Bleeding Disorders

Isolated communities in the Canadian province of Newfoundland and Labrador have an “unusual prevalence” of certain hereditary bleeding disorders, a fact attributable to the province’s unique topography and settlement patterns, according to a new study.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The prevalence of hemophilia A in Newfoundland and Labrador (NL) is 2.89 times higher than in the rest of Canada. Deficiencies in Factors V, XI, and XIII are 4.54, 5.44, and 9.22 times more prevalent in NL than mainland Canada, respectively. The study also found more cases than expected of the extremely rare hereditary bleeding disorder, Glanzmann thrombasthenia (n = 4). One case of Bernard-Soulier syndrome was also seen, the investigators reported in Transfusion and Apheresis Science.

“This comparatively high prevalence provides a potential pool of patients for genotype/phenotype research,” wrote Mary-Frances Scully, MD, a hematologist at Memorial University, St. John’s, Nfld., and her associates.

In addition to founding populations of indigenous Innu, Inuit, and Mi’kmaq populations, present-day residents of Canada’s easternmost province trace their lineages to about 28,000 settlers who came from southwest England and southeast Ireland for the area’s rich fisheries, explained Dr. Scully and her coauthors. The overall population density of NL is still very low, at about 1.38 individuals per square kilometer, less than half that of Canada overall and far less than the United States’ 36 per square kilometer.

Overall, the investigators reviewed records for 180 patients with hereditary bleeding disorders who were receiving specialty care in St. John’s. Most (n = 127) had hemophilia A; of these patients, those who had mutation testing primarily had the Val 2016A1 mutation. This was particularly true for patients with mild hemophilia A. More than 73% (83/111 patients) carried this mutation, demonstrating a founder effect, wrote Dr. Scully and her coauthors. The next most common hereditary bleeding disorder was Factor XI deficiency, seen in 29 patients.

Additionally, of the seven patients with Factor XIII deficiency, five were homozygous for the c.691-1 G greater than A mutation.

More males in NL than in global comparator data had Factor V deficiency and Glanzmann thrombasthenia, though Dr. Scully and her colleagues acknowledged that the numbers were low overall.

Coagulation tests performed at the time of diagnosis and before treatment initiation were used, when available, to ascertain the severity of the bleeding disorder. Patients were included whether they were heterozygous or homozygous for hereditary bleeding disorders, so long as their baseline coagulation factor levels were below predetermined cutoff levels.

Comparing the prevalence of all the hereditary bleeding disorders identified in the NL population against mainland Canada and that of four other reference countries – Iran, Ireland, the United Kingdom, and the United States – the increased prevalence rates in NL were highly statistically significant (P less than .0001) for all but the single case of Bernard-Soulier syndrome.

Hemophilia B was the only hereditary bleeding disorder seen less frequently in the NL population than in Canada or the other reference populations.

“These results show that NL’s unique geography and population distribution led to a genetic drift that increased the prevalence of some rare factor deficiencies,” wrote Dr. Scully and her colleagues.

The investigators plan to continue investigating and reporting genotype and phenotype correlations among their patient population; they also invite broader international collaboration into the prevalence of rare hereditary bleeding disorders in isolated populations.

The authors reported having no conflicts of interest and no outside sources of funding.
 

[email protected]

SOURCE: Scully M-F et al. Transfus Apher Sci. 2018 Dec;57(6):713-6.

Isolated communities in the Canadian province of Newfoundland and Labrador have an “unusual prevalence” of certain hereditary bleeding disorders, a fact attributable to the province’s unique topography and settlement patterns, according to a new study.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The prevalence of hemophilia A in Newfoundland and Labrador (NL) is 2.89 times higher than in the rest of Canada. Deficiencies in Factors V, XI, and XIII are 4.54, 5.44, and 9.22 times more prevalent in NL than mainland Canada, respectively. The study also found more cases than expected of the extremely rare hereditary bleeding disorder, Glanzmann thrombasthenia (n = 4). One case of Bernard-Soulier syndrome was also seen, the investigators reported in Transfusion and Apheresis Science.

“This comparatively high prevalence provides a potential pool of patients for genotype/phenotype research,” wrote Mary-Frances Scully, MD, a hematologist at Memorial University, St. John’s, Nfld., and her associates.

