Bleeding Disorders

The PROBE (Patient Reported Outcomes Burdens and Experience) questionnaire was found to be a valid instrument to evaluate health status in patients with hemophilia in an cross‐cultural context, according to an international study.

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“This study [aimed] to investigate the variation in the PROBE questionnaire–driven measurements across four broad geographical regions,” wrote Chatree Chai‐Adisaksopha, MD, of McMaster University in Hamilton, Ontario, and his colleagues. The results of the study were published in Haemophilia.

The researchers analyzed data from 862 study participants who resided in various geographical regions, including North America, South America, Europe, and the Western Pacific. The majority of participants were male and had greater than 12 years of education.

The team assessed common characteristics of participants through collection of demographic data, including age, gender, years of education, among others. With respect to hemophilia, they evaluated patient‐reported outcome measures across these four regions.

“Outcome measurement in haemophilia has been developed to capture clinically relevant outcomes like bleeding rates, pharmacokinetics, joint pain, joint function scores, radiologic changes and mortality rates,” the researchers wrote.

After analysis, Dr. Chai‐Adisaksopha and his colleagues found that the PROBE questionnaire showed low variability when used on a multinational, cross‐cultural level. In particular, limited variation was found with respect to years of education and geographical region in all subcategories, with the exception of mobility score. In contrast, diagnosis and age had the highest levels of variation.

Region contributed 0.26% of variance in the PROBE score. Similarly, education level contributed 0.34% of the variance. However, age contributed 3.42% and diagnosis contributed 22.42% of the variance in the PROBE score.

The authors acknowledged a key limitation of the study was the inability to include all geographical regions, largely due to an inadequate number of participants in certain areas, such as Africa.

“Despite being used in disparate groups of patients, in 14 countries, in four regions and in 20 languages, the tool produced comparable results, suggesting it can be reliably used across these groups,” the researchers wrote.

The study was funded by Baxalta, Bayer, Bioverativ, CSL Behring, Novo Nordisk, Roche, and Sobi, with additional support from the U.S. National Hemophilia Foundation. Co-author Mark W. Skinner is the principal investigator and no other investigators reported relevant conflicts of interest.

SOURCE: Chai-Adisaksopha C et al. Haemophilia. 2019 Mar 12. doi: 10.1111/hae.13703 .

The PROBE (Patient Reported Outcomes Burdens and Experience) questionnaire was found to be a valid instrument to evaluate health status in patients with hemophilia in an cross‐cultural context, according to an international study.

PeopleImages/gettyimages

“This study [aimed] to investigate the variation in the PROBE questionnaire–driven measurements across four broad geographical regions,” wrote Chatree Chai‐Adisaksopha, MD, of McMaster University in Hamilton, Ontario, and his colleagues. The results of the study were published in Haemophilia.

The researchers analyzed data from 862 study participants who resided in various geographical regions, including North America, South America, Europe, and the Western Pacific. The majority of participants were male and had greater than 12 years of education.

The team assessed common characteristics of participants through collection of demographic data, including age, gender, years of education, among others. With respect to hemophilia, they evaluated patient‐reported outcome measures across these four regions.

“Outcome measurement in haemophilia has been developed to capture clinically relevant outcomes like bleeding rates, pharmacokinetics, joint pain, joint function scores, radiologic changes and mortality rates,” the researchers wrote.

After analysis, Dr. Chai‐Adisaksopha and his colleagues found that the PROBE questionnaire showed low variability when used on a multinational, cross‐cultural level. In particular, limited variation was found with respect to years of education and geographical region in all subcategories, with the exception of mobility score. In contrast, diagnosis and age had the highest levels of variation.

Region contributed 0.26% of variance in the PROBE score. Similarly, education level contributed 0.34% of the variance. However, age contributed 3.42% and diagnosis contributed 22.42% of the variance in the PROBE score.

The authors acknowledged a key limitation of the study was the inability to include all geographical regions, largely due to an inadequate number of participants in certain areas, such as Africa.

“Despite being used in disparate groups of patients, in 14 countries, in four regions and in 20 languages, the tool produced comparable results, suggesting it can be reliably used across these groups,” the researchers wrote.

The study was funded by Baxalta, Bayer, Bioverativ, CSL Behring, Novo Nordisk, Roche, and Sobi, with additional support from the U.S. National Hemophilia Foundation. Co-author Mark W. Skinner is the principal investigator and no other investigators reported relevant conflicts of interest.

SOURCE: Chai-Adisaksopha C et al. Haemophilia. 2019 Mar 12. doi: 10.1111/hae.13703 .

The PROBE (Patient Reported Outcomes Burdens and Experience) questionnaire was found to be a valid instrument to evaluate health status in patients with hemophilia in an cross‐cultural context, according to an international study.

PeopleImages/gettyimages

“This study [aimed] to investigate the variation in the PROBE questionnaire–driven measurements across four broad geographical regions,” wrote Chatree Chai‐Adisaksopha, MD, of McMaster University in Hamilton, Ontario, and his colleagues. The results of the study were published in Haemophilia.

The researchers analyzed data from 862 study participants who resided in various geographical regions, including North America, South America, Europe, and the Western Pacific. The majority of participants were male and had greater than 12 years of education.

The team assessed common characteristics of participants through collection of demographic data, including age, gender, years of education, among others. With respect to hemophilia, they evaluated patient‐reported outcome measures across these four regions.

“Outcome measurement in haemophilia has been developed to capture clinically relevant outcomes like bleeding rates, pharmacokinetics, joint pain, joint function scores, radiologic changes and mortality rates,” the researchers wrote.

After analysis, Dr. Chai‐Adisaksopha and his colleagues found that the PROBE questionnaire showed low variability when used on a multinational, cross‐cultural level. In particular, limited variation was found with respect to years of education and geographical region in all subcategories, with the exception of mobility score. In contrast, diagnosis and age had the highest levels of variation.

Region contributed 0.26% of variance in the PROBE score. Similarly, education level contributed 0.34% of the variance. However, age contributed 3.42% and diagnosis contributed 22.42% of the variance in the PROBE score.

The authors acknowledged a key limitation of the study was the inability to include all geographical regions, largely due to an inadequate number of participants in certain areas, such as Africa.

“Despite being used in disparate groups of patients, in 14 countries, in four regions and in 20 languages, the tool produced comparable results, suggesting it can be reliably used across these groups,” the researchers wrote.

The study was funded by Baxalta, Bayer, Bioverativ, CSL Behring, Novo Nordisk, Roche, and Sobi, with additional support from the U.S. National Hemophilia Foundation. Co-author Mark W. Skinner is the principal investigator and no other investigators reported relevant conflicts of interest.

SOURCE: Chai-Adisaksopha C et al. Haemophilia. 2019 Mar 12. doi: 10.1111/hae.13703 .

The use of concurrent anticoagulation and emicizumab prophylaxis eliminated the need for bypassing therapy and improved a life-threatening central venous access device (CVAD)–associated thrombus in a patient with severe hemophilia A.

“Systemic anticoagulation with concomitant emicizumab has not been previously described,” Angela Weyand, MD, of the University of Michigan, Ann Arbor, and her colleagues wrote in a letter to the editor published in Haemophilia.

The researchers reported findings from a case of a 6-year-old boy with severe hemophilia A who developed a CVAD‐associated thrombus during immune tolerance induction with recombinant factor VIII (rFVIII). As his clinical condition worsened, the team hypothesized thrombus development was being caused by the ongoing use of bypassing therapy.

Dr. Weyand and her colleagues started prophylaxis with subcutaneous emicizumab (3 mg/kg once weekly for 4 weeks followed by 1.5 mg/kg weekly thereafter) and anticoagulation therapy (low-molecular-weight heparin given twice daily; anti‐Xa target of 0.3‐0.5 IU/ mL, later increased to 0.5‐0.7 IU/mL).

After 2 months of concurrent therapy, the team saw major symptomatic improvement and the thrombus had substantially decreased in size. One month later, his port access was removed without any bleeding complications and no further hemostatic agents were required.

“Follow‐up echocardiogram 3 months after discontinuation of anticoagulation demonstrated continued improvement with increasing organization of the thrombus,” they wrote.

Afterward, the patient was continued on emicizumab prophylaxis and did not require additional bypassing agent therapy.

