one-time infusion, she explained. “At least for now, redosing with the same AAV vector is not an option due to the immune response induced.”
“The durability of therapeutic response is one of the critical issues involving this new treatment for hemophilia. Currently, we cannot predict how long the transgene expression will last,” she added.
In the study, Dr. Ozelo and colleagues noted that “expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible.”
Editorialist Dr. Thornburg touched on this point in an interview with this news organization.
Complete elimination of factor VIII replacement therapy is an ambitious goal, but gene therapy could obviate the need for prophylaxis in a substantial proportion of patients, she said. “Any increase of about 3%-5% in endogenous factor VIII production would eliminate the need for regular preventive treatments, either with regular factor or nonfactor replacements.
“How long that will be sustained is an open question,” she added. “With hemophilia B [factor IX deficiency] we have longer-term data showing quite good sustainability of the treatment, but I think it’s still an open question for hemophilia A.”
Dr. Thornburg also noted that further studies are needed to find similar therapies to benefit women and children with hemophilia, as well as for patients with factor VIII inhibitors, those with immunity to adenoviral vectors, and patients with hemophilia and concomitant liver disease or HIV infection.
GENEr8-1 study details and results
The trial was conducted in men 18 and older with severe congenital hemophilia A who had received prophylaxis with factor VIII concentrates for at least 1 year and were negative for factor VIII inhibitors.
The patient sample included 20 men enrolled directly, and 110 participants in a prospective noninterventional study of bleeding episodes, factor VIII infusions, and patient-reported outcomes in individuals with severe hemophilia A.
Participants received one infusion of valoctocogene roxaparvovec, at a dose of 6x1013 vector genomes per kilogram of body weight.
They remained on factor VIII prophylaxis for 4 weeks after the infusion of the gene therapy product, but after that factor VIII was used on an as-needed basis.
A total of 134 patients received an infusion and were included in the safety analysis. Two patients who were HIV positive were excluded from the modified intention-to-treat efficacy analysis.
As noted above, the trial met its primary efficacy endpoint of change from baseline in factor VIII activity 49-52 weeks after infusion, and the secondary endpoints of change from baseline to after week 4 in annualized use of factor VIII concentrate and the annualized number of treated bleeding episodes.
The most common adverse event was an elevation in alanine aminotransferase levels, the investigators noted.
These elevations in ALT levels, which have also been seen with gene therapy for hemophilia B, occurred in 85.8% of patients and could be safely managed with immunosuppressants, the authors commented.
Other common adverse events were headache, nausea, and elevations in aspartate aminotransferase levels, each occurring in slightly more than one third of patients.
“Overall, the risk-benefit profile appears favorable,” the team commented.
The study was supported by BioMarin Pharmaceutical. Dr. Ozelo disclosed grant support from the company. Dr. Thornburg disclosed serving as a consultant to BioMarin and others.
A version of this article first appeared on Medscape.com.
Significant results were seen 1 year after receiving a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), investigators from the international GENEr8-1 trial reported in the New England Journal of Medicine.
‘Truly transformative and liberating’
“If approved, this first-generation gene therapy would offer a new choice for care that could be truly transformative and liberating for eligible men with hemophilia,” writes Courtney D. Thornburg, from the Hemophilia and Thrombosis Treatment Center at Rady Children’s Hospital, San Diego, in an accompanying editorial.
Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding for coagulation factor VIII. Although rare, it is nevertheless the most common type, affecting about 12 per 100,000. Hemophilia B affects about 3.7 per 100,000.
The current treatment for hemophilia A is prophylactic infusions of factor VIII, often given three times per week.
With the gene therapy, such a patient could avoid at least 150 intravenous infusions of prophylactic factor in the span of a year, and have zero bleeds, Dr. Thornburg noted.
Valoctocogene roxaparvovec is an adeno-associated virus 5-based gene therapy vector that expresses a human factor VIII coding sequence, and is designed to correct the central genetic defect in hemophilia A.
Results from the phase 3 open-label trial show that it was associated with improved endogenous clotting factor production, and also a significant decrease in bleeding.
At 49-52 weeks of follow-up, 132 patients in a modified intention-to-treat analysis had a mean increase in factor VIII activity levels of 41.9 IU/dL (P < .001).
In a subgroup of 112 patients, the mean annualized factor concentrate use at 4 weeks decreased by 98.6%, and annualized rates of treated bleeding declined by 83.8% (P < .001 for both comparisons).
“Valoctocogene roxaparvovec gene transfer for severe hemophilia A provided significant increases in factor VIII activity, with reduced bleeding and factor VIII use for most participants over a period of up to 2 years,” conclude the investigators, led by Margareth C. Ozelo, MD, PhD, from the University of Campinas (Brazil).
“We are very enthusiastic about the results of this phase 3 clinical trial,” Dr. Ozelo commented to this news organization.
“It is important to recognize the clinical benefit achieved so far with treatment. During the first year, 90% of study participants had either zero treated bleeds or fewer treated bleeds post infusion than with factor VIII prophylaxis,” she said. “In addition, most of the study participants, including those from the phase 1/2 clinical trial, in the 5-year follow-up remain free of the use of additional prophylactic treatments.”
One issue that remains unanswered is how long the effects may last.
Valoctocogene roxaparvovec is a one-time infusion, she explained. “At least for now, redosing with the same AAV vector is not an option due to the immune response induced.”
“The durability of therapeutic response is one of the critical issues involving this new treatment for hemophilia. Currently, we cannot predict how long the transgene expression will last,” she added.
In the study, Dr. Ozelo and colleagues noted that “expression of the transferred gene appears to decline over time; further study is needed to address whether repeat treatment will be necessary or possible.”
Editorialist Dr. Thornburg touched on this point in an interview with this news organization.
Complete elimination of factor VIII replacement therapy is an ambitious goal, but gene therapy could obviate the need for prophylaxis in a substantial proportion of patients, she said. “Any increase of about 3%-5% in endogenous factor VIII production would eliminate the need for regular preventive treatments, either with regular factor or nonfactor replacements.
“How long that will be sustained is an open question,” she added. “With hemophilia B [factor IX deficiency] we have longer-term data showing quite good sustainability of the treatment, but I think it’s still an open question for hemophilia A.”
Dr. Thornburg also noted that further studies are needed to find similar therapies to benefit women and children with hemophilia, as well as for patients with factor VIII inhibitors, those with immunity to adenoviral vectors, and patients with hemophilia and concomitant liver disease or HIV infection.
GENEr8-1 study details and results
The trial was conducted in men 18 and older with severe congenital hemophilia A who had received prophylaxis with factor VIII concentrates for at least 1 year and were negative for factor VIII inhibitors.
The patient sample included 20 men enrolled directly, and 110 participants in a prospective noninterventional study of bleeding episodes, factor VIII infusions, and patient-reported outcomes in individuals with severe hemophilia A.
Participants received one infusion of valoctocogene roxaparvovec, at a dose of 6x1013 vector genomes per kilogram of body weight.
They remained on factor VIII prophylaxis for 4 weeks after the infusion of the gene therapy product, but after that factor VIII was used on an as-needed basis.
A total of 134 patients received an infusion and were included in the safety analysis. Two patients who were HIV positive were excluded from the modified intention-to-treat efficacy analysis.
As noted above, the trial met its primary efficacy endpoint of change from baseline in factor VIII activity 49-52 weeks after infusion, and the secondary endpoints of change from baseline to after week 4 in annualized use of factor VIII concentrate and the annualized number of treated bleeding episodes.
The most common adverse event was an elevation in alanine aminotransferase levels, the investigators noted.
These elevations in ALT levels, which have also been seen with gene therapy for hemophilia B, occurred in 85.8% of patients and could be safely managed with immunosuppressants, the authors commented.
Other common adverse events were headache, nausea, and elevations in aspartate aminotransferase levels, each occurring in slightly more than one third of patients.
“Overall, the risk-benefit profile appears favorable,” the team commented.