In addition to founding populations of indigenous Innu, Inuit, and Mi’kmaq populations, present-day residents of Canada’s easternmost province trace their lineages to about 28,000 settlers who came from southwest England and southeast Ireland for the area’s rich fisheries, explained Dr. Scully and her coauthors. The overall population density of NL is still very low, at about 1.38 individuals per square kilometer, less than half that of Canada overall and far less than the United States’ 36 per square kilometer.

Overall, the investigators reviewed records for 180 patients with hereditary bleeding disorders who were receiving specialty care in St. John’s. Most (n = 127) had hemophilia A; of these patients, those who had mutation testing primarily had the Val 2016A1 mutation. This was particularly true for patients with mild hemophilia A. More than 73% (83/111 patients) carried this mutation, demonstrating a founder effect, wrote Dr. Scully and her coauthors. The next most common hereditary bleeding disorder was Factor XI deficiency, seen in 29 patients.

Additionally, of the seven patients with Factor XIII deficiency, five were homozygous for the c.691-1 G greater than A mutation.

More males in NL than in global comparator data had Factor V deficiency and Glanzmann thrombasthenia, though Dr. Scully and her colleagues acknowledged that the numbers were low overall.

Coagulation tests performed at the time of diagnosis and before treatment initiation were used, when available, to ascertain the severity of the bleeding disorder. Patients were included whether they were heterozygous or homozygous for hereditary bleeding disorders, so long as their baseline coagulation factor levels were below predetermined cutoff levels.

Comparing the prevalence of all the hereditary bleeding disorders identified in the NL population against mainland Canada and that of four other reference countries – Iran, Ireland, the United Kingdom, and the United States – the increased prevalence rates in NL were highly statistically significant (P less than .0001) for all but the single case of Bernard-Soulier syndrome.

Hemophilia B was the only hereditary bleeding disorder seen less frequently in the NL population than in Canada or the other reference populations.

“These results show that NL’s unique geography and population distribution led to a genetic drift that increased the prevalence of some rare factor deficiencies,” wrote Dr. Scully and her colleagues.

The investigators plan to continue investigating and reporting genotype and phenotype correlations among their patient population; they also invite broader international collaboration into the prevalence of rare hereditary bleeding disorders in isolated populations.

The authors reported having no conflicts of interest and no outside sources of funding.
 

[email protected]

SOURCE: Scully M-F et al. Transfus Apher Sci. 2018 Dec;57(6):713-6.

Isolated communities in the Canadian province of Newfoundland and Labrador have an “unusual prevalence” of certain hereditary bleeding disorders, a fact attributable to the province’s unique topography and settlement patterns, according to a new study.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

The prevalence of hemophilia A in Newfoundland and Labrador (NL) is 2.89 times higher than in the rest of Canada. Deficiencies in Factors V, XI, and XIII are 4.54, 5.44, and 9.22 times more prevalent in NL than mainland Canada, respectively. The study also found more cases than expected of the extremely rare hereditary bleeding disorder, Glanzmann thrombasthenia (n = 4). One case of Bernard-Soulier syndrome was also seen, the investigators reported in Transfusion and Apheresis Science.

“This comparatively high prevalence provides a potential pool of patients for genotype/phenotype research,” wrote Mary-Frances Scully, MD, a hematologist at Memorial University, St. John’s, Nfld., and her associates.

In addition to founding populations of indigenous Innu, Inuit, and Mi’kmaq populations, present-day residents of Canada’s easternmost province trace their lineages to about 28,000 settlers who came from southwest England and southeast Ireland for the area’s rich fisheries, explained Dr. Scully and her coauthors. The overall population density of NL is still very low, at about 1.38 individuals per square kilometer, less than half that of Canada overall and far less than the United States’ 36 per square kilometer.

Overall, the investigators reviewed records for 180 patients with hereditary bleeding disorders who were receiving specialty care in St. John’s. Most (n = 127) had hemophilia A; of these patients, those who had mutation testing primarily had the Val 2016A1 mutation. This was particularly true for patients with mild hemophilia A. More than 73% (83/111 patients) carried this mutation, demonstrating a founder effect, wrote Dr. Scully and her coauthors. The next most common hereditary bleeding disorder was Factor XI deficiency, seen in 29 patients.