“Consideration was given to surgical thrombectomy as that would be the recommendation in a non-haemophilic patient, but ultimately anticoagulation was deemed to be a safer alternative,” they wrote.

The researchers acknowledged that very little evidence is available to guide treatment of patients similar to the one described in this case. “Although this particular scenario is rare, its real‐life efficacy data in these types of settings will help inform emicizumab use, which is critical given its expanding indications,” they concluded.

No funding sources were reported. The authors reported financial disclosures related to Bayer, CSL Behring, Novo Nordisk, Octapharma, Shire, and others.

SOURCE: Weyand AC et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13721.

The use of concurrent anticoagulation and emicizumab prophylaxis eliminated the need for bypassing therapy and improved a life-threatening central venous access device (CVAD)–associated thrombus in a patient with severe hemophilia A.

“Systemic anticoagulation with concomitant emicizumab has not been previously described,” Angela Weyand, MD, of the University of Michigan, Ann Arbor, and her colleagues wrote in a letter to the editor published in Haemophilia.

The researchers reported findings from a case of a 6-year-old boy with severe hemophilia A who developed a CVAD‐associated thrombus during immune tolerance induction with recombinant factor VIII (rFVIII). As his clinical condition worsened, the team hypothesized thrombus development was being caused by the ongoing use of bypassing therapy.

Dr. Weyand and her colleagues started prophylaxis with subcutaneous emicizumab (3 mg/kg once weekly for 4 weeks followed by 1.5 mg/kg weekly thereafter) and anticoagulation therapy (low-molecular-weight heparin given twice daily; anti‐Xa target of 0.3‐0.5 IU/ mL, later increased to 0.5‐0.7 IU/mL).

After 2 months of concurrent therapy, the team saw major symptomatic improvement and the thrombus had substantially decreased in size. One month later, his port access was removed without any bleeding complications and no further hemostatic agents were required.

“Follow‐up echocardiogram 3 months after discontinuation of anticoagulation demonstrated continued improvement with increasing organization of the thrombus,” they wrote.

Afterward, the patient was continued on emicizumab prophylaxis and did not require additional bypassing agent therapy.

“Consideration was given to surgical thrombectomy as that would be the recommendation in a non-haemophilic patient, but ultimately anticoagulation was deemed to be a safer alternative,” they wrote.

The researchers acknowledged that very little evidence is available to guide treatment of patients similar to the one described in this case. “Although this particular scenario is rare, its real‐life efficacy data in these types of settings will help inform emicizumab use, which is critical given its expanding indications,” they concluded.

No funding sources were reported. The authors reported financial disclosures related to Bayer, CSL Behring, Novo Nordisk, Octapharma, Shire, and others.

SOURCE: Weyand AC et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13721.

The use of concurrent anticoagulation and emicizumab prophylaxis eliminated the need for bypassing therapy and improved a life-threatening central venous access device (CVAD)–associated thrombus in a patient with severe hemophilia A.

“Systemic anticoagulation with concomitant emicizumab has not been previously described,” Angela Weyand, MD, of the University of Michigan, Ann Arbor, and her colleagues wrote in a letter to the editor published in Haemophilia.

The researchers reported findings from a case of a 6-year-old boy with severe hemophilia A who developed a CVAD‐associated thrombus during immune tolerance induction with recombinant factor VIII (rFVIII). As his clinical condition worsened, the team hypothesized thrombus development was being caused by the ongoing use of bypassing therapy.

Dr. Weyand and her colleagues started prophylaxis with subcutaneous emicizumab (3 mg/kg once weekly for 4 weeks followed by 1.5 mg/kg weekly thereafter) and anticoagulation therapy (low-molecular-weight heparin given twice daily; anti‐Xa target of 0.3‐0.5 IU/ mL, later increased to 0.5‐0.7 IU/mL).

After 2 months of concurrent therapy, the team saw major symptomatic improvement and the thrombus had substantially decreased in size. One month later, his port access was removed without any bleeding complications and no further hemostatic agents were required.

“Follow‐up echocardiogram 3 months after discontinuation of anticoagulation demonstrated continued improvement with increasing organization of the thrombus,” they wrote.

Afterward, the patient was continued on emicizumab prophylaxis and did not require additional bypassing agent therapy.

“Consideration was given to surgical thrombectomy as that would be the recommendation in a non-haemophilic patient, but ultimately anticoagulation was deemed to be a safer alternative,” they wrote.

The researchers acknowledged that very little evidence is available to guide treatment of patients similar to the one described in this case. “Although this particular scenario is rare, its real‐life efficacy data in these types of settings will help inform emicizumab use, which is critical given its expanding indications,” they concluded.

No funding sources were reported. The authors reported financial disclosures related to Bayer, CSL Behring, Novo Nordisk, Octapharma, Shire, and others.

SOURCE: Weyand AC et al. Haemophilia. 2019 Mar 13. doi: 10.1111/hae.13721.

Earlier this year, the Food and Drug Administration approved Cablivi (caplacizumab-yhdp) (Sanofi Genzyme, Cambridge, Mass.) for the treatment of acquired thrombotic thrombocytopenic purpura (TTP), making it the first medication specifically indicated for the treatment of TTP.

The approval of caplacizumab and the clinical trial results that approval is based on are the most promising developments in the treatment of TTP since the introduction of plasma exchange (PE) therapy. However, many questions remain about how to best administer caplacizumab, specifically, which patients should receive it? Should all TTP patients start on caplacizumab therapy or should it be limited to patients with histories of TTP or those slow to respond to standard therapy with PE and immunosuppression?

TTP is a rare thrombotic microangiopathy characterized by thrombocytopenia and microangiopathic hemolytic anemia caused by the inhibition of ADAMTS13, a metalloproteinase, which cleaves large-molecular-weight von Willebrand factor (vWF) multimers. Caplacizumab is a humanized bivalent, variable domain-only immunoglobulin fragment. The drug targets the A1 domain of vWF and inhibits the binding between vWF and the platelet glycoprotein Ib-IX-V receptor, preventing the formation of the microvascular thrombi and platelet loss associated with TTP.

FDA approval of caplacizumab came shortly after the publication of the results of the HERCULES trial in the New England Journal of Medicine by Marie Scully, MD, and her colleagues (N Engl J Med. 2019; 380[4]: 335-46).

HERCULES was an international phase 3, double blinded, placebo-controlled, randomized study designed to evaluate the efficacy and safety of caplacizumab. In total, 145 patients participated in the trial. Caplacizumab or placebo were given in addition to standard therapy of plasma exchange (PE) and immunosuppression. Caplacizumab or placebo were administered as an intravenous loading dose prior to the first PE after randomization and subcutaneously once daily until 30 days after the last PE. All patients received daily PE until 2 days after platelet count normalization.

The primary measure of the study was the time to platelet count response of greater than 150 x 10⁹/L following the cessation of daily PE. Secondary measures included TTP-related death; TTP relapse; major thromboembolic events; proportion of subjects with refractory TTP; normalization of organ damage markers including lactate dehydrogenase, cardiac troponin I, and serum creatinine; and other adverse events.

The authors found that the median time of normalization of the platelet count was shorter in the caplacizumab group, compared with placebo, with the caplacizumab group being 1.55 times more likely to have a normalized platelet count at any given time point in the study. While statistically significant differences were identified in the rate of platelet normalization, the median number of days of PE until normalization was only 2 days less in the caplacizumab group (five treatments) than in the placebo group (seven treatments), which may not be clinically significant for the treating physician.

In fact, the secondary endpoints of the study seem much more clinically promising in the treatment of TTP. The composite rate of TTP-related death, TTP recurrence, or major thromboembolic events during the treatment period was significantly lower in the caplacizumab group (12%) versus placebo (49%). No TTP-related deaths occurred in the caplacizumab group. The caplacizumab group was also statistically less likely to have a TTP exacerbation, defined as disease recurrence within 30 days from the last PE, than the placebo group.

End organ damage serum markers also improved faster in the caplacizumab group, although there was no significant difference between groups. Overall hospitalization (median of 9 vs. 12 days) and ICU stays (median of 3 vs. 5 days) were shorter in the caplacizumab group, compared with the placebo group.