The study was supported by BioMarin Pharmaceutical. Dr. Ozelo disclosed grant support from the company. Dr. Thornburg disclosed serving as a consultant to BioMarin and others.
A version of this article first appeared on Medscape.com.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Hemophilia: There’s a new app for that
Armed with data from multiple studies about how to implement goal-setting in hemophilia, a national nonprofit organization has released a free app designed to help patients track their illness and develop and monitor their objectives.
Robust Health, available for the iPhone and Android, “can really enhance the physician-patient relationship. This is a good approach to capture the many facets of what’s important to patients and help them improve their therapy management in their lives,” Jonathan C. Roberts, MD, a hematologist/oncologist at the University of Illinois at Peoria, said in an interview.
Working with colleagues, Dr. Roberts helped the app developer, the American Thrombosis and Hemostasis Network, devise the app’s goal-setting tool. Researchers reported their findings on the tool – known as Goal Attainment Scaling for Hemophilia, or “GOAL‐Hēm” – in a series of studies that emphasized the importance of including the “patient voice.”
The tool was developed to monitor patient outcomes in terms of “meaningful change,” beyond data points such as annualized bleed rate, Dr. Roberts said.
“Metrics like this are definitely important to joint health and quality of life,” he said, but researchers hoped to expand to more outcomes that matter to patients.
Consider a pediatric patient, for example, who may set a goal of preparing his or her clotting-factor treatment and making one attempt at a puncture. The tool allows a benchmark and timetable to be set up, Dr. Roberts said, and can provide both positive reinforcement and a score that reflects how well the patient is doing. “That really can help the multidisciplinary treatment team measure improvements in the patient’s overall treatment adherence.”
For the most recent study, published in the January 2022 issue of Research and Practice in Thrombosis and Haemostasis, researchers interviewed 19 adult patients with hemophilia (mean age 35, 68% male) and 19 caregivers of children with hemophilia (mean age of children 13, 83% male) about the language used in the tool. They responded in surveys, interviews, and focus groups.
“Thematic analysis indicated that participants were enthusiastic about patient‐centric language, empowered through the goal‐setting process, and recognized GOAL‐Hēm could measure clinically meaningful change,” the researchers reported.
They wrote that the participants kept 15 of 48 goals unchanged (32%), modified or deleted the others, and added three new goals. Their revisions included renaming one goal “bleeds,” instead of both“muscle bleeds” and “bleeds.” They renamed “work attendance” and “career planning” as simply “work.” “Depression,” “feelings of anger” and “self-esteem” were consolidated as a new heading: “emotional well-being.”
Each goal provides answers that patients can use to respond to queries about how they’re doing. For example, under the pediatric goal of “independent self-care management,” a descriptor could be “Always sets their own reminders to self‐infuse. Mother never needs to remind them.” This answer would be considered “much better than expected.”
Out of 635 responses, known as “descriptors,” most (75%) were revised or deleted in response to input from patients and caregivers. In the end, the total number of answers was reduced to 368 – 218 in the adult section, and 150 in the pediatric section.
“Our study highlights the importance of patient engagement in developing the tool and how it can be used in day-to-day practice,” Dr. Roberts said.
Going forward, he said, “we’re hoping this tool could potentially be an important player in studies of new therapeutic options for patients. The metrics could be used as kind of a common language to measure how our patients are doing on a particular therapy.”
Jayson Stoffman, MD, a pediatric hematologist/oncologist at Children’s Hospital of Winnipeg and the University of Manitoba, who was not involved in the research, welcomed the new app.
“The big challenge is always how to balance hemophilia and its management against the lifestyle needs and wants of the individual,” Dr. Stoffman said in an interview. “We don’t want people to be held back by their hemophilia, so it’s important to find the best ways to support them in their choices while optimizing their management.”
An app that helps patients define and delineate goals will be a “great benchmark to use in making treatment decisions and adjustments,” he said.
The study was funded by Takeda. Dr. Roberts disclosed grants and/or contracts from Takeda and consulting fees from Sanofi Genzyme, Takeda, Octapharma, uniQure, Novo Nordisk, Pfizer, Spark, and CSL Behring. The other authors reported various disclosures. Dr. Stoffman disclosed a consulting agreement with F. Hoffman La Roche AG.
Armed with data from multiple studies about how to implement goal-setting in hemophilia, a national nonprofit organization has released a free app designed to help patients track their illness and develop and monitor their objectives.
Robust Health, available for the iPhone and Android, “can really enhance the physician-patient relationship. This is a good approach to capture the many facets of what’s important to patients and help them improve their therapy management in their lives,” Jonathan C. Roberts, MD, a hematologist/oncologist at the University of Illinois at Peoria, said in an interview.
Working with colleagues, Dr. Roberts helped the app developer, the American Thrombosis and Hemostasis Network, devise the app’s goal-setting tool. Researchers reported their findings on the tool – known as Goal Attainment Scaling for Hemophilia, or “GOAL‐Hēm” – in a series of studies that emphasized the importance of including the “patient voice.”
The tool was developed to monitor patient outcomes in terms of “meaningful change,” beyond data points such as annualized bleed rate, Dr. Roberts said.
“Metrics like this are definitely important to joint health and quality of life,” he said, but researchers hoped to expand to more outcomes that matter to patients.
Consider a pediatric patient, for example, who may set a goal of preparing his or her clotting-factor treatment and making one attempt at a puncture. The tool allows a benchmark and timetable to be set up, Dr. Roberts said, and can provide both positive reinforcement and a score that reflects how well the patient is doing. “That really can help the multidisciplinary treatment team measure improvements in the patient’s overall treatment adherence.”
For the most recent study, published in the January 2022 issue of Research and Practice in Thrombosis and Haemostasis, researchers interviewed 19 adult patients with hemophilia (mean age 35, 68% male) and 19 caregivers of children with hemophilia (mean age of children 13, 83% male) about the language used in the tool. They responded in surveys, interviews, and focus groups.
“Thematic analysis indicated that participants were enthusiastic about patient‐centric language, empowered through the goal‐setting process, and recognized GOAL‐Hēm could measure clinically meaningful change,” the researchers reported.
They wrote that the participants kept 15 of 48 goals unchanged (32%), modified or deleted the others, and added three new goals. Their revisions included renaming one goal “bleeds,” instead of both“muscle bleeds” and “bleeds.” They renamed “work attendance” and “career planning” as simply “work.” “Depression,” “feelings of anger” and “self-esteem” were consolidated as a new heading: “emotional well-being.”
Each goal provides answers that patients can use to respond to queries about how they’re doing. For example, under the pediatric goal of “independent self-care management,” a descriptor could be “Always sets their own reminders to self‐infuse. Mother never needs to remind them.” This answer would be considered “much better than expected.”
Out of 635 responses, known as “descriptors,” most (75%) were revised or deleted in response to input from patients and caregivers. In the end, the total number of answers was reduced to 368 – 218 in the adult section, and 150 in the pediatric section.
“Our study highlights the importance of patient engagement in developing the tool and how it can be used in day-to-day practice,” Dr. Roberts said.
Going forward, he said, “we’re hoping this tool could potentially be an important player in studies of new therapeutic options for patients. The metrics could be used as kind of a common language to measure how our patients are doing on a particular therapy.”
Jayson Stoffman, MD, a pediatric hematologist/oncologist at Children’s Hospital of Winnipeg and the University of Manitoba, who was not involved in the research, welcomed the new app.
“The big challenge is always how to balance hemophilia and its management against the lifestyle needs and wants of the individual,” Dr. Stoffman said in an interview. “We don’t want people to be held back by their hemophilia, so it’s important to find the best ways to support them in their choices while optimizing their management.”
An app that helps patients define and delineate goals will be a “great benchmark to use in making treatment decisions and adjustments,” he said.
The study was funded by Takeda. Dr. Roberts disclosed grants and/or contracts from Takeda and consulting fees from Sanofi Genzyme, Takeda, Octapharma, uniQure, Novo Nordisk, Pfizer, Spark, and CSL Behring. The other authors reported various disclosures. Dr. Stoffman disclosed a consulting agreement with F. Hoffman La Roche AG.