Additionally, of the seven patients with Factor XIII deficiency, five were homozygous for the c.691-1 G greater than A mutation.

More males in NL than in global comparator data had Factor V deficiency and Glanzmann thrombasthenia, though Dr. Scully and her colleagues acknowledged that the numbers were low overall.

Coagulation tests performed at the time of diagnosis and before treatment initiation were used, when available, to ascertain the severity of the bleeding disorder. Patients were included whether they were heterozygous or homozygous for hereditary bleeding disorders, so long as their baseline coagulation factor levels were below predetermined cutoff levels.

Comparing the prevalence of all the hereditary bleeding disorders identified in the NL population against mainland Canada and that of four other reference countries – Iran, Ireland, the United Kingdom, and the United States – the increased prevalence rates in NL were highly statistically significant (P less than .0001) for all but the single case of Bernard-Soulier syndrome.

Hemophilia B was the only hereditary bleeding disorder seen less frequently in the NL population than in Canada or the other reference populations.

“These results show that NL’s unique geography and population distribution led to a genetic drift that increased the prevalence of some rare factor deficiencies,” wrote Dr. Scully and her colleagues.

The investigators plan to continue investigating and reporting genotype and phenotype correlations among their patient population; they also invite broader international collaboration into the prevalence of rare hereditary bleeding disorders in isolated populations.

The authors reported having no conflicts of interest and no outside sources of funding.
 

[email protected]

SOURCE: Scully M-F et al. Transfus Apher Sci. 2018 Dec;57(6):713-6.

A small but substantial proportion of patients with hemophilia A develop immediate acting factor VIII inhibitors, the diversity and complexity of which create a diagnostic challenge in the laboratory, according to authors of a recent observational study.

©designer491/Thinkstock

The great majority of the inhibitor-positive patients in the 4,900-patient study had classical FVIII inhibitors, which are typically time- and temperature-dependent and react more slowly in mixing studies, the researchers reported.

By contrast, about 1 in 10 patients demonstrated immediate acting inhibitors, and of those, some had lupus anticoagulants, some had factor VIII inhibitors, and some had both, according to Shrimati Shetty, PhD, of the National Institute of Immunohaematology in Mumbai, India, and her colleagues.

“There is a possibility of misdiagnosis of the patient when they present for the first time,” the researchers wrote. The report is in Thrombosis Research.

In the case of immediate-acting inhibitors, use of ELISA or chromogenic assays alongside lupus anticoagulant testing may help clarify the diagnosis; however, those tests are costly and may not be routinely available.

In the study by Dr. Shetty and her colleagues, patients in India with congenital hemophilia were initially screened for inhibitors. A total of 451 were found to be positive, and of those, 398 were observed to have classical factor VIII inhibitors, while the remaining 53 had immediate-acting inhibitors.

Looking specifically at hemophilia A patients with immediate-acting inhibitors, which comprised 48 of those 53 patients, the majority, or 42 patients, were positive for lupus anticoagulants, and of those, 38 were positive for both lupus anticoagulants and factor VIII inhibitors, while 4 patients were positive for lupus anticoagulants only.

“These are a heterogeneous group of antibodies interfering with all phospholipid dependent reactions,” the researchers wrote.

Properly interpreting factor inhibitor assays is an important step that helps guide later management of inhibitor-positive patients, according to Dr. Shetty and her coauthors.

“Once the patients become positive for inhibitors, they have to opt for alternate modalities of treatment, i.e. bypassing agents like activated prothrombin complex concentrate and activated recombinant factor VII, which are much more expensive,” they wrote.

In light of the diagnostic difficulties they highlighted, Dr. Shetty and her coauthors recommended a “systematic approach” to testing. Both factor VIII and factor IX assays need to be conducted, along with a lupus anticoagulant test. For inhibitor titer, either chromogenic assays or ELISA tests are recommended, they wrote.

Dr. Shetty and her coauthors reported that they had no conflicts of interest.

SOURCE: Patil R et al. Thromb Res. 2018 Dec;172:29-35.