While several relapses, defined as disease recurrence after 30 days from the last PE, occurred in the caplacizumab group, the relapses were only found in patients with ADAMTS13 activity of less than 10% at the end of the treatment period. Mild side effects, such as mucocutaneous bleeding were more frequent in the caplacizumab group. No major bleeding complications were observed.

The HERCULES trial generates more questions about the role of ADAMTS13 activity testing to monitor treatment response and to make therapy decisions. Extremely low ADAMTS13 activity levels at the cessation of therapy may be a sign of treatment inadequacy and may warrant closer follow-up of at-risk patients on caplacizumab.

Sanofi Genzyme estimates that the U.S. list price will be approximately $270,000 for a standard treatment course, according to a news release from the company. Whether payers will add it to formularies remains uncertain, but the high drug cost may be countered by potential savings in the reduction of hospital and ICU days with caplacizumab therapy. Sanofi Genzyme will also have a patient support program for eligible patients.

Caplacizumab has been approved in Europe since August 2018, but is not readily available in the United States. Given the dearth of clinical experience with the drug outside of the TITAN and HERCULES trials, strong recommendations for when and how to initiate therapy remain elusive.

As caplacizumab is further introduced into clinical practice, more studies are needed to identify which patient groups will benefit most from therapy. The current data for caplacizumab shows that it will be used as an adjunct to standard PE therapy, rather than as a replacement. How the drug is used in combination with current TTP treatments – such as corticosteroids, rituximab, bortezomib, vincristine, N-acetylcysteine, and splenectomy – should be evaluated to identify which treatment combinations not only improve platelet counts, but also reduce mortality and morbidity while remaining cost effective.

Dr. Ricci is a staff physician and Apheresis Director at the Taussig Cancer Institute at the Cleveland Clinic. She reported having no conflicts of interest.

Earlier this year, the Food and Drug Administration approved Cablivi (caplacizumab-yhdp) (Sanofi Genzyme, Cambridge, Mass.) for the treatment of acquired thrombotic thrombocytopenic purpura (TTP), making it the first medication specifically indicated for the treatment of TTP.

The approval of caplacizumab and the clinical trial results that approval is based on are the most promising developments in the treatment of TTP since the introduction of plasma exchange (PE) therapy. However, many questions remain about how to best administer caplacizumab, specifically, which patients should receive it? Should all TTP patients start on caplacizumab therapy or should it be limited to patients with histories of TTP or those slow to respond to standard therapy with PE and immunosuppression?

TTP is a rare thrombotic microangiopathy characterized by thrombocytopenia and microangiopathic hemolytic anemia caused by the inhibition of ADAMTS13, a metalloproteinase, which cleaves large-molecular-weight von Willebrand factor (vWF) multimers. Caplacizumab is a humanized bivalent, variable domain-only immunoglobulin fragment. The drug targets the A1 domain of vWF and inhibits the binding between vWF and the platelet glycoprotein Ib-IX-V receptor, preventing the formation of the microvascular thrombi and platelet loss associated with TTP.

FDA approval of caplacizumab came shortly after the publication of the results of the HERCULES trial in the New England Journal of Medicine by Marie Scully, MD, and her colleagues (N Engl J Med. 2019; 380[4]: 335-46).

HERCULES was an international phase 3, double blinded, placebo-controlled, randomized study designed to evaluate the efficacy and safety of caplacizumab. In total, 145 patients participated in the trial. Caplacizumab or placebo were given in addition to standard therapy of plasma exchange (PE) and immunosuppression. Caplacizumab or placebo were administered as an intravenous loading dose prior to the first PE after randomization and subcutaneously once daily until 30 days after the last PE. All patients received daily PE until 2 days after platelet count normalization.

The primary measure of the study was the time to platelet count response of greater than 150 x 10⁹/L following the cessation of daily PE. Secondary measures included TTP-related death; TTP relapse; major thromboembolic events; proportion of subjects with refractory TTP; normalization of organ damage markers including lactate dehydrogenase, cardiac troponin I, and serum creatinine; and other adverse events.

The authors found that the median time of normalization of the platelet count was shorter in the caplacizumab group, compared with placebo, with the caplacizumab group being 1.55 times more likely to have a normalized platelet count at any given time point in the study. While statistically significant differences were identified in the rate of platelet normalization, the median number of days of PE until normalization was only 2 days less in the caplacizumab group (five treatments) than in the placebo group (seven treatments), which may not be clinically significant for the treating physician.

In fact, the secondary endpoints of the study seem much more clinically promising in the treatment of TTP. The composite rate of TTP-related death, TTP recurrence, or major thromboembolic events during the treatment period was significantly lower in the caplacizumab group (12%) versus placebo (49%). No TTP-related deaths occurred in the caplacizumab group. The caplacizumab group was also statistically less likely to have a TTP exacerbation, defined as disease recurrence within 30 days from the last PE, than the placebo group.

End organ damage serum markers also improved faster in the caplacizumab group, although there was no significant difference between groups. Overall hospitalization (median of 9 vs. 12 days) and ICU stays (median of 3 vs. 5 days) were shorter in the caplacizumab group, compared with the placebo group.

While several relapses, defined as disease recurrence after 30 days from the last PE, occurred in the caplacizumab group, the relapses were only found in patients with ADAMTS13 activity of less than 10% at the end of the treatment period. Mild side effects, such as mucocutaneous bleeding were more frequent in the caplacizumab group. No major bleeding complications were observed.

The HERCULES trial generates more questions about the role of ADAMTS13 activity testing to monitor treatment response and to make therapy decisions. Extremely low ADAMTS13 activity levels at the cessation of therapy may be a sign of treatment inadequacy and may warrant closer follow-up of at-risk patients on caplacizumab.

Sanofi Genzyme estimates that the U.S. list price will be approximately $270,000 for a standard treatment course, according to a news release from the company. Whether payers will add it to formularies remains uncertain, but the high drug cost may be countered by potential savings in the reduction of hospital and ICU days with caplacizumab therapy. Sanofi Genzyme will also have a patient support program for eligible patients.

Caplacizumab has been approved in Europe since August 2018, but is not readily available in the United States. Given the dearth of clinical experience with the drug outside of the TITAN and HERCULES trials, strong recommendations for when and how to initiate therapy remain elusive.

As caplacizumab is further introduced into clinical practice, more studies are needed to identify which patient groups will benefit most from therapy. The current data for caplacizumab shows that it will be used as an adjunct to standard PE therapy, rather than as a replacement. How the drug is used in combination with current TTP treatments – such as corticosteroids, rituximab, bortezomib, vincristine, N-acetylcysteine, and splenectomy – should be evaluated to identify which treatment combinations not only improve platelet counts, but also reduce mortality and morbidity while remaining cost effective.

Dr. Ricci is a staff physician and Apheresis Director at the Taussig Cancer Institute at the Cleveland Clinic. She reported having no conflicts of interest.

Earlier this year, the Food and Drug Administration approved Cablivi (caplacizumab-yhdp) (Sanofi Genzyme, Cambridge, Mass.) for the treatment of acquired thrombotic thrombocytopenic purpura (TTP), making it the first medication specifically indicated for the treatment of TTP.

The approval of caplacizumab and the clinical trial results that approval is based on are the most promising developments in the treatment of TTP since the introduction of plasma exchange (PE) therapy. However, many questions remain about how to best administer caplacizumab, specifically, which patients should receive it? Should all TTP patients start on caplacizumab therapy or should it be limited to patients with histories of TTP or those slow to respond to standard therapy with PE and immunosuppression?

TTP is a rare thrombotic microangiopathy characterized by thrombocytopenia and microangiopathic hemolytic anemia caused by the inhibition of ADAMTS13, a metalloproteinase, which cleaves large-molecular-weight von Willebrand factor (vWF) multimers. Caplacizumab is a humanized bivalent, variable domain-only immunoglobulin fragment. The drug targets the A1 domain of vWF and inhibits the binding between vWF and the platelet glycoprotein Ib-IX-V receptor, preventing the formation of the microvascular thrombi and platelet loss associated with TTP.

FDA approval of caplacizumab came shortly after the publication of the results of the HERCULES trial in the New England Journal of Medicine by Marie Scully, MD, and her colleagues (N Engl J Med. 2019; 380[4]: 335-46).