Armed with data from multiple studies about how to implement goal-setting in hemophilia, a national nonprofit organization has released a free app designed to help patients track their illness and develop and monitor their objectives.
Robust Health, available for the iPhone and Android, “can really enhance the physician-patient relationship. This is a good approach to capture the many facets of what’s important to patients and help them improve their therapy management in their lives,” Jonathan C. Roberts, MD, a hematologist/oncologist at the University of Illinois at Peoria, said in an interview.
Working with colleagues, Dr. Roberts helped the app developer, the American Thrombosis and Hemostasis Network, devise the app’s goal-setting tool. Researchers reported their findings on the tool – known as Goal Attainment Scaling for Hemophilia, or “GOAL‐Hēm” – in a series of studies that emphasized the importance of including the “patient voice.”
The tool was developed to monitor patient outcomes in terms of “meaningful change,” beyond data points such as annualized bleed rate, Dr. Roberts said.
“Metrics like this are definitely important to joint health and quality of life,” he said, but researchers hoped to expand to more outcomes that matter to patients.
Consider a pediatric patient, for example, who may set a goal of preparing his or her clotting-factor treatment and making one attempt at a puncture. The tool allows a benchmark and timetable to be set up, Dr. Roberts said, and can provide both positive reinforcement and a score that reflects how well the patient is doing. “That really can help the multidisciplinary treatment team measure improvements in the patient’s overall treatment adherence.”
For the most recent study, published in the January 2022 issue of Research and Practice in Thrombosis and Haemostasis, researchers interviewed 19 adult patients with hemophilia (mean age 35, 68% male) and 19 caregivers of children with hemophilia (mean age of children 13, 83% male) about the language used in the tool. They responded in surveys, interviews, and focus groups.
“Thematic analysis indicated that participants were enthusiastic about patient‐centric language, empowered through the goal‐setting process, and recognized GOAL‐Hēm could measure clinically meaningful change,” the researchers reported.
They wrote that the participants kept 15 of 48 goals unchanged (32%), modified or deleted the others, and added three new goals. Their revisions included renaming one goal “bleeds,” instead of both“muscle bleeds” and “bleeds.” They renamed “work attendance” and “career planning” as simply “work.” “Depression,” “feelings of anger” and “self-esteem” were consolidated as a new heading: “emotional well-being.”
Each goal provides answers that patients can use to respond to queries about how they’re doing. For example, under the pediatric goal of “independent self-care management,” a descriptor could be “Always sets their own reminders to self‐infuse. Mother never needs to remind them.” This answer would be considered “much better than expected.”
Out of 635 responses, known as “descriptors,” most (75%) were revised or deleted in response to input from patients and caregivers. In the end, the total number of answers was reduced to 368 – 218 in the adult section, and 150 in the pediatric section.
“Our study highlights the importance of patient engagement in developing the tool and how it can be used in day-to-day practice,” Dr. Roberts said.
Going forward, he said, “we’re hoping this tool could potentially be an important player in studies of new therapeutic options for patients. The metrics could be used as kind of a common language to measure how our patients are doing on a particular therapy.”
Jayson Stoffman, MD, a pediatric hematologist/oncologist at Children’s Hospital of Winnipeg and the University of Manitoba, who was not involved in the research, welcomed the new app.
“The big challenge is always how to balance hemophilia and its management against the lifestyle needs and wants of the individual,” Dr. Stoffman said in an interview. “We don’t want people to be held back by their hemophilia, so it’s important to find the best ways to support them in their choices while optimizing their management.”
An app that helps patients define and delineate goals will be a “great benchmark to use in making treatment decisions and adjustments,” he said.
The study was funded by Takeda. Dr. Roberts disclosed grants and/or contracts from Takeda and consulting fees from Sanofi Genzyme, Takeda, Octapharma, uniQure, Novo Nordisk, Pfizer, Spark, and CSL Behring. The other authors reported various disclosures. Dr. Stoffman disclosed a consulting agreement with F. Hoffman La Roche AG.
FROM RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
More exercise for people with hemophilia, experts advise
Clinicians should do more to encourage people with hemophilia to undertake regular physical activity and sporting activities, a panel of Italian experts has advised.
they wrote in a consensus paper published in Blood Transfusion.
Physical activity is not only recommended by the World Federation of Hemophilia for people with this bleeding disorder, but also recommended for everyone, depending on their age, by the World Health Organization.
People with hemophilia “are not exempt” from the WHO recommendations, noted Dr. Chiara Biasoli of the unit of transfusion medicine and Centre for Inherited Bleeding Disorders, Maurizio Bufalini Hospital in Cesena, Italy, and fellow expert panel members.
MEMO expert consensus project
To help clinicians decide when and how to recommend physical exercise to people with hemophilia, Dr. Biasoli and colleagues initiated the MEMO (Movement for Persons With Haemophilia) expert consensus project. The aim was to offer some clear practical guidance for routine practice.
The project began with a core group of 11 hemophilia experts meeting virtually in early 2020 because of the COVID-19 pandemic. The MEMO scientific committee, as they became known, formulated a set of consensus statements which they then put before members of the Italian Association of Hemophilia Centres, asking them to vote online on their level of agreement with each statement.
A modified Delphi approach was used to reach a consensus, with statements that scored 7 or higher on a 9-point rating scale moving forward into the next round of voting. A total of three voting rounds was made, which took into account the views of 40 experts, overall.
Overview of the MEMO consensus statements
The MEMO consensus statements cover three topic areas: the first four statements focus on the impact of hemophilia on movement, the next three give physical activity recommendations, and the final three look at choice and management of sporting activities.
Regarding the impact of hemophilia on movement, Dr. Biasoli and colleagues noted that “overweight and obesity are an increasing problem in PwH” and, due to their known association with poor physical health, urgently need to be addressed.
Perhaps “insufficient education by hematologists and other invoiced specialists” is at play, they suggested. Importantly, in children, “parents’ fears with consequent overprotection” may be contributing factors.
Not only is movement beneficial for improving joint function, they stated, but it’s also crucial to improving bone density and reducing the risk of joint bleeds.
Even people with inhibitors should be encouraged to be active more regularly, the expert panel said. This should of course be done with “particular caution and monitoring of the effectiveness of prophylaxis for the prevention of acute bleeding events, so that physical activity is conducted safely.”
The panel’s recommendations on sporting activities include the advice to work in a multidisciplinary team that involves hematologists, musculoskeletal specialists and specialists in sports medicine, with the latter helping decide on what sporting activity might be most appropriate. They also suggest that participation in sport should be encouraged from a young age, noting that the Canadian Hemophilia Society has issued some good tips in that regard.
Alongside the recommendations the MEMO expert panel has created four “pyramids of movement” to help clinicians visualize and discuss the recommendations with their patients.
“Physical activity can be considered as a low price intervention that can prevent/reduce the occurrence of chronic diseases and should be further encouraged,” Dr. Biasoli and fellow MEMO expert panel members concluded.
The members of the MEMO expert panel disclosed multiple financial ties with pharmaceutical companies, but none are relevant to the recommendations they made.
Clinicians should do more to encourage people with hemophilia to undertake regular physical activity and sporting activities, a panel of Italian experts has advised.
they wrote in a consensus paper published in Blood Transfusion.
Physical activity is not only recommended by the World Federation of Hemophilia for people with this bleeding disorder, but also recommended for everyone, depending on their age, by the World Health Organization.
People with hemophilia “are not exempt” from the WHO recommendations, noted Dr. Chiara Biasoli of the unit of transfusion medicine and Centre for Inherited Bleeding Disorders, Maurizio Bufalini Hospital in Cesena, Italy, and fellow expert panel members.
MEMO expert consensus project
To help clinicians decide when and how to recommend physical exercise to people with hemophilia, Dr. Biasoli and colleagues initiated the MEMO (Movement for Persons With Haemophilia) expert consensus project. The aim was to offer some clear practical guidance for routine practice.