A small but substantial proportion of patients with hemophilia A develop immediate acting factor VIII inhibitors, the diversity and complexity of which create a diagnostic challenge in the laboratory, according to authors of a recent observational study.

©designer491/Thinkstock

The great majority of the inhibitor-positive patients in the 4,900-patient study had classical FVIII inhibitors, which are typically time- and temperature-dependent and react more slowly in mixing studies, the researchers reported.

By contrast, about 1 in 10 patients demonstrated immediate acting inhibitors, and of those, some had lupus anticoagulants, some had factor VIII inhibitors, and some had both, according to Shrimati Shetty, PhD, of the National Institute of Immunohaematology in Mumbai, India, and her colleagues.

“There is a possibility of misdiagnosis of the patient when they present for the first time,” the researchers wrote. The report is in Thrombosis Research.

In the case of immediate-acting inhibitors, use of ELISA or chromogenic assays alongside lupus anticoagulant testing may help clarify the diagnosis; however, those tests are costly and may not be routinely available.

In the study by Dr. Shetty and her colleagues, patients in India with congenital hemophilia were initially screened for inhibitors. A total of 451 were found to be positive, and of those, 398 were observed to have classical factor VIII inhibitors, while the remaining 53 had immediate-acting inhibitors.

Looking specifically at hemophilia A patients with immediate-acting inhibitors, which comprised 48 of those 53 patients, the majority, or 42 patients, were positive for lupus anticoagulants, and of those, 38 were positive for both lupus anticoagulants and factor VIII inhibitors, while 4 patients were positive for lupus anticoagulants only.

“These are a heterogeneous group of antibodies interfering with all phospholipid dependent reactions,” the researchers wrote.

Properly interpreting factor inhibitor assays is an important step that helps guide later management of inhibitor-positive patients, according to Dr. Shetty and her coauthors.

“Once the patients become positive for inhibitors, they have to opt for alternate modalities of treatment, i.e. bypassing agents like activated prothrombin complex concentrate and activated recombinant factor VII, which are much more expensive,” they wrote.

In light of the diagnostic difficulties they highlighted, Dr. Shetty and her coauthors recommended a “systematic approach” to testing. Both factor VIII and factor IX assays need to be conducted, along with a lupus anticoagulant test. For inhibitor titer, either chromogenic assays or ELISA tests are recommended, they wrote.

Dr. Shetty and her coauthors reported that they had no conflicts of interest.

SOURCE: Patil R et al. Thromb Res. 2018 Dec;172:29-35.

A small but substantial proportion of patients with hemophilia A develop immediate acting factor VIII inhibitors, the diversity and complexity of which create a diagnostic challenge in the laboratory, according to authors of a recent observational study.

©designer491/Thinkstock

The great majority of the inhibitor-positive patients in the 4,900-patient study had classical FVIII inhibitors, which are typically time- and temperature-dependent and react more slowly in mixing studies, the researchers reported.

By contrast, about 1 in 10 patients demonstrated immediate acting inhibitors, and of those, some had lupus anticoagulants, some had factor VIII inhibitors, and some had both, according to Shrimati Shetty, PhD, of the National Institute of Immunohaematology in Mumbai, India, and her colleagues.

“There is a possibility of misdiagnosis of the patient when they present for the first time,” the researchers wrote. The report is in Thrombosis Research.

In the case of immediate-acting inhibitors, use of ELISA or chromogenic assays alongside lupus anticoagulant testing may help clarify the diagnosis; however, those tests are costly and may not be routinely available.

In the study by Dr. Shetty and her colleagues, patients in India with congenital hemophilia were initially screened for inhibitors. A total of 451 were found to be positive, and of those, 398 were observed to have classical factor VIII inhibitors, while the remaining 53 had immediate-acting inhibitors.

Looking specifically at hemophilia A patients with immediate-acting inhibitors, which comprised 48 of those 53 patients, the majority, or 42 patients, were positive for lupus anticoagulants, and of those, 38 were positive for both lupus anticoagulants and factor VIII inhibitors, while 4 patients were positive for lupus anticoagulants only.

“These are a heterogeneous group of antibodies interfering with all phospholipid dependent reactions,” the researchers wrote.