HERCULES was an international phase 3, double blinded, placebo-controlled, randomized study designed to evaluate the efficacy and safety of caplacizumab. In total, 145 patients participated in the trial. Caplacizumab or placebo were given in addition to standard therapy of plasma exchange (PE) and immunosuppression. Caplacizumab or placebo were administered as an intravenous loading dose prior to the first PE after randomization and subcutaneously once daily until 30 days after the last PE. All patients received daily PE until 2 days after platelet count normalization.

The primary measure of the study was the time to platelet count response of greater than 150 x 10⁹/L following the cessation of daily PE. Secondary measures included TTP-related death; TTP relapse; major thromboembolic events; proportion of subjects with refractory TTP; normalization of organ damage markers including lactate dehydrogenase, cardiac troponin I, and serum creatinine; and other adverse events.

The authors found that the median time of normalization of the platelet count was shorter in the caplacizumab group, compared with placebo, with the caplacizumab group being 1.55 times more likely to have a normalized platelet count at any given time point in the study. While statistically significant differences were identified in the rate of platelet normalization, the median number of days of PE until normalization was only 2 days less in the caplacizumab group (five treatments) than in the placebo group (seven treatments), which may not be clinically significant for the treating physician.

In fact, the secondary endpoints of the study seem much more clinically promising in the treatment of TTP. The composite rate of TTP-related death, TTP recurrence, or major thromboembolic events during the treatment period was significantly lower in the caplacizumab group (12%) versus placebo (49%). No TTP-related deaths occurred in the caplacizumab group. The caplacizumab group was also statistically less likely to have a TTP exacerbation, defined as disease recurrence within 30 days from the last PE, than the placebo group.

End organ damage serum markers also improved faster in the caplacizumab group, although there was no significant difference between groups. Overall hospitalization (median of 9 vs. 12 days) and ICU stays (median of 3 vs. 5 days) were shorter in the caplacizumab group, compared with the placebo group.

While several relapses, defined as disease recurrence after 30 days from the last PE, occurred in the caplacizumab group, the relapses were only found in patients with ADAMTS13 activity of less than 10% at the end of the treatment period. Mild side effects, such as mucocutaneous bleeding were more frequent in the caplacizumab group. No major bleeding complications were observed.

The HERCULES trial generates more questions about the role of ADAMTS13 activity testing to monitor treatment response and to make therapy decisions. Extremely low ADAMTS13 activity levels at the cessation of therapy may be a sign of treatment inadequacy and may warrant closer follow-up of at-risk patients on caplacizumab.

Sanofi Genzyme estimates that the U.S. list price will be approximately $270,000 for a standard treatment course, according to a news release from the company. Whether payers will add it to formularies remains uncertain, but the high drug cost may be countered by potential savings in the reduction of hospital and ICU days with caplacizumab therapy. Sanofi Genzyme will also have a patient support program for eligible patients.

Caplacizumab has been approved in Europe since August 2018, but is not readily available in the United States. Given the dearth of clinical experience with the drug outside of the TITAN and HERCULES trials, strong recommendations for when and how to initiate therapy remain elusive.

As caplacizumab is further introduced into clinical practice, more studies are needed to identify which patient groups will benefit most from therapy. The current data for caplacizumab shows that it will be used as an adjunct to standard PE therapy, rather than as a replacement. How the drug is used in combination with current TTP treatments – such as corticosteroids, rituximab, bortezomib, vincristine, N-acetylcysteine, and splenectomy – should be evaluated to identify which treatment combinations not only improve platelet counts, but also reduce mortality and morbidity while remaining cost effective.

Dr. Ricci is a staff physician and Apheresis Director at the Taussig Cancer Institute at the Cleveland Clinic. She reported having no conflicts of interest.

FROM HAEMOPHILIA

Some patients with severe hemophilia A can be managed with weekly injections of the recombinant factor VIII (rFVIII) product turoctocog alfa pegol (N8-GP), based on results from an extension of the pathfinder 2 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In patients who had two or fewer bleeding episodes during the preceding 6 months, N8-GP was effective for prophylaxis and treating bleeding episodes without causing inhibitor development, reported lead author Nicola Curry, MD, of the Oxford (England) Haemophilia and Thrombosis Centre at Churchill Hospital and her colleagues.

The trial exemplifies an ongoing effort to reduce frequency of prophylaxis in hemophilia A.

N8-GP, given every 4 days (or twice weekly in children), was approved by the Food and Drug Administration in February 2019; however, the investigators hypothesized that dose frequency could be stepped down in those who responded well to initial treatment.

“Many patients struggle to integrate prophylactic schedules into their daily lives, leading to missed injections and increased bleeding episodes,” the investigators wrote in a Haemophilia. “Therefore, prophylactic strategies offering effective haemostatic coverage with more convenient administration schedules are needed.”

To this end, the investigators identified 55 patients (at least 12 years old) from the pathfinder 2 trial who had two or fewer bleeding episodes during the preceding 6 months. From this group, 17 patients continued to receive 50 IU/kg of N8-GP every 4 days, as they had done during the main trial, while 38 patients received a higher dose – 75 IU/kg – every 7 days.

When necessary, N8-GP was used to treat bleeding episodes. Primary coendpoints were immunogenicity and efficacy, while all secondary endpoints were safety measures.

For both cohorts, median annualized bleeding rate (ABR) was 0.00 days, and greater than 50% of patients experienced no bleeds (53% every 4 days vs. 58% weekly). No inhibitors developed during the extension phase of the trial.

Along with strong support for weekly prophylaxis, N8-GP demonstrated efficiency in treating bleeding episodes; 87.5% of episodes were controlled with just one injection. This rate increased to 94.7% when including two or fewer injections.

During the study, 108 adverse events were reported in 65.5% of patients, although almost all were mild or moderate in severity, and unrelated to N8-GP. Five adverse events in five patients were related to treatment, including rash, headache, purpura, increased aspartate aminotransferase, and thrombocytopenia. No thromboembolic events were reported.

“These findings suggest that weekly N8-GP may provide effective prophylaxis with a reduced treatment burden for a selected subset of low-bleeding patients with severe haemophilia A,” the investigators wrote.

The study was funded by Novo Nordisk. The investigators reported financial relationships with Bayer, CSL, Novo Nordisk, Octapharma, Genentech, Shire, and others.

SOURCE: Curry N et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13712.

FROM HAEMOPHILIA

Some patients with severe hemophilia A can be managed with weekly injections of the recombinant factor VIII (rFVIII) product turoctocog alfa pegol (N8-GP), based on results from an extension of the pathfinder 2 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In patients who had two or fewer bleeding episodes during the preceding 6 months, N8-GP was effective for prophylaxis and treating bleeding episodes without causing inhibitor development, reported lead author Nicola Curry, MD, of the Oxford (England) Haemophilia and Thrombosis Centre at Churchill Hospital and her colleagues.

The trial exemplifies an ongoing effort to reduce frequency of prophylaxis in hemophilia A.

N8-GP, given every 4 days (or twice weekly in children), was approved by the Food and Drug Administration in February 2019; however, the investigators hypothesized that dose frequency could be stepped down in those who responded well to initial treatment.

“Many patients struggle to integrate prophylactic schedules into their daily lives, leading to missed injections and increased bleeding episodes,” the investigators wrote in a Haemophilia. “Therefore, prophylactic strategies offering effective haemostatic coverage with more convenient administration schedules are needed.”

To this end, the investigators identified 55 patients (at least 12 years old) from the pathfinder 2 trial who had two or fewer bleeding episodes during the preceding 6 months. From this group, 17 patients continued to receive 50 IU/kg of N8-GP every 4 days, as they had done during the main trial, while 38 patients received a higher dose – 75 IU/kg – every 7 days.

When necessary, N8-GP was used to treat bleeding episodes. Primary coendpoints were immunogenicity and efficacy, while all secondary endpoints were safety measures.

For both cohorts, median annualized bleeding rate (ABR) was 0.00 days, and greater than 50% of patients experienced no bleeds (53% every 4 days vs. 58% weekly). No inhibitors developed during the extension phase of the trial.

Along with strong support for weekly prophylaxis, N8-GP demonstrated efficiency in treating bleeding episodes; 87.5% of episodes were controlled with just one injection. This rate increased to 94.7% when including two or fewer injections.