The project began with a core group of 11 hemophilia experts meeting virtually in early 2020 because of the COVID-19 pandemic. The MEMO scientific committee, as they became known, formulated a set of consensus statements which they then put before members of the Italian Association of Hemophilia Centres, asking them to vote online on their level of agreement with each statement.
A modified Delphi approach was used to reach a consensus, with statements that scored 7 or higher on a 9-point rating scale moving forward into the next round of voting. A total of three voting rounds was made, which took into account the views of 40 experts, overall.
Overview of the MEMO consensus statements
The MEMO consensus statements cover three topic areas: the first four statements focus on the impact of hemophilia on movement, the next three give physical activity recommendations, and the final three look at choice and management of sporting activities.
Regarding the impact of hemophilia on movement, Dr. Biasoli and colleagues noted that “overweight and obesity are an increasing problem in PwH” and, due to their known association with poor physical health, urgently need to be addressed.
Perhaps “insufficient education by hematologists and other invoiced specialists” is at play, they suggested. Importantly, in children, “parents’ fears with consequent overprotection” may be contributing factors.
Not only is movement beneficial for improving joint function, they stated, but it’s also crucial to improving bone density and reducing the risk of joint bleeds.
Even people with inhibitors should be encouraged to be active more regularly, the expert panel said. This should of course be done with “particular caution and monitoring of the effectiveness of prophylaxis for the prevention of acute bleeding events, so that physical activity is conducted safely.”
The panel’s recommendations on sporting activities include the advice to work in a multidisciplinary team that involves hematologists, musculoskeletal specialists and specialists in sports medicine, with the latter helping decide on what sporting activity might be most appropriate. They also suggest that participation in sport should be encouraged from a young age, noting that the Canadian Hemophilia Society has issued some good tips in that regard.
Alongside the recommendations the MEMO expert panel has created four “pyramids of movement” to help clinicians visualize and discuss the recommendations with their patients.
“Physical activity can be considered as a low price intervention that can prevent/reduce the occurrence of chronic diseases and should be further encouraged,” Dr. Biasoli and fellow MEMO expert panel members concluded.
The members of the MEMO expert panel disclosed multiple financial ties with pharmaceutical companies, but none are relevant to the recommendations they made.
Clinicians should do more to encourage people with hemophilia to undertake regular physical activity and sporting activities, a panel of Italian experts has advised.
they wrote in a consensus paper published in Blood Transfusion.
Physical activity is not only recommended by the World Federation of Hemophilia for people with this bleeding disorder, but also recommended for everyone, depending on their age, by the World Health Organization.
People with hemophilia “are not exempt” from the WHO recommendations, noted Dr. Chiara Biasoli of the unit of transfusion medicine and Centre for Inherited Bleeding Disorders, Maurizio Bufalini Hospital in Cesena, Italy, and fellow expert panel members.
MEMO expert consensus project
To help clinicians decide when and how to recommend physical exercise to people with hemophilia, Dr. Biasoli and colleagues initiated the MEMO (Movement for Persons With Haemophilia) expert consensus project. The aim was to offer some clear practical guidance for routine practice.
The project began with a core group of 11 hemophilia experts meeting virtually in early 2020 because of the COVID-19 pandemic. The MEMO scientific committee, as they became known, formulated a set of consensus statements which they then put before members of the Italian Association of Hemophilia Centres, asking them to vote online on their level of agreement with each statement.
A modified Delphi approach was used to reach a consensus, with statements that scored 7 or higher on a 9-point rating scale moving forward into the next round of voting. A total of three voting rounds was made, which took into account the views of 40 experts, overall.
Overview of the MEMO consensus statements
The MEMO consensus statements cover three topic areas: the first four statements focus on the impact of hemophilia on movement, the next three give physical activity recommendations, and the final three look at choice and management of sporting activities.
Regarding the impact of hemophilia on movement, Dr. Biasoli and colleagues noted that “overweight and obesity are an increasing problem in PwH” and, due to their known association with poor physical health, urgently need to be addressed.
Perhaps “insufficient education by hematologists and other invoiced specialists” is at play, they suggested. Importantly, in children, “parents’ fears with consequent overprotection” may be contributing factors.
Not only is movement beneficial for improving joint function, they stated, but it’s also crucial to improving bone density and reducing the risk of joint bleeds.
Even people with inhibitors should be encouraged to be active more regularly, the expert panel said. This should of course be done with “particular caution and monitoring of the effectiveness of prophylaxis for the prevention of acute bleeding events, so that physical activity is conducted safely.”
The panel’s recommendations on sporting activities include the advice to work in a multidisciplinary team that involves hematologists, musculoskeletal specialists and specialists in sports medicine, with the latter helping decide on what sporting activity might be most appropriate. They also suggest that participation in sport should be encouraged from a young age, noting that the Canadian Hemophilia Society has issued some good tips in that regard.
Alongside the recommendations the MEMO expert panel has created four “pyramids of movement” to help clinicians visualize and discuss the recommendations with their patients.
“Physical activity can be considered as a low price intervention that can prevent/reduce the occurrence of chronic diseases and should be further encouraged,” Dr. Biasoli and fellow MEMO expert panel members concluded.
The members of the MEMO expert panel disclosed multiple financial ties with pharmaceutical companies, but none are relevant to the recommendations they made.
FROM BLOOD TRANSFUSION
Women with von Willebrand disease: Managing menstrual and postpartum bleeding
Women with von Willebrand disease (VWD) experience many obstetric and gynecologic challenges, including higher levels of von Willebrand factor (VWF) in pregnancy, Romina Brignardello-Petersen, PhD, of McMaster University, Hamilton, Ont., and colleagues wrote.
The American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia convened a working group in 2017 to address updated guidelines on VWD with a focus on women, the researchers said.
In an article published in Blood Advances, the researchers described the evidence from three systematic reviews conducted to inform three recommendations for the guidelines: first-line management of heavy menstrual bleeding (HMB), treatment of women requiring or desiring neuraxial analgesia, and management of postpartum hemorrhage. The authors identified studies published through October 2019.
The first systematic review of first-line therapies for HMB included five case series, one retrospective cohort study, and one randomized controlled trial. In the randomized controlled trial of 232 patients, low-certainty evidence suggested less reduction of blood loss with desmopressin, compared with tranexamic acid (TxA), with no significant differences in side effects. Very-low-certainty evidence from an observational study also supported lower effectiveness of desmopressin versus hormonal therapy. Finally, the case series showed very-low-certainty evidence for the comparative effectiveness of hormonal therapy delivered via a levonorgestrel-releasing intrauterine system (LNG-IUS) and other therapies for HMB control.
The second systematic review compared VWF levels in women who received neuraxial anesthesia during labor.
The review included five case series that described outcomes of women with VWF levels greater than 0.50 IU/mL; however, the studies did not describe outcomes according to VWF levels and did not cite the proportion of women with VWF levels greater than 1.50 IU/mL. Consequently, the evidence for the effects of increasing VWF levels was very low certainty, the authors said. In a meta-analysis, the proportion of anesthesia complications in these women was 6% (very low certainty). The complications included hypotension, accidental dural puncture, inadequate analgesia, bloody tap with no further complications, and failed block requiring general anesthesia.
The third systemic review included two retrospective cohort studies on the use of TxA during the postpartum period. In these studies, the authors found very-low-certainty evidence that TxA reduced the risk of severe primary postpartum hemorrhage, primary postpartum hemorrhage, and secondary postpartum hemorrhage (risk ratios, 0.36, 0.25, and 0.42, respectively). The effects of TxA on blood transfusions, vaginal hematoma, blood loss, and thrombotic complications also showed very-low-certainty evidence.
The currently available evidence for treatment options in women with VWD remains very low certainty, the researchers wrote in their discussion. “Because hormonal therapy is effective in controlling HMB (based on data from women without bleeding disorders), we believe the most effective strategy to be hormonal therapy with a LNG-IUS or combined oral contraceptives, followed by TxA and desmopressin.”