Properly interpreting factor inhibitor assays is an important step that helps guide later management of inhibitor-positive patients, according to Dr. Shetty and her coauthors.

“Once the patients become positive for inhibitors, they have to opt for alternate modalities of treatment, i.e. bypassing agents like activated prothrombin complex concentrate and activated recombinant factor VII, which are much more expensive,” they wrote.

In light of the diagnostic difficulties they highlighted, Dr. Shetty and her coauthors recommended a “systematic approach” to testing. Both factor VIII and factor IX assays need to be conducted, along with a lupus anticoagulant test. For inhibitor titer, either chromogenic assays or ELISA tests are recommended, they wrote.

Dr. Shetty and her coauthors reported that they had no conflicts of interest.

SOURCE: Patil R et al. Thromb Res. 2018 Dec;172:29-35.

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).

Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.

The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.

Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.

The FDA previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.

The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.

The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.

Efficacy in inhibitor-experienced patients

In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.

The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).

Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:

• Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
• Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
• Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
• Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
• Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).

Efficacy in inhibitor-naïve patients

In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.

Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:

• Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
• LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
• Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
• Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
• Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
• Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).

Safety in both trials

The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.

The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).

Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.

There was one fatal case of sepsis in a patient treated with ravulizumab.

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).

Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.

The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.

Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.

The FDA previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.

The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.

The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.

Efficacy in inhibitor-experienced patients

In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.

The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).

Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:

• Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
• Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
• Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
• Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
• Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).

Efficacy in inhibitor-naïve patients

In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.

Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:

• Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
• LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
• Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
• Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
• Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
• Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).

Safety in both trials

The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.

The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).

Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.

There was one fatal case of sepsis in a patient treated with ravulizumab.

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) has approved ravulizumab-cwvz (Ultomiris) to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).

Ravulizumab is a long-acting C5 complement inhibitor, administered every 8 weeks, that has been shown to prevent hemolysis.

The prescribing information for ravulizumab includes a boxed warning stating that meningococcal infections/sepsis have occurred in patients treated with the drug, and these adverse effects can become life-threatening or fatal if not recognized and treated early.

Ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy.

The FDA previously granted the application for ravulizumab priority review, and the product received orphan drug designation from the FDA.

The FDA granted the approval of ravulizumab to Alexion Pharmaceuticals.

The FDA’s approval of ravulizumab is based on results from two phase 3 studies, one in patients who had previously received treatment with a complement inhibitor and one in patients who were complement-inhibitor-naïve. Both studies were recently published in Blood.

Efficacy in inhibitor-experienced patients

In one study (NCT03056040), researchers compared ravulizumab administered every 8 weeks to eculizumab administered every 2 weeks in complement-inhibitor-experienced patients.

The trial included 195 PNH patients who were taking eculizumab for more than 6 months. They were randomized to switch to ravulizumab (n=97) or continue on eculizumab (n=98).

Ravulizumab proved noninferior to eculizumab for all endpoints studied (P<0.0006), including:

• Percentage change in lactate dehydrogenase (LDH): difference, 9.21% (95% CI: -0.42 to 18.84; P=0.058 for superiority)
• Breakthrough hemolysis: difference, 5.1 (95% CI: -8.89 to 18.99)
• Change in FACIT-Fatigue score: difference, 1.47 (95% CI: -0.21 to 3.15)
• Transfusion avoidance: difference, 5.5 (95% CI: -4.27 to 15.68)
• Stabilized hemoglobin: difference, 1.4 (95% CI: -10.41 to 13.31).

Efficacy in inhibitor-naïve patients

In another study (NCT02946463), researchers compared ravulizumab and eculizumab in 246 PNH patients who had not previously received a complement inhibitor.

Ravulizumab was noninferior to eculizumab for all endpoints (P<0.0001), including:

• Transfusion avoidance: 73.6% vs 66.1%; difference of 6.8% (95% CI: -4.66 to 18.14)
• LDH normalization: 53.6% vs 49.4%; odds ratio=1.19 (95% CI: 0.80 to 1.77)
• Percent reduction in LDH: -76.8% vs -76.0%; difference of -0.83% (95% CI: -5.21 to 3.56)
• Change in FACIT-Fatigue score: 7.07 vs 6.40; difference of 0.67 (95% CI: -1.21 to 2.55)
• Breakthrough hemolysis: 4.0% vs 10.7%; difference of -6.7% (95% CI: -14.21 to 0.18)
• Stabilized hemoglobin: 68.0% vs 64.5%; difference of 2.9 (95% CI: -8.80 to 14.64).