During the study, 108 adverse events were reported in 65.5% of patients, although almost all were mild or moderate in severity, and unrelated to N8-GP. Five adverse events in five patients were related to treatment, including rash, headache, purpura, increased aspartate aminotransferase, and thrombocytopenia. No thromboembolic events were reported.

“These findings suggest that weekly N8-GP may provide effective prophylaxis with a reduced treatment burden for a selected subset of low-bleeding patients with severe haemophilia A,” the investigators wrote.

The study was funded by Novo Nordisk. The investigators reported financial relationships with Bayer, CSL, Novo Nordisk, Octapharma, Genentech, Shire, and others.

SOURCE: Curry N et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13712.

FROM HAEMOPHILIA

Some patients with severe hemophilia A can be managed with weekly injections of the recombinant factor VIII (rFVIII) product turoctocog alfa pegol (N8-GP), based on results from an extension of the pathfinder 2 trial.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In patients who had two or fewer bleeding episodes during the preceding 6 months, N8-GP was effective for prophylaxis and treating bleeding episodes without causing inhibitor development, reported lead author Nicola Curry, MD, of the Oxford (England) Haemophilia and Thrombosis Centre at Churchill Hospital and her colleagues.

The trial exemplifies an ongoing effort to reduce frequency of prophylaxis in hemophilia A.

N8-GP, given every 4 days (or twice weekly in children), was approved by the Food and Drug Administration in February 2019; however, the investigators hypothesized that dose frequency could be stepped down in those who responded well to initial treatment.

“Many patients struggle to integrate prophylactic schedules into their daily lives, leading to missed injections and increased bleeding episodes,” the investigators wrote in a Haemophilia. “Therefore, prophylactic strategies offering effective haemostatic coverage with more convenient administration schedules are needed.”

To this end, the investigators identified 55 patients (at least 12 years old) from the pathfinder 2 trial who had two or fewer bleeding episodes during the preceding 6 months. From this group, 17 patients continued to receive 50 IU/kg of N8-GP every 4 days, as they had done during the main trial, while 38 patients received a higher dose – 75 IU/kg – every 7 days.

When necessary, N8-GP was used to treat bleeding episodes. Primary coendpoints were immunogenicity and efficacy, while all secondary endpoints were safety measures.

For both cohorts, median annualized bleeding rate (ABR) was 0.00 days, and greater than 50% of patients experienced no bleeds (53% every 4 days vs. 58% weekly). No inhibitors developed during the extension phase of the trial.

Along with strong support for weekly prophylaxis, N8-GP demonstrated efficiency in treating bleeding episodes; 87.5% of episodes were controlled with just one injection. This rate increased to 94.7% when including two or fewer injections.

During the study, 108 adverse events were reported in 65.5% of patients, although almost all were mild or moderate in severity, and unrelated to N8-GP. Five adverse events in five patients were related to treatment, including rash, headache, purpura, increased aspartate aminotransferase, and thrombocytopenia. No thromboembolic events were reported.

“These findings suggest that weekly N8-GP may provide effective prophylaxis with a reduced treatment burden for a selected subset of low-bleeding patients with severe haemophilia A,” the investigators wrote.

The study was funded by Novo Nordisk. The investigators reported financial relationships with Bayer, CSL, Novo Nordisk, Octapharma, Genentech, Shire, and others.

SOURCE: Curry N et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13712.

When managed by an experienced team, patients with inherited bleeding disorders undergoing gastrointestinal endoscopy are not at increased bleeding risk, according to researchers reporting the largest series of such patients to date.

The postendoscopy bleeding rate was less than 1% for the patients in this series, many of whom underwent high-risk procedures or had comorbid conditions putting them at risk of bleeding, the researchers reported.

The rate of colonoscopic postpolypectomy bleeding was less than 5%, which is comparable to the general population rate for such high-risk procedures, said investigator Marcel Tomaszewski, MD, of McGill University, Montreal, and colleagues.

Those results favor the use of the “interdisciplinary approach provided by a hemophilia treatment center, communication between services, and the use of periprocedure prophylaxis including tranexamic acid,” Dr. Tomaszewski and coinvestigators said in their report in Haemophilia.

The study cohort included 48 individuals undergoing a total of 104 endoscopies, which is believed to be the largest case series of digestive endoscopy procedures ever reported in patients with congenital bleeding disorders, according to the researchers.

Hemophilia A and von Willebrand disease were the most common bleeding disorders among these patients, accounting for 49 and 40 of the 104 procedures, respectively. The remaining 17 procedures were performed in patients with factor XI deficiency, hemophilia B, or factor VII deficiency.

Before their endoscopies, patients received bleeding prophylaxis, which consisted of combinations of recombinant factor for hemophilia patients, plasma-derived factor for von Willebrand disease patients, desmopressin, and tranexamic acid.

The rate of bleeding within 72 hours of the endoscopic procedure was 0.96% (95% confidence interval, 0.17%-5.25%). The bleeding rate for hemophilia A patients, regardless of severity, was 2.2%, while the rate for hemophilia B, von Willebrand disease, factor VII deficiency and factor XI deficiency was 0%.

The only endoscopic procedures associated with bleeding were colonoscopy, with a bleeding rate of 2%, and colonoscopy with polypectomy, which had a 4.8% bleeding rate, they added, noting that the reported rate of postpolypectomy bleeding in the general population ranges between 0.3% and 10%.

“The very low incidence of bleeding adverse events limited further planned inferential statistical analysis,” the researchers wrote.

These findings stand in contrast to some previous reports, including one series of 19 patients with hemophilia in which 31% experienced gastrointestinal bleeding after colonoscopy polypectomy, despite preprocedure prophylaxis.

“Our approach, particularly with the addition of tranexamic acid, and our patient mix may explain the lower bleeding rate,” they wrote.

The most common indications for endoscopy in the present report were anemia, colorectal cancer screening or polyp surveillance, upper GI symptoms, and screening or surveillance of varices.

Many patients had conditions that might predispose them to bleeding, investigators said. Most commonly, those conditions included hepatitis C virus infection, cirrhosis, esophageal varices, and previous gastrointestinal bleeding.

Dr. Tomaszewski reported that he had no potential conflicts of interest related to the research. Coauthors reported financial disclosures related to AbbVie, Pfizer, Takeda, Janssen, and others.

SOURCE: Tomaszewski M et al. Haemophilia. 2019 Feb 12. doi: 10.1111/hae.13691

When managed by an experienced team, patients with inherited bleeding disorders undergoing gastrointestinal endoscopy are not at increased bleeding risk, according to researchers reporting the largest series of such patients to date.

The postendoscopy bleeding rate was less than 1% for the patients in this series, many of whom underwent high-risk procedures or had comorbid conditions putting them at risk of bleeding, the researchers reported.

The rate of colonoscopic postpolypectomy bleeding was less than 5%, which is comparable to the general population rate for such high-risk procedures, said investigator Marcel Tomaszewski, MD, of McGill University, Montreal, and colleagues.

Those results favor the use of the “interdisciplinary approach provided by a hemophilia treatment center, communication between services, and the use of periprocedure prophylaxis including tranexamic acid,” Dr. Tomaszewski and coinvestigators said in their report in Haemophilia.

The study cohort included 48 individuals undergoing a total of 104 endoscopies, which is believed to be the largest case series of digestive endoscopy procedures ever reported in patients with congenital bleeding disorders, according to the researchers.

Hemophilia A and von Willebrand disease were the most common bleeding disorders among these patients, accounting for 49 and 40 of the 104 procedures, respectively. The remaining 17 procedures were performed in patients with factor XI deficiency, hemophilia B, or factor VII deficiency.

Before their endoscopies, patients received bleeding prophylaxis, which consisted of combinations of recombinant factor for hemophilia patients, plasma-derived factor for von Willebrand disease patients, desmopressin, and tranexamic acid.

The rate of bleeding within 72 hours of the endoscopic procedure was 0.96% (95% confidence interval, 0.17%-5.25%). The bleeding rate for hemophilia A patients, regardless of severity, was 2.2%, while the rate for hemophilia B, von Willebrand disease, factor VII deficiency and factor XI deficiency was 0%.