The study findings were limited by several factors including scarce evidence, the risk of bias in the observational studies, and lack of comparisons/controls in the case series, the researchers noted. Notable literature gaps included data on outcomes including major bleeding and the need for surgery or additional treatments in the first review; mortality, major bleeding, spinal hematoma, transfusion, and thrombotic events in the second review; and mortality, major bleeding, and the need for other procedures in the third review.
However, the findings were strengthened by the use of broad eligibility criteria to include any studies with potential useful advice, including case series, if these were the only available options. In developing recommendations, “the guideline panel interpreted the evidence adding their experience and knowledge of indirect evidence,” the authors noted.
The current evidence, though mainly very low certainty, “is the best available to inform decisions about management. Clinicians seeking advice on how to manage their patients with VWD should refer to the practice guidelines and assess to what extent they are applicable to their patients,” the researchers concluded.
Meeting the need for evidence-based guidelines
The review is important at this time because current evidence-based guidelines are limited, said coauthor Veronica Flood, MD, a pediatric hematologist at the Medical College of Wisconsin, Milwaukee, and a VWD researcher.
“While we have some guidelines that address von Willebrand disease, these were primarily based on expert opinion and not necessarily based on the best available evidence,” said Dr. Flood.
“Given how many people have von Willebrand disease, it is important that we actually base our recommendations on the data,” she emphasized. The new guidelines also incorporate patient feedback, with the inclusion of multiple panelists who are individuals living with VWD. “The final recommendations looked at not only the evidence, but the cost effectiveness, feasibility, and patient values and preferences,” she added.
“I was surprised we did not have better evidence for some of these common issues for patients with VWD,” said Dr. Flood. “I think that speaks to the need to do more high-quality research in this area.”
From a clinical standpoint, “we now have evidence-based guidelines that support the use of prophylaxis in patients with VWD and significant bleeding, as well as recommendations for surgery and bleeding issues around menstruation,” said Dr. Flood. “I do think it is also important to recognize that many of these are conditional recommendations, meaning there is room for patient preferences in implementation, which is helpful since we know that some people will have different priorities.”
Dr. Flood noted that more research is needed in many aspects of VWD. “We definitely need to better understand best options for surgical treatment, and I consider that a high priority. We are also hoping, along with the National Hemophilia Foundation, to develop some patient decision aids to help with some of these issues.”
Coauthor Nathan T. Connell, MD, an adult hematologist at the Brigham and Women’s Hospital and Harvard Medical School, both in Boston, served as the vice chair for the guideline panel. Dr. Connell agreed with the importance of the reviews and the need for additional research. “I, too, was surprised to see the lack of robust data to answer many of the basic questions about how to manage people living with VWD. Regarding the systematic reviews, I was surprised to see the power of combining the limited data in this way to come up with an evidence base for the panels to review,” he added.
The study was supported by the ASH, ISTH, NHF, and the WFH 2020 Guidelines for Management of VWD. The researchers had no financial conflicts to disclose.
Women with von Willebrand disease (VWD) experience many obstetric and gynecologic challenges, including higher levels of von Willebrand factor (VWF) in pregnancy, Romina Brignardello-Petersen, PhD, of McMaster University, Hamilton, Ont., and colleagues wrote.
The American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia convened a working group in 2017 to address updated guidelines on VWD with a focus on women, the researchers said.
In an article published in Blood Advances, the researchers described the evidence from three systematic reviews conducted to inform three recommendations for the guidelines: first-line management of heavy menstrual bleeding (HMB), treatment of women requiring or desiring neuraxial analgesia, and management of postpartum hemorrhage. The authors identified studies published through October 2019.
The first systematic review of first-line therapies for HMB included five case series, one retrospective cohort study, and one randomized controlled trial. In the randomized controlled trial of 232 patients, low-certainty evidence suggested less reduction of blood loss with desmopressin, compared with tranexamic acid (TxA), with no significant differences in side effects. Very-low-certainty evidence from an observational study also supported lower effectiveness of desmopressin versus hormonal therapy. Finally, the case series showed very-low-certainty evidence for the comparative effectiveness of hormonal therapy delivered via a levonorgestrel-releasing intrauterine system (LNG-IUS) and other therapies for HMB control.
The second systematic review compared VWF levels in women who received neuraxial anesthesia during labor.
The review included five case series that described outcomes of women with VWF levels greater than 0.50 IU/mL; however, the studies did not describe outcomes according to VWF levels and did not cite the proportion of women with VWF levels greater than 1.50 IU/mL. Consequently, the evidence for the effects of increasing VWF levels was very low certainty, the authors said. In a meta-analysis, the proportion of anesthesia complications in these women was 6% (very low certainty). The complications included hypotension, accidental dural puncture, inadequate analgesia, bloody tap with no further complications, and failed block requiring general anesthesia.
The third systemic review included two retrospective cohort studies on the use of TxA during the postpartum period. In these studies, the authors found very-low-certainty evidence that TxA reduced the risk of severe primary postpartum hemorrhage, primary postpartum hemorrhage, and secondary postpartum hemorrhage (risk ratios, 0.36, 0.25, and 0.42, respectively). The effects of TxA on blood transfusions, vaginal hematoma, blood loss, and thrombotic complications also showed very-low-certainty evidence.
The currently available evidence for treatment options in women with VWD remains very low certainty, the researchers wrote in their discussion. “Because hormonal therapy is effective in controlling HMB (based on data from women without bleeding disorders), we believe the most effective strategy to be hormonal therapy with a LNG-IUS or combined oral contraceptives, followed by TxA and desmopressin.”
The study findings were limited by several factors including scarce evidence, the risk of bias in the observational studies, and lack of comparisons/controls in the case series, the researchers noted. Notable literature gaps included data on outcomes including major bleeding and the need for surgery or additional treatments in the first review; mortality, major bleeding, spinal hematoma, transfusion, and thrombotic events in the second review; and mortality, major bleeding, and the need for other procedures in the third review.
However, the findings were strengthened by the use of broad eligibility criteria to include any studies with potential useful advice, including case series, if these were the only available options. In developing recommendations, “the guideline panel interpreted the evidence adding their experience and knowledge of indirect evidence,” the authors noted.
The current evidence, though mainly very low certainty, “is the best available to inform decisions about management. Clinicians seeking advice on how to manage their patients with VWD should refer to the practice guidelines and assess to what extent they are applicable to their patients,” the researchers concluded.
Meeting the need for evidence-based guidelines
The review is important at this time because current evidence-based guidelines are limited, said coauthor Veronica Flood, MD, a pediatric hematologist at the Medical College of Wisconsin, Milwaukee, and a VWD researcher.
“While we have some guidelines that address von Willebrand disease, these were primarily based on expert opinion and not necessarily based on the best available evidence,” said Dr. Flood.
“Given how many people have von Willebrand disease, it is important that we actually base our recommendations on the data,” she emphasized. The new guidelines also incorporate patient feedback, with the inclusion of multiple panelists who are individuals living with VWD. “The final recommendations looked at not only the evidence, but the cost effectiveness, feasibility, and patient values and preferences,” she added.
“I was surprised we did not have better evidence for some of these common issues for patients with VWD,” said Dr. Flood. “I think that speaks to the need to do more high-quality research in this area.”
From a clinical standpoint, “we now have evidence-based guidelines that support the use of prophylaxis in patients with VWD and significant bleeding, as well as recommendations for surgery and bleeding issues around menstruation,” said Dr. Flood. “I do think it is also important to recognize that many of these are conditional recommendations, meaning there is room for patient preferences in implementation, which is helpful since we know that some people will have different priorities.”
Dr. Flood noted that more research is needed in many aspects of VWD. “We definitely need to better understand best options for surgical treatment, and I consider that a high priority. We are also hoping, along with the National Hemophilia Foundation, to develop some patient decision aids to help with some of these issues.”