Safety in both trials

The safety data from both trials included 441 adults who received ravulizumab (n=222) or eculizumab (n=219) for a median of 6 months.

The most frequent adverse events in both arms (ravulizumab and eculizumab, respectively) were upper respiratory tract infection (39% and 39%) and headache (32% and 26%).

Serious adverse events occurred in 15 (6.8%) patients treated with ravulizumab. These events included hyperthermia and pyrexia.

There was one fatal case of sepsis in a patient treated with ravulizumab.

SAN DIEGO – A novel human factor VIII variant shows promise for the treatment of severe hemophilia A, according to preliminary findings from the ongoing Gene Therapy for Hemophilia A (GO-8) phase 1/2 dose-escalation study.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

A single peripheral vein infusion of the factor VIII (FVIII) variant resulted in FVIII activity levels of about 6% versus levels of no more than 1% of normal at study entry in the first four patients, Pratima Chowdary, MD, reported at the annual meeting of the American Society of Hematology.

The variant, known as scAAV2/8-LP1-hFIXco, is being investigated for safety and efficacy in the GO-8 investigator-led, open-label, nonrandomized trial at a low, mid, and high dose (2 x 10¹¹ vector genomes/kg, 6 x 10¹¹ vector genomes/kg, and 2 x 10¹² vector genomes/kg), said Dr. Chowdary, a consultant hematologist at Royal Free Hospital London.

The main study period is 6 months and 15 years of follow-up are offered.

The first patient received the low dose and achieved FVIII of about 6% within 1 week. That level persisted for about 6 weeks when the patient developed a transaminitis, which promptly responded to steroids.

His steady-state FVIII within a few weeks was 7% by one-stage assay and about 3% by chromogenic assay, Dr. Chowdary said.

The remaining patients received the mid dose and also achieved FVIII levels of about 6% within a week. Patient 2 started on prophylactic steroids at week 6, per protocol, and did not experience transaminitis, but also had no increase in FVIII level, compared with the low-dose patient, which may be explained by the potential drug half-life, she noted.

Patient 3 reached a FVIII level of about 30% by week 4. He developed transaminitis at that time, which was about 2 weeks before planned prophylactic drug administration, but the transaminitis was controlled by steroids over a period of about 8-10 weeks.

“His steady-state FVIII level by one stage was 34% and by chromogenic assay was 17%. He has not had any bleeds since his gene transfer and has not required any FVIII concentrate either,” she said.

Patient 4 reached a FVIII level of about 40% by week 4. He was given prophylactic steroids at that time because of the occurrence of transaminitis at week 4 in Patient 3.

The patient developed transaminitis during steroid taper about 4 weeks later, perhaps because of the rapid taper, Dr. Chowdary said, adding that the transaminitis was well controlled with steroids, but follow-up in this patient has only been about 12 weeks.

“The characteristics of FVIII expression in this patient are very similar to the previous patient. ... We suspect he will have a steady-state level of about 30%,” she said. “Again, he’s had no bleeds since his gene transfer and has not required any FVIII concentrate.”

The single infusion of this novel vector was well tolerated in each patient, with no evidence of infusion-related reactions, neutralizing anti-FVIII antibodies, or vector-related adverse events.

“The transgene expression was achieved in all patients and at both vector dosages,” Dr. Chowdary said. “What is very important is that the levels of less than 10% had only a modest impact on the bleed rates and FVIII usage, whereas an expression of more than 10% resulted in zero bleeds and the patient did not require any additional FVIII treatment.”

The data are “encouraging,” she said. “We look forward to escalating the dose in the next patient.”

Dr. Chowdary reported financial relationships with Bayer, CSL Behring, Baxalta, Baxter, Biogen, Freeline, Novo Nordisk, Pfizer, Roche, Shire, and SOBI.

[email protected]

SOURCE: Chowdary P et al. ASH 2018, Abstract 489.