The only endoscopic procedures associated with bleeding were colonoscopy, with a bleeding rate of 2%, and colonoscopy with polypectomy, which had a 4.8% bleeding rate, they added, noting that the reported rate of postpolypectomy bleeding in the general population ranges between 0.3% and 10%.

“The very low incidence of bleeding adverse events limited further planned inferential statistical analysis,” the researchers wrote.

These findings stand in contrast to some previous reports, including one series of 19 patients with hemophilia in which 31% experienced gastrointestinal bleeding after colonoscopy polypectomy, despite preprocedure prophylaxis.

“Our approach, particularly with the addition of tranexamic acid, and our patient mix may explain the lower bleeding rate,” they wrote.

The most common indications for endoscopy in the present report were anemia, colorectal cancer screening or polyp surveillance, upper GI symptoms, and screening or surveillance of varices.

Many patients had conditions that might predispose them to bleeding, investigators said. Most commonly, those conditions included hepatitis C virus infection, cirrhosis, esophageal varices, and previous gastrointestinal bleeding.

Dr. Tomaszewski reported that he had no potential conflicts of interest related to the research. Coauthors reported financial disclosures related to AbbVie, Pfizer, Takeda, Janssen, and others.

SOURCE: Tomaszewski M et al. Haemophilia. 2019 Feb 12. doi: 10.1111/hae.13691

When managed by an experienced team, patients with inherited bleeding disorders undergoing gastrointestinal endoscopy are not at increased bleeding risk, according to researchers reporting the largest series of such patients to date.

The postendoscopy bleeding rate was less than 1% for the patients in this series, many of whom underwent high-risk procedures or had comorbid conditions putting them at risk of bleeding, the researchers reported.

The rate of colonoscopic postpolypectomy bleeding was less than 5%, which is comparable to the general population rate for such high-risk procedures, said investigator Marcel Tomaszewski, MD, of McGill University, Montreal, and colleagues.

Those results favor the use of the “interdisciplinary approach provided by a hemophilia treatment center, communication between services, and the use of periprocedure prophylaxis including tranexamic acid,” Dr. Tomaszewski and coinvestigators said in their report in Haemophilia.

The study cohort included 48 individuals undergoing a total of 104 endoscopies, which is believed to be the largest case series of digestive endoscopy procedures ever reported in patients with congenital bleeding disorders, according to the researchers.

Hemophilia A and von Willebrand disease were the most common bleeding disorders among these patients, accounting for 49 and 40 of the 104 procedures, respectively. The remaining 17 procedures were performed in patients with factor XI deficiency, hemophilia B, or factor VII deficiency.

Before their endoscopies, patients received bleeding prophylaxis, which consisted of combinations of recombinant factor for hemophilia patients, plasma-derived factor for von Willebrand disease patients, desmopressin, and tranexamic acid.

The rate of bleeding within 72 hours of the endoscopic procedure was 0.96% (95% confidence interval, 0.17%-5.25%). The bleeding rate for hemophilia A patients, regardless of severity, was 2.2%, while the rate for hemophilia B, von Willebrand disease, factor VII deficiency and factor XI deficiency was 0%.

The only endoscopic procedures associated with bleeding were colonoscopy, with a bleeding rate of 2%, and colonoscopy with polypectomy, which had a 4.8% bleeding rate, they added, noting that the reported rate of postpolypectomy bleeding in the general population ranges between 0.3% and 10%.

“The very low incidence of bleeding adverse events limited further planned inferential statistical analysis,” the researchers wrote.

These findings stand in contrast to some previous reports, including one series of 19 patients with hemophilia in which 31% experienced gastrointestinal bleeding after colonoscopy polypectomy, despite preprocedure prophylaxis.

“Our approach, particularly with the addition of tranexamic acid, and our patient mix may explain the lower bleeding rate,” they wrote.

The most common indications for endoscopy in the present report were anemia, colorectal cancer screening or polyp surveillance, upper GI symptoms, and screening or surveillance of varices.

Many patients had conditions that might predispose them to bleeding, investigators said. Most commonly, those conditions included hepatitis C virus infection, cirrhosis, esophageal varices, and previous gastrointestinal bleeding.

Dr. Tomaszewski reported that he had no potential conflicts of interest related to the research. Coauthors reported financial disclosures related to AbbVie, Pfizer, Takeda, Janssen, and others.

SOURCE: Tomaszewski M et al. Haemophilia. 2019 Feb 12. doi: 10.1111/hae.13691

Erectile dysfunction (ED) appears prevalent among men with hemophilia and becomes increasingly common with age, according to results from a recent survey.

Although the findings may not be generalizable because of small sample size (44 respondents), the survey offers a general sense of the sexual health of patients with hemophilia, which is a minimally researched topic, reported lead author Ming Yang, PhD, of the British Columbia Provincial Bleeding Disorders Program at St. Paul’s Hospital in Vancouver and colleagues.

Such data become increasingly important as new hemophilia therapies further extend the lifespan of patients, which thereby exposes them to diseases of old age, the investigators noted in Haemophilia.

Additionally, ED is considered an early sign of endothelial dysfunction in the general population, but data are lacking for patients with hemophilia.

Among the 56 men with hemophilia A or B who were surveyed with the International Index of Erectile Function (IIEF) questionnaire, 44 completed the survey (median age, 49 years). Specifically, respondents completed the “erectile function” component of the questionnaire because this is the only domain that has been validated.

To assess associations between ED and well-established risk factors, the investigators recorded prior surgeries, medications, atherosclerotic diseases, viral infections, and hemophilia-specific factors. To better characterize the population and look for other associations, the investigators had patients undergo baseline laboratory testing and measurements of blood pressure, anthropomorphic indexes, and endothelial function.

According to the IIEF, 38.6% of patients had ED, which was subcategorized as mild and mild to moderate in 4.5% of patients, moderate in 18.2%, and severe in 15.9%.

The investigators found significant associations between ED and coronary artery disease, hypertension, smoking, higher waist/hip ratio, homocysteine level, and age. However, on multivariable analysis, only age was correlated with ED domain score (P = .03). No associations between ED and endothelial dysfunction were reported.

While the findings may offer a rare look at ED rates in patients with hemophilia, they are insufficient for comparisons and generalizations, the investigators cautioned.

“Without comparative studies within the haemophilia population in Canada or elsewhere and due to limited sample size and non‐normalized distribution of our age group, this prevalence cannot reasonably be generalized to the entire haemophilia population,” the investigators wrote.

Instead, the investigators suggested that more studies are needed, especially ones involving customized questionnaires.

The study was funded by Pfizer. Dr. Yang reported having no conflicts of interest. One coauthor reported an unrestricted educational award from the Association of Hemophilia Clinic Directors of Canada/Baxter Canadian Hemostasis Fellowship, and another coauthor reported research funding from Pfizer.

SOURCE: Yang M et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13707.

Erectile dysfunction (ED) appears prevalent among men with hemophilia and becomes increasingly common with age, according to results from a recent survey.

Although the findings may not be generalizable because of small sample size (44 respondents), the survey offers a general sense of the sexual health of patients with hemophilia, which is a minimally researched topic, reported lead author Ming Yang, PhD, of the British Columbia Provincial Bleeding Disorders Program at St. Paul’s Hospital in Vancouver and colleagues.

Such data become increasingly important as new hemophilia therapies further extend the lifespan of patients, which thereby exposes them to diseases of old age, the investigators noted in Haemophilia.

Additionally, ED is considered an early sign of endothelial dysfunction in the general population, but data are lacking for patients with hemophilia.

Among the 56 men with hemophilia A or B who were surveyed with the International Index of Erectile Function (IIEF) questionnaire, 44 completed the survey (median age, 49 years). Specifically, respondents completed the “erectile function” component of the questionnaire because this is the only domain that has been validated.

To assess associations between ED and well-established risk factors, the investigators recorded prior surgeries, medications, atherosclerotic diseases, viral infections, and hemophilia-specific factors. To better characterize the population and look for other associations, the investigators had patients undergo baseline laboratory testing and measurements of blood pressure, anthropomorphic indexes, and endothelial function.

According to the IIEF, 38.6% of patients had ED, which was subcategorized as mild and mild to moderate in 4.5% of patients, moderate in 18.2%, and severe in 15.9%.