Coauthor Nathan T. Connell, MD, an adult hematologist at the Brigham and Women’s Hospital and Harvard Medical School, both in Boston, served as the vice chair for the guideline panel. Dr. Connell agreed with the importance of the reviews and the need for additional research. “I, too, was surprised to see the lack of robust data to answer many of the basic questions about how to manage people living with VWD. Regarding the systematic reviews, I was surprised to see the power of combining the limited data in this way to come up with an evidence base for the panels to review,” he added.
The study was supported by the ASH, ISTH, NHF, and the WFH 2020 Guidelines for Management of VWD. The researchers had no financial conflicts to disclose.
Women with von Willebrand disease (VWD) experience many obstetric and gynecologic challenges, including higher levels of von Willebrand factor (VWF) in pregnancy, Romina Brignardello-Petersen, PhD, of McMaster University, Hamilton, Ont., and colleagues wrote.
The American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia convened a working group in 2017 to address updated guidelines on VWD with a focus on women, the researchers said.
In an article published in Blood Advances, the researchers described the evidence from three systematic reviews conducted to inform three recommendations for the guidelines: first-line management of heavy menstrual bleeding (HMB), treatment of women requiring or desiring neuraxial analgesia, and management of postpartum hemorrhage. The authors identified studies published through October 2019.
The first systematic review of first-line therapies for HMB included five case series, one retrospective cohort study, and one randomized controlled trial. In the randomized controlled trial of 232 patients, low-certainty evidence suggested less reduction of blood loss with desmopressin, compared with tranexamic acid (TxA), with no significant differences in side effects. Very-low-certainty evidence from an observational study also supported lower effectiveness of desmopressin versus hormonal therapy. Finally, the case series showed very-low-certainty evidence for the comparative effectiveness of hormonal therapy delivered via a levonorgestrel-releasing intrauterine system (LNG-IUS) and other therapies for HMB control.
The second systematic review compared VWF levels in women who received neuraxial anesthesia during labor.
The review included five case series that described outcomes of women with VWF levels greater than 0.50 IU/mL; however, the studies did not describe outcomes according to VWF levels and did not cite the proportion of women with VWF levels greater than 1.50 IU/mL. Consequently, the evidence for the effects of increasing VWF levels was very low certainty, the authors said. In a meta-analysis, the proportion of anesthesia complications in these women was 6% (very low certainty). The complications included hypotension, accidental dural puncture, inadequate analgesia, bloody tap with no further complications, and failed block requiring general anesthesia.
The third systemic review included two retrospective cohort studies on the use of TxA during the postpartum period. In these studies, the authors found very-low-certainty evidence that TxA reduced the risk of severe primary postpartum hemorrhage, primary postpartum hemorrhage, and secondary postpartum hemorrhage (risk ratios, 0.36, 0.25, and 0.42, respectively). The effects of TxA on blood transfusions, vaginal hematoma, blood loss, and thrombotic complications also showed very-low-certainty evidence.
The currently available evidence for treatment options in women with VWD remains very low certainty, the researchers wrote in their discussion. “Because hormonal therapy is effective in controlling HMB (based on data from women without bleeding disorders), we believe the most effective strategy to be hormonal therapy with a LNG-IUS or combined oral contraceptives, followed by TxA and desmopressin.”
The study findings were limited by several factors including scarce evidence, the risk of bias in the observational studies, and lack of comparisons/controls in the case series, the researchers noted. Notable literature gaps included data on outcomes including major bleeding and the need for surgery or additional treatments in the first review; mortality, major bleeding, spinal hematoma, transfusion, and thrombotic events in the second review; and mortality, major bleeding, and the need for other procedures in the third review.
However, the findings were strengthened by the use of broad eligibility criteria to include any studies with potential useful advice, including case series, if these were the only available options. In developing recommendations, “the guideline panel interpreted the evidence adding their experience and knowledge of indirect evidence,” the authors noted.
The current evidence, though mainly very low certainty, “is the best available to inform decisions about management. Clinicians seeking advice on how to manage their patients with VWD should refer to the practice guidelines and assess to what extent they are applicable to their patients,” the researchers concluded.
Meeting the need for evidence-based guidelines
The review is important at this time because current evidence-based guidelines are limited, said coauthor Veronica Flood, MD, a pediatric hematologist at the Medical College of Wisconsin, Milwaukee, and a VWD researcher.
“While we have some guidelines that address von Willebrand disease, these were primarily based on expert opinion and not necessarily based on the best available evidence,” said Dr. Flood.
“Given how many people have von Willebrand disease, it is important that we actually base our recommendations on the data,” she emphasized. The new guidelines also incorporate patient feedback, with the inclusion of multiple panelists who are individuals living with VWD. “The final recommendations looked at not only the evidence, but the cost effectiveness, feasibility, and patient values and preferences,” she added.
“I was surprised we did not have better evidence for some of these common issues for patients with VWD,” said Dr. Flood. “I think that speaks to the need to do more high-quality research in this area.”
From a clinical standpoint, “we now have evidence-based guidelines that support the use of prophylaxis in patients with VWD and significant bleeding, as well as recommendations for surgery and bleeding issues around menstruation,” said Dr. Flood. “I do think it is also important to recognize that many of these are conditional recommendations, meaning there is room for patient preferences in implementation, which is helpful since we know that some people will have different priorities.”
Dr. Flood noted that more research is needed in many aspects of VWD. “We definitely need to better understand best options for surgical treatment, and I consider that a high priority. We are also hoping, along with the National Hemophilia Foundation, to develop some patient decision aids to help with some of these issues.”
Coauthor Nathan T. Connell, MD, an adult hematologist at the Brigham and Women’s Hospital and Harvard Medical School, both in Boston, served as the vice chair for the guideline panel. Dr. Connell agreed with the importance of the reviews and the need for additional research. “I, too, was surprised to see the lack of robust data to answer many of the basic questions about how to manage people living with VWD. Regarding the systematic reviews, I was surprised to see the power of combining the limited data in this way to come up with an evidence base for the panels to review,” he added.
The study was supported by the ASH, ISTH, NHF, and the WFH 2020 Guidelines for Management of VWD. The researchers had no financial conflicts to disclose.
FROM BLOOD ADVANCES
Post–COVID vaccine AHA cases raise eyebrows in Italy
“The overall number of cases observed does not allow ... any definitive conclusion over a possible causal relationship between SARS-CoV-2 vaccination and AHA, which would need more epidemiological and pharmacovigilance data about suspected vaccine-related adverse events,” Maria Cristina Leone, MD, of Azienda USL-IRCCS di Reggio Emilia (Italy), and colleagues reported online on Jan. 19, 2022, in a letter to the editors of Thrombosis Research.
The cases, observed in Reggio Emilia during the first 8 months of the vaccination campaign, occurred following receipt of mRNA BNT162b2 (Pfizer-BioNTech) vaccine. The AHA patients included two men and two women who ranged in age from 67 to 86 years.
During this time frame, 235,597 people received at least one dose of BNT162b2 vaccine, the authors noted.
In the 5 years prior, from January 2016 to December 2020, only zero to two cases of AHA were observed each year, totaling five cases, or 1.9 cases per million people/year. These numbers are in line with the estimated incidence of the disease, the researchers noted, adding that “it should nonetheless be underlined that vaccination benefits exceed potential side effects and play a central role in individual and public health to effectively protect people from COVID-19 and stop the pandemic.”
However, they also wrote that the “unusual observation of four cases of a rare disease during the first months of the vaccination campaign in our province could be of interest and could sensitize health care personnel toward a possible complication of SARS-CoV-2 immunization.”
AHA is a rare autoimmune disease caused by neutralizing autoantibodies against coagulation factor VIII. It is mainly associated with malignancy, autoimmune diseases, certain medications, and postnatal status.
“Sporadic AHA cases have been reported in association with infectious diseases or vaccinations,” the author noted, adding that associations between the BNT162b2 vaccine immune complications, including AHA, have also been reported by other authors.