SAN DIEGO – A novel human factor VIII variant shows promise for the treatment of severe hemophilia A, according to preliminary findings from the ongoing Gene Therapy for Hemophilia A (GO-8) phase 1/2 dose-escalation study.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

A single peripheral vein infusion of the factor VIII (FVIII) variant resulted in FVIII activity levels of about 6% versus levels of no more than 1% of normal at study entry in the first four patients, Pratima Chowdary, MD, reported at the annual meeting of the American Society of Hematology.

The variant, known as scAAV2/8-LP1-hFIXco, is being investigated for safety and efficacy in the GO-8 investigator-led, open-label, nonrandomized trial at a low, mid, and high dose (2 x 10¹¹ vector genomes/kg, 6 x 10¹¹ vector genomes/kg, and 2 x 10¹² vector genomes/kg), said Dr. Chowdary, a consultant hematologist at Royal Free Hospital London.

The main study period is 6 months and 15 years of follow-up are offered.

The first patient received the low dose and achieved FVIII of about 6% within 1 week. That level persisted for about 6 weeks when the patient developed a transaminitis, which promptly responded to steroids.

His steady-state FVIII within a few weeks was 7% by one-stage assay and about 3% by chromogenic assay, Dr. Chowdary said.

The remaining patients received the mid dose and also achieved FVIII levels of about 6% within a week. Patient 2 started on prophylactic steroids at week 6, per protocol, and did not experience transaminitis, but also had no increase in FVIII level, compared with the low-dose patient, which may be explained by the potential drug half-life, she noted.

Patient 3 reached a FVIII level of about 30% by week 4. He developed transaminitis at that time, which was about 2 weeks before planned prophylactic drug administration, but the transaminitis was controlled by steroids over a period of about 8-10 weeks.

“His steady-state FVIII level by one stage was 34% and by chromogenic assay was 17%. He has not had any bleeds since his gene transfer and has not required any FVIII concentrate either,” she said.

Patient 4 reached a FVIII level of about 40% by week 4. He was given prophylactic steroids at that time because of the occurrence of transaminitis at week 4 in Patient 3.

The patient developed transaminitis during steroid taper about 4 weeks later, perhaps because of the rapid taper, Dr. Chowdary said, adding that the transaminitis was well controlled with steroids, but follow-up in this patient has only been about 12 weeks.

“The characteristics of FVIII expression in this patient are very similar to the previous patient. ... We suspect he will have a steady-state level of about 30%,” she said. “Again, he’s had no bleeds since his gene transfer and has not required any FVIII concentrate.”

The single infusion of this novel vector was well tolerated in each patient, with no evidence of infusion-related reactions, neutralizing anti-FVIII antibodies, or vector-related adverse events.

“The transgene expression was achieved in all patients and at both vector dosages,” Dr. Chowdary said. “What is very important is that the levels of less than 10% had only a modest impact on the bleed rates and FVIII usage, whereas an expression of more than 10% resulted in zero bleeds and the patient did not require any additional FVIII treatment.”

The data are “encouraging,” she said. “We look forward to escalating the dose in the next patient.”

Dr. Chowdary reported financial relationships with Bayer, CSL Behring, Baxalta, Baxter, Biogen, Freeline, Novo Nordisk, Pfizer, Roche, Shire, and SOBI.

[email protected]

SOURCE: Chowdary P et al. ASH 2018, Abstract 489.

SAN DIEGO – A novel human factor VIII variant shows promise for the treatment of severe hemophilia A, according to preliminary findings from the ongoing Gene Therapy for Hemophilia A (GO-8) phase 1/2 dose-escalation study.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

A single peripheral vein infusion of the factor VIII (FVIII) variant resulted in FVIII activity levels of about 6% versus levels of no more than 1% of normal at study entry in the first four patients, Pratima Chowdary, MD, reported at the annual meeting of the American Society of Hematology.

The variant, known as scAAV2/8-LP1-hFIXco, is being investigated for safety and efficacy in the GO-8 investigator-led, open-label, nonrandomized trial at a low, mid, and high dose (2 x 10¹¹ vector genomes/kg, 6 x 10¹¹ vector genomes/kg, and 2 x 10¹² vector genomes/kg), said Dr. Chowdary, a consultant hematologist at Royal Free Hospital London.