The investigators found significant associations between ED and coronary artery disease, hypertension, smoking, higher waist/hip ratio, homocysteine level, and age. However, on multivariable analysis, only age was correlated with ED domain score (P = .03). No associations between ED and endothelial dysfunction were reported.

While the findings may offer a rare look at ED rates in patients with hemophilia, they are insufficient for comparisons and generalizations, the investigators cautioned.

“Without comparative studies within the haemophilia population in Canada or elsewhere and due to limited sample size and non‐normalized distribution of our age group, this prevalence cannot reasonably be generalized to the entire haemophilia population,” the investigators wrote.

Instead, the investigators suggested that more studies are needed, especially ones involving customized questionnaires.

The study was funded by Pfizer. Dr. Yang reported having no conflicts of interest. One coauthor reported an unrestricted educational award from the Association of Hemophilia Clinic Directors of Canada/Baxter Canadian Hemostasis Fellowship, and another coauthor reported research funding from Pfizer.

SOURCE: Yang M et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13707.

Erectile dysfunction (ED) appears prevalent among men with hemophilia and becomes increasingly common with age, according to results from a recent survey.

Although the findings may not be generalizable because of small sample size (44 respondents), the survey offers a general sense of the sexual health of patients with hemophilia, which is a minimally researched topic, reported lead author Ming Yang, PhD, of the British Columbia Provincial Bleeding Disorders Program at St. Paul’s Hospital in Vancouver and colleagues.

Such data become increasingly important as new hemophilia therapies further extend the lifespan of patients, which thereby exposes them to diseases of old age, the investigators noted in Haemophilia.

Additionally, ED is considered an early sign of endothelial dysfunction in the general population, but data are lacking for patients with hemophilia.

Among the 56 men with hemophilia A or B who were surveyed with the International Index of Erectile Function (IIEF) questionnaire, 44 completed the survey (median age, 49 years). Specifically, respondents completed the “erectile function” component of the questionnaire because this is the only domain that has been validated.

To assess associations between ED and well-established risk factors, the investigators recorded prior surgeries, medications, atherosclerotic diseases, viral infections, and hemophilia-specific factors. To better characterize the population and look for other associations, the investigators had patients undergo baseline laboratory testing and measurements of blood pressure, anthropomorphic indexes, and endothelial function.

According to the IIEF, 38.6% of patients had ED, which was subcategorized as mild and mild to moderate in 4.5% of patients, moderate in 18.2%, and severe in 15.9%.

The investigators found significant associations between ED and coronary artery disease, hypertension, smoking, higher waist/hip ratio, homocysteine level, and age. However, on multivariable analysis, only age was correlated with ED domain score (P = .03). No associations between ED and endothelial dysfunction were reported.

While the findings may offer a rare look at ED rates in patients with hemophilia, they are insufficient for comparisons and generalizations, the investigators cautioned.

“Without comparative studies within the haemophilia population in Canada or elsewhere and due to limited sample size and non‐normalized distribution of our age group, this prevalence cannot reasonably be generalized to the entire haemophilia population,” the investigators wrote.

Instead, the investigators suggested that more studies are needed, especially ones involving customized questionnaires.

The study was funded by Pfizer. Dr. Yang reported having no conflicts of interest. One coauthor reported an unrestricted educational award from the Association of Hemophilia Clinic Directors of Canada/Baxter Canadian Hemostasis Fellowship, and another coauthor reported research funding from Pfizer.

SOURCE: Yang M et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13707.

Measurement of factor XIII levels, followed by replacing deficiencies if found, may help to achieve sustained hemostasis in the management of bleeding in patients with acquired hemophilia A.

Jameel Abdulrehman, MD, of the University of Toronto in Ontario and his colleagues retrospectively reviewed cases of acquired hemophilia A with bleeding at a large hospital from 2015-2016. The findings were published in a letter to the editor in Haemophilia.

The researchers reported that depletion of Factor XIII (FXIII) in the setting of acquired hemophilia A has only been reported in a single case. In the present analysis, the researchers identified a total of seven patients with acquired hemophilia A from 2015-2016. FXIII antigen levels were measured in five cases and were found to be low in four cases, and three patients required FXIII replacement to secure hemostasis.

The relationship between acquired hemophilia A and FXIII deficiency was evaluated using descriptive case analysis.

After analysis, the team reported that measuring FXIII levels may be useful in refractory patients, in whom bleeding remains uncontrolled despite the use of standard therapy. Additionally, the results supported FXIII supplementation if a deficiency is detected.

“FXIII replacement was not complicated by any infusion reactions or thromboembolic events,” they wrote.

The replaced FXIII levels dropped more rapidly than expected, the researchers noted. The established half-life of pd-XIII is 6.6 days plus or minus 2.29 days; however, in the most severe of the cases reported, it was depleted “within a few days,” they wrote. “This is compatible with either consumption of FXIII or inhibition/clearance by an autoantibody.”

Dr. Abdulrehman and his colleagues acknowledged that FXIII deficiency can be challenging to identify because the majority of coagulation assays do not measure FXIII levels.

“As we gain a greater appreciation for the role of FXIII in various pathological states, access to accurate FXIII testing will become increasingly important,” they added.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Abdulrehman J et al. Haemophilia. 2019 Mar 7. doi: 10.1111/hae.13690.

Measurement of factor XIII levels, followed by replacing deficiencies if found, may help to achieve sustained hemostasis in the management of bleeding in patients with acquired hemophilia A.

Jameel Abdulrehman, MD, of the University of Toronto in Ontario and his colleagues retrospectively reviewed cases of acquired hemophilia A with bleeding at a large hospital from 2015-2016. The findings were published in a letter to the editor in Haemophilia.

The researchers reported that depletion of Factor XIII (FXIII) in the setting of acquired hemophilia A has only been reported in a single case. In the present analysis, the researchers identified a total of seven patients with acquired hemophilia A from 2015-2016. FXIII antigen levels were measured in five cases and were found to be low in four cases, and three patients required FXIII replacement to secure hemostasis.

The relationship between acquired hemophilia A and FXIII deficiency was evaluated using descriptive case analysis.

After analysis, the team reported that measuring FXIII levels may be useful in refractory patients, in whom bleeding remains uncontrolled despite the use of standard therapy. Additionally, the results supported FXIII supplementation if a deficiency is detected.

“FXIII replacement was not complicated by any infusion reactions or thromboembolic events,” they wrote.

The replaced FXIII levels dropped more rapidly than expected, the researchers noted. The established half-life of pd-XIII is 6.6 days plus or minus 2.29 days; however, in the most severe of the cases reported, it was depleted “within a few days,” they wrote. “This is compatible with either consumption of FXIII or inhibition/clearance by an autoantibody.”

Dr. Abdulrehman and his colleagues acknowledged that FXIII deficiency can be challenging to identify because the majority of coagulation assays do not measure FXIII levels.

“As we gain a greater appreciation for the role of FXIII in various pathological states, access to accurate FXIII testing will become increasingly important,” they added.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Abdulrehman J et al. Haemophilia. 2019 Mar 7. doi: 10.1111/hae.13690.

Measurement of factor XIII levels, followed by replacing deficiencies if found, may help to achieve sustained hemostasis in the management of bleeding in patients with acquired hemophilia A.

Jameel Abdulrehman, MD, of the University of Toronto in Ontario and his colleagues retrospectively reviewed cases of acquired hemophilia A with bleeding at a large hospital from 2015-2016. The findings were published in a letter to the editor in Haemophilia.

The researchers reported that depletion of Factor XIII (FXIII) in the setting of acquired hemophilia A has only been reported in a single case. In the present analysis, the researchers identified a total of seven patients with acquired hemophilia A from 2015-2016. FXIII antigen levels were measured in five cases and were found to be low in four cases, and three patients required FXIII replacement to secure hemostasis.

The relationship between acquired hemophilia A and FXIII deficiency was evaluated using descriptive case analysis.

After analysis, the team reported that measuring FXIII levels may be useful in refractory patients, in whom bleeding remains uncontrolled despite the use of standard therapy. Additionally, the results supported FXIII supplementation if a deficiency is detected.

“FXIII replacement was not complicated by any infusion reactions or thromboembolic events,” they wrote.