Three of the four case patients in Reggio Emilia had “at least one common clinical association of AHA,” they found, suggesting that these associations could “reflect susceptibility to autoimmunity potentially triggered by vaccination.”
“Case four died due to complications from sepsis after being treated with steroid and rituximab, whereas the first three cases underwent clinical and laboratory remission after immunosuppressive therapy, and no relapse has been observed during follow-up, as in the other two cases reported: This could suggest a more favorable prognosis in respect to other non–vaccine-associated cases, but longer-term data are definitely needed,” they concluded.
The authors reported having no disclosures.
“The overall number of cases observed does not allow ... any definitive conclusion over a possible causal relationship between SARS-CoV-2 vaccination and AHA, which would need more epidemiological and pharmacovigilance data about suspected vaccine-related adverse events,” Maria Cristina Leone, MD, of Azienda USL-IRCCS di Reggio Emilia (Italy), and colleagues reported online on Jan. 19, 2022, in a letter to the editors of Thrombosis Research.
The cases, observed in Reggio Emilia during the first 8 months of the vaccination campaign, occurred following receipt of mRNA BNT162b2 (Pfizer-BioNTech) vaccine. The AHA patients included two men and two women who ranged in age from 67 to 86 years.
During this time frame, 235,597 people received at least one dose of BNT162b2 vaccine, the authors noted.
In the 5 years prior, from January 2016 to December 2020, only zero to two cases of AHA were observed each year, totaling five cases, or 1.9 cases per million people/year. These numbers are in line with the estimated incidence of the disease, the researchers noted, adding that “it should nonetheless be underlined that vaccination benefits exceed potential side effects and play a central role in individual and public health to effectively protect people from COVID-19 and stop the pandemic.”
However, they also wrote that the “unusual observation of four cases of a rare disease during the first months of the vaccination campaign in our province could be of interest and could sensitize health care personnel toward a possible complication of SARS-CoV-2 immunization.”
AHA is a rare autoimmune disease caused by neutralizing autoantibodies against coagulation factor VIII. It is mainly associated with malignancy, autoimmune diseases, certain medications, and postnatal status.
“Sporadic AHA cases have been reported in association with infectious diseases or vaccinations,” the author noted, adding that associations between the BNT162b2 vaccine immune complications, including AHA, have also been reported by other authors.
Three of the four case patients in Reggio Emilia had “at least one common clinical association of AHA,” they found, suggesting that these associations could “reflect susceptibility to autoimmunity potentially triggered by vaccination.”
“Case four died due to complications from sepsis after being treated with steroid and rituximab, whereas the first three cases underwent clinical and laboratory remission after immunosuppressive therapy, and no relapse has been observed during follow-up, as in the other two cases reported: This could suggest a more favorable prognosis in respect to other non–vaccine-associated cases, but longer-term data are definitely needed,” they concluded.
The authors reported having no disclosures.
“The overall number of cases observed does not allow ... any definitive conclusion over a possible causal relationship between SARS-CoV-2 vaccination and AHA, which would need more epidemiological and pharmacovigilance data about suspected vaccine-related adverse events,” Maria Cristina Leone, MD, of Azienda USL-IRCCS di Reggio Emilia (Italy), and colleagues reported online on Jan. 19, 2022, in a letter to the editors of Thrombosis Research.
The cases, observed in Reggio Emilia during the first 8 months of the vaccination campaign, occurred following receipt of mRNA BNT162b2 (Pfizer-BioNTech) vaccine. The AHA patients included two men and two women who ranged in age from 67 to 86 years.
During this time frame, 235,597 people received at least one dose of BNT162b2 vaccine, the authors noted.
In the 5 years prior, from January 2016 to December 2020, only zero to two cases of AHA were observed each year, totaling five cases, or 1.9 cases per million people/year. These numbers are in line with the estimated incidence of the disease, the researchers noted, adding that “it should nonetheless be underlined that vaccination benefits exceed potential side effects and play a central role in individual and public health to effectively protect people from COVID-19 and stop the pandemic.”
However, they also wrote that the “unusual observation of four cases of a rare disease during the first months of the vaccination campaign in our province could be of interest and could sensitize health care personnel toward a possible complication of SARS-CoV-2 immunization.”
AHA is a rare autoimmune disease caused by neutralizing autoantibodies against coagulation factor VIII. It is mainly associated with malignancy, autoimmune diseases, certain medications, and postnatal status.
“Sporadic AHA cases have been reported in association with infectious diseases or vaccinations,” the author noted, adding that associations between the BNT162b2 vaccine immune complications, including AHA, have also been reported by other authors.
Three of the four case patients in Reggio Emilia had “at least one common clinical association of AHA,” they found, suggesting that these associations could “reflect susceptibility to autoimmunity potentially triggered by vaccination.”
“Case four died due to complications from sepsis after being treated with steroid and rituximab, whereas the first three cases underwent clinical and laboratory remission after immunosuppressive therapy, and no relapse has been observed during follow-up, as in the other two cases reported: This could suggest a more favorable prognosis in respect to other non–vaccine-associated cases, but longer-term data are definitely needed,” they concluded.
The authors reported having no disclosures.
FROM THROMBOSIS RESEARCH
Gene therapy: A ‘one and done’ hemophilia B treatment?
The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.
In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”
Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).
High adherence and high prices
Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Dr. Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.
Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Dr. Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”
For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.
The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.
“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).
Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).
Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.
“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Dr. Miesbach said.
“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.
Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.
A ‘one and done’ treatment
While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Dr. Miesbach said. “According to our current knowledge, it cannot be repeated.”
No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.
The trial was funded by CSL Behring. Dr. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.
The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.
In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”
Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).
High adherence and high prices
Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Dr. Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.
Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Dr. Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”
For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.
The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.
“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).
Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).
Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.
“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Dr. Miesbach said.
“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.
Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.
A ‘one and done’ treatment
While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Dr. Miesbach said. “According to our current knowledge, it cannot be repeated.”
No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.
The trial was funded by CSL Behring. Dr. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.
The report on the gene therapy treatment, known as etranacogene dezaparvovec (EtranaDez), was released at the Feb. 2-4, 2022, annual meeting of the European Association of Hemophilia and Allied Disorders.
In an interview, study lead author Wolfgang Miesbach, MD, PhD, of University Hospital Frankfurt in Germany, touted the decline in ABR. “This statistically significant reduction not only met the primary endpoint for non-inferiority but also demonstrates clear superiority of etranacogene dezaparvovec to prophylaxis in the lead-in period,” he said. “In addition to that, the quality of life improved significantly, [and] there was an overall favorable safety profile.”
Hemophilia B is much rarer than hemophilia A. In a 2020 report, the CDC estimated that type A accounted for less than a quarter of the 29,761-32,985 cases of U.S. males who had hemophilia from 2012-2018. The rest had type B. Most of the males with hemophilia were white (81.2%) and fairly young (just 20.6% were older than 39).
High adherence and high prices
Factor IX (FIX) replacement therapy aims to boost levels of the blood-clotting protein in patients with severe hepatitis B. However, the intravenous prophylactic treatment requires a “high level of adherence” due to the need for self-administration several times a week, Dr. Miesbach said, adding that the treatment does not reliably prevent bleeding and joint destruction.
Also, the price of FIX replacement therapy in the United States is exorbitant, costing an average of $397,491 a year for the conventional treatment and an average of $788,861 a year for an extended half-life treatment, according to a 2019 report.
The gene therapy treatment, formerly known as AMT-061, “consists of a functional FIX gene with higher activity than the wild-type FIX (Padua variant), together with an AAV (AAV5),” Dr. Miesbach said. “AAV 5 is a vector with high liver tropism to transduce the liver cells and lead to the production of the functional FIX gene there.”
For the new open-label, single-dose, single-arm HOPE-B study, researchers treated 54 adult men with severe or moderately severe HB (FIX ≤2%), 31 with and 23 without preexisting AAV5 neutralizing antibodies. The average age was 41.5, 81.5% had severe cases (FIX<1%), and 25.9% had no bleeds at lead-in.
The participants began 12 months of treatment with gene therapy following a 6-month lead-in period of FIX prophylaxis. All but one completed follow-up.
“Mean FIX activity was 39.0 IU/dL (±18.7; 8.2, 97.1) (standard deviation; min, max) at month 6 and 36.9 IU/dL (±21.4; 4.5, 122.9) at month 18,” the researchers reported. ABR dropped by 64% from the lead-in period to the 12-month treatment period (4.19 vs. 1.51, P = .0002), and FIX-treated bleeds fell by 77% (ABR=3.65 vs. 0.83, P < .0001).
Fifty-two of 54 patients stopped full-dose prophylaxis and didn’t return to it. Mean unadjusted annualized FIX use dropped by 97% overall from the lead-in period to months 13-18 (257,338.8 vs. 8,486.6 IU/year/participant).
Thirty-seven participants experienced 92 treatment-related adverse events such as abnormal alanine aminotransferase (16.7%), headache (14.8%), influenza-like illness (13.0%), infusion-related infection (13.0%), and abnormal aspartate aminotransferase (9.3). Researchers determined 74 (80.4%) of the adverse effects were mild.
“Transaminase increases were reported, and corticosteroids were required in nine participants, but the mean duration of corticosteroids, including taper, was only 79 days,” Dr. Miesbach said.
“There was no prophylactic use of steroids in this study. FIX expression was maintained. One death was found to be unrelated to study treatment. One case of hepatocellular carcinoma, which has been reported in detail previously, was reported. But after detailed molecular analysis, this was found to be unrelated to study treatment,” he noted.
Quality of life scores improved by 21.5%-28.78%. The P values, ranging from < .0001 to .0036, were considered to be “nominally significant” due to analysis limitations.
A ‘one and done’ treatment
While the trial is expected to continue until 2025, no further treatment with etranacogene dezaparvovec was given. “Gene therapy is a ‘one and done’ treatment,” Dr. Miesbach said. “According to our current knowledge, it cannot be repeated.”
No information about the expected cost of the treatment is available. CSL Behring, which licensed global rights for the gene therapy from developer uniQure, is expected to seek Food and Drug Administration approval this year.
The trial was funded by CSL Behring. Dr. Miesbach and other study authors report various disclosures including support from CSL Behring and uniQure. Some authors are employees of CSL Behring and uniQure.
REPORTING FROM EAHAD
New hemophilia treatments: ‘Our cup runneth over’
It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.
In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, .
Factor concentrates
Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.
“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.
As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.
Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.
“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.
The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.
The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.
“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.
There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.
The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.
Factor mimetic and rebalancing therapies
With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.
Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.
She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.
Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.
It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.
Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).
One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.
However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.
Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.
“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”
Considerable optimism over gene therapy
“There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that’s really driving this field,” said Lindsey A. George, MD, of the University of Pennsylvania and Children’s Hospital of Philadelphia.
She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.
There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.
Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, Dr. George said.
“Thankfully, short-term safety in the context of hemophilia has really been quite good,” she said.
Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in factor VIII and factor IX activity.
In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.
There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.
Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.
“That’s obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we’re achieving the same phenotypic observations deserves a bit of a deeper dive,” she said.
Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.
In canine models for hemophilia A and B, factor VIII and factor IX expression have been demonstrated for 8-10 years post vector, and in humans factor IX expression in patients with hemophilia B has been reported for up to 8 years.
In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.
Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.
Regarding the future of gene therapy, Dr. George said that “we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy “will fulfill its promise to alter the paradigm of hemophilia care.”
Dr. Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Dr. Ma disclosed honoraria and research funding from Takeda. Dr. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.
A version of this article first appeared on Medscape.com.
It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.
In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, .
Factor concentrates
Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.
“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.
As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.
Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.
“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.
The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.
The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.
“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.
There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.
The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.
Factor mimetic and rebalancing therapies
With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.
Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.
She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.
Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.
It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.
Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).
One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.
However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.
Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.
“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”
Considerable optimism over gene therapy
“There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that’s really driving this field,” said Lindsey A. George, MD, of the University of Pennsylvania and Children’s Hospital of Philadelphia.
She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.
There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.
Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, Dr. George said.
“Thankfully, short-term safety in the context of hemophilia has really been quite good,” she said.
Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in factor VIII and factor IX activity.
In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.
There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.
Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.
“That’s obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we’re achieving the same phenotypic observations deserves a bit of a deeper dive,” she said.
Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.
In canine models for hemophilia A and B, factor VIII and factor IX expression have been demonstrated for 8-10 years post vector, and in humans factor IX expression in patients with hemophilia B has been reported for up to 8 years.
In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.
Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.
Regarding the future of gene therapy, Dr. George said that “we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy “will fulfill its promise to alter the paradigm of hemophilia care.”
Dr. Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Dr. Ma disclosed honoraria and research funding from Takeda. Dr. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.
A version of this article first appeared on Medscape.com.
It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.
In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, .
Factor concentrates
Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.
“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.
As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.
Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.
“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.
The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.
The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.
“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.
There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.
The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.
Factor mimetic and rebalancing therapies
With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.
Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.
She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.
Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.
It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.
Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).
One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.
However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.
Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.
“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”
Considerable optimism over gene therapy
“There is now repeated proof of concept success for hemophilia A and B gene therapy. I think this supports the considerable optimism that’s really driving this field,” said Lindsey A. George, MD, of the University of Pennsylvania and Children’s Hospital of Philadelphia.
She reviewed adeno-associated virus (AAV) vector and AAV-mediated gene transfer approaches for hemophilia A and B.
There are currently four clinical trials of gene therapy for patients with hemophilia B, and five for patients with hemophilia A.
Because AAV efficiently targets the liver, most safety considerations about systemic AAV-mediated gene therapy are focused around potential hepatotoxicity, Dr. George said.
“Thankfully, short-term safety in the context of hemophilia has really been quite good,” she said.
Patients who undergo gene therapy for hemophilia are typically monitored twice weekly for 3 months for evidence of a capsid-specific CD8 T cell response, also called a capsid immune response. This presents with transient transaminase elevations (primarily ALT) and a decline in factor VIII and factor IX activity.
In clinical trials for patients with hemophilia, the capsid immune response has limited the efficacy of the therapy in the short term, but has not been a major cause for safety concerns. It is typically managed with glucocorticoids or other immunomodulating agents such as mycophenolate mofetil or tacrolimus.
There have also been reported cases of transaminase elevations without evidence of a capsid immune response, which warrants further investigation, she added.
Regarding efficacy, she noted that across clinical trials, the observed annualized bleeding rate has been less than 1%, despite heterogeneity of vectors and dosing used.
“That’s obviously quite optimistic for the field, but it also sort of raises the point that the heterogeneity at which we’re achieving the same phenotypic observations deserves a bit of a deeper dive,” she said.
Although hemophilia B gene transfer appears to be durable, the same cannot be said as yet for hemophilia A.
In canine models for hemophilia A and B, factor VIII and factor IX expression have been demonstrated for 8-10 years post vector, and in humans factor IX expression in patients with hemophilia B has been reported for up to 8 years.
In contrast, in the three hemophilia A trials in which patients have been followed for a minimum of 2 years, there was an approximately 40% loss of transgene vector from year 1 to year 2 with two vectors, but not a third.
Potential explanations for the loss of expression seen include an unfolded protein response, promoter silence, and an ongoing undetected or unmitigated immune response to AAV or to the transgene.
Regarding the future of gene therapy, Dr. George said that “we anticipate that there will be licensed vectors in the very near future, and predicted that gene therapy “will fulfill its promise to alter the paradigm of hemophilia care.”
Dr. Lim disclosed honoraria from several companies and travel support from Novo Nordisk. Dr. Ma disclosed honoraria and research funding from Takeda. Dr. George disclosed FVIII-QQ patents and royalties, research funding from AskBio, and consulting activities/advisory board participation with others.
A version of this article first appeared on Medscape.com.
REPORTING FROM ASH 2021