The replaced FXIII levels dropped more rapidly than expected, the researchers noted. The established half-life of pd-XIII is 6.6 days plus or minus 2.29 days; however, in the most severe of the cases reported, it was depleted “within a few days,” they wrote. “This is compatible with either consumption of FXIII or inhibition/clearance by an autoantibody.”

Dr. Abdulrehman and his colleagues acknowledged that FXIII deficiency can be challenging to identify because the majority of coagulation assays do not measure FXIII levels.

“As we gain a greater appreciation for the role of FXIII in various pathological states, access to accurate FXIII testing will become increasingly important,” they added.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Abdulrehman J et al. Haemophilia. 2019 Mar 7. doi: 10.1111/hae.13690.

The number of women being screened for von Willebrand disease (VWD) before undergoing hysterectomy for heavy menstrual bleeding is “very low” and appears not to align with current recommendations, according to a retrospective analysis.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

“One essential reason to identify females with VWD prior to hysterectomy or hysterectomy alternative is to avoid peri‐ and postoperative complications,” Amanda E. Jacobson‐Kelly, MD, of Ohio State University in Columbus and her colleagues wrote in a letter to the editor published in Haemophilia.

Current recommendations from the American College of Obstetricians and Gynecologists and other groups call for consideration of underlying bleeding disorders in women with heavy menstrual bleeding and additional risks factors, such as family history of abnormal bleeding.

In this study, researchers retrospectively analyzed 8,998 women under the age of 40 years who had a hysterectomy for heavy menstrual bleeding without a known bleeding disorder. Patient data was collected from a national insurance claims database representative of the entire U.S. population.

“We hypothesized that the overall frequency of VWD screening would be low, despite [more than] 15 years of expert recommendations,” the team wrote.

Study participants were included if they had a diagnosis of anemia or heavy menstrual bleeding before surgery, while women with certain genital malignancies and fibroids were excluded. Other information, such as age, geographical factors, and insurance-related factors were also included to evaluate whether these parameters affected disease screening.

After analysis, the researchers found that just 0.6% (n = 57) of women were screened for VWD in the 12 months leading up to surgery. Additionally, they reported that 14% (n = 1,276) of women underwent other forms of coagulation testing before surgery, such as partial thromboplastin time and prothrombin time.

“We found that greater distance to a [hemophilia treatment center] was strongly predictive of decreased likelihood of undergoing VWD screening,” Dr. Jacobson‐Kelly and her colleagues wrote.

The authors acknowledged that a key limitation of the study was the inability to account for factors not recorded in the database, including drug use, family history of bleeding disorders, and ethnicity.

“This study brings to light the need for the hematology community to improve education and awareness among women’s health providers,” they wrote.

The study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Jacobson-Kelly AE et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13709.

The number of women being screened for von Willebrand disease (VWD) before undergoing hysterectomy for heavy menstrual bleeding is “very low” and appears not to align with current recommendations, according to a retrospective analysis.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

“One essential reason to identify females with VWD prior to hysterectomy or hysterectomy alternative is to avoid peri‐ and postoperative complications,” Amanda E. Jacobson‐Kelly, MD, of Ohio State University in Columbus and her colleagues wrote in a letter to the editor published in Haemophilia.

Current recommendations from the American College of Obstetricians and Gynecologists and other groups call for consideration of underlying bleeding disorders in women with heavy menstrual bleeding and additional risks factors, such as family history of abnormal bleeding.

In this study, researchers retrospectively analyzed 8,998 women under the age of 40 years who had a hysterectomy for heavy menstrual bleeding without a known bleeding disorder. Patient data was collected from a national insurance claims database representative of the entire U.S. population.

“We hypothesized that the overall frequency of VWD screening would be low, despite [more than] 15 years of expert recommendations,” the team wrote.

Study participants were included if they had a diagnosis of anemia or heavy menstrual bleeding before surgery, while women with certain genital malignancies and fibroids were excluded. Other information, such as age, geographical factors, and insurance-related factors were also included to evaluate whether these parameters affected disease screening.

After analysis, the researchers found that just 0.6% (n = 57) of women were screened for VWD in the 12 months leading up to surgery. Additionally, they reported that 14% (n = 1,276) of women underwent other forms of coagulation testing before surgery, such as partial thromboplastin time and prothrombin time.

“We found that greater distance to a [hemophilia treatment center] was strongly predictive of decreased likelihood of undergoing VWD screening,” Dr. Jacobson‐Kelly and her colleagues wrote.

The authors acknowledged that a key limitation of the study was the inability to account for factors not recorded in the database, including drug use, family history of bleeding disorders, and ethnicity.

“This study brings to light the need for the hematology community to improve education and awareness among women’s health providers,” they wrote.

The study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Jacobson-Kelly AE et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13709.

The number of women being screened for von Willebrand disease (VWD) before undergoing hysterectomy for heavy menstrual bleeding is “very low” and appears not to align with current recommendations, according to a retrospective analysis.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

“One essential reason to identify females with VWD prior to hysterectomy or hysterectomy alternative is to avoid peri‐ and postoperative complications,” Amanda E. Jacobson‐Kelly, MD, of Ohio State University in Columbus and her colleagues wrote in a letter to the editor published in Haemophilia.

Current recommendations from the American College of Obstetricians and Gynecologists and other groups call for consideration of underlying bleeding disorders in women with heavy menstrual bleeding and additional risks factors, such as family history of abnormal bleeding.

In this study, researchers retrospectively analyzed 8,998 women under the age of 40 years who had a hysterectomy for heavy menstrual bleeding without a known bleeding disorder. Patient data was collected from a national insurance claims database representative of the entire U.S. population.

“We hypothesized that the overall frequency of VWD screening would be low, despite [more than] 15 years of expert recommendations,” the team wrote.

Study participants were included if they had a diagnosis of anemia or heavy menstrual bleeding before surgery, while women with certain genital malignancies and fibroids were excluded. Other information, such as age, geographical factors, and insurance-related factors were also included to evaluate whether these parameters affected disease screening.

After analysis, the researchers found that just 0.6% (n = 57) of women were screened for VWD in the 12 months leading up to surgery. Additionally, they reported that 14% (n = 1,276) of women underwent other forms of coagulation testing before surgery, such as partial thromboplastin time and prothrombin time.

“We found that greater distance to a [hemophilia treatment center] was strongly predictive of decreased likelihood of undergoing VWD screening,” Dr. Jacobson‐Kelly and her colleagues wrote.

The authors acknowledged that a key limitation of the study was the inability to account for factors not recorded in the database, including drug use, family history of bleeding disorders, and ethnicity.

“This study brings to light the need for the hematology community to improve education and awareness among women’s health providers,” they wrote.

The study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported having no conflicts of interest.

SOURCE: Jacobson-Kelly AE et al. Haemophilia. 2019 Feb 28. doi: 10.1111/hae.13709.

PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.

Will Pass/MDedge News

“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.

Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.

“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”

A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.


Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”

When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.

Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).

In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.

“This has stepped up the game hugely,” Dr. Pasi said.

The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.

Gene modification is also not coming anytime soon.

“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”

Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.

“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”

Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.

Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.

“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”

The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.

Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”

Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.

“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”

PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.

Will Pass/MDedge News

“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.

Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.

“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”

A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.


Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”

When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.

Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).

In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.

“This has stepped up the game hugely,” Dr. Pasi said.

The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.

Gene modification is also not coming anytime soon.

“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”

Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.

“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”

Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.

Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.

“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”

The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.

Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”

Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.

“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”

PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.

Will Pass/MDedge News

“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.

Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.

“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”

A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.


Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”

When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.

Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).

In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.

“This has stepped up the game hugely,” Dr. Pasi said.

The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.

Gene modification is also not coming anytime soon.

“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”

Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.

“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”

Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.

Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.

“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”

The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.

Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”

Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.

“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”

PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.

Will Pass/MDedge News

Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.

These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.

“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.

Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”

With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.

Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).

Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.

“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”

Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”

Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.

This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.

Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.

PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.

Will Pass/MDedge News

Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.

These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.

“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.

Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”

With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.

Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).

Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.

“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”

Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”

Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.

This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.

Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.

PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.

Will Pass/MDedge News

Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.

These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.

“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.

Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”

With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.

Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).

Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.

“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”

Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”

Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.

This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.

Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.