The main study period is 6 months and 15 years of follow-up are offered.

The first patient received the low dose and achieved FVIII of about 6% within 1 week. That level persisted for about 6 weeks when the patient developed a transaminitis, which promptly responded to steroids.

His steady-state FVIII within a few weeks was 7% by one-stage assay and about 3% by chromogenic assay, Dr. Chowdary said.

The remaining patients received the mid dose and also achieved FVIII levels of about 6% within a week. Patient 2 started on prophylactic steroids at week 6, per protocol, and did not experience transaminitis, but also had no increase in FVIII level, compared with the low-dose patient, which may be explained by the potential drug half-life, she noted.

Patient 3 reached a FVIII level of about 30% by week 4. He developed transaminitis at that time, which was about 2 weeks before planned prophylactic drug administration, but the transaminitis was controlled by steroids over a period of about 8-10 weeks.

“His steady-state FVIII level by one stage was 34% and by chromogenic assay was 17%. He has not had any bleeds since his gene transfer and has not required any FVIII concentrate either,” she said.

Patient 4 reached a FVIII level of about 40% by week 4. He was given prophylactic steroids at that time because of the occurrence of transaminitis at week 4 in Patient 3.

The patient developed transaminitis during steroid taper about 4 weeks later, perhaps because of the rapid taper, Dr. Chowdary said, adding that the transaminitis was well controlled with steroids, but follow-up in this patient has only been about 12 weeks.

“The characteristics of FVIII expression in this patient are very similar to the previous patient. ... We suspect he will have a steady-state level of about 30%,” she said. “Again, he’s had no bleeds since his gene transfer and has not required any FVIII concentrate.”

The single infusion of this novel vector was well tolerated in each patient, with no evidence of infusion-related reactions, neutralizing anti-FVIII antibodies, or vector-related adverse events.

“The transgene expression was achieved in all patients and at both vector dosages,” Dr. Chowdary said. “What is very important is that the levels of less than 10% had only a modest impact on the bleed rates and FVIII usage, whereas an expression of more than 10% resulted in zero bleeds and the patient did not require any additional FVIII treatment.”

The data are “encouraging,” she said. “We look forward to escalating the dose in the next patient.”

Dr. Chowdary reported financial relationships with Bayer, CSL Behring, Baxalta, Baxter, Biogen, Freeline, Novo Nordisk, Pfizer, Roche, Shire, and SOBI.

[email protected]

SOURCE: Chowdary P et al. ASH 2018, Abstract 489.

The Food and Drug Administration is asking for comments on its newly released draft guidance on how industry can reduce the risk of bacterial contamination in platelets destined for transfusion, especially those stored at room temperature.

The draft document, “Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion,” will be open for public comment through Feb. 4, 2019.

It is the first update to the policy document since 2016.

In the draft guidance, the FDA recommended three strategies for platelets stored for 5 days from collection. For apheresis platelets and prestorage pools, the FDA suggested an initial primary culture followed by a secondary culture on day 3 or day 4 or an initial primary culture followed by secondary testing with a rapid test. The third strategy – for apheresis platelets – is pathogen reduction alone.

The FDA also outlined three strategies for testing platelets stored for 7 days, all of which apply to apheresis platelets. The methods include an initial primary culture followed by a secondary culture no earlier than day 4, using a device labeled as a safety measure; an initial primary culture followed by a secondary rapid test, labeled as a safety measure; or large volume delayed sampling.

The supply of blood and blood components in the United States is among the safest in the world, FDA Commissioner Scott Gottlieb, MD, said in a statement. The FDA’s continuously updated protocols are intended to keep it that way.

“Blood and blood components are some of the most critical medical products American patients depend upon,” Dr. Gottlieb wrote. “But there remains risk, albeit uncommon, of contamination with infectious diseases, particularly with blood products that are stored at room temperature. While we’ve made great strides in reducing the risk of blood contamination through donor screening and laboratory testing, we continue to support innovations and blood product alternatives that can better keep pace with emerging pathogens and reduce some of the logistical challenges and costs associated with ensuring the safety of blood products.”

Since the 2016 guidance document was issued, new strategies for bacterial detection have become available that could potentially reduce the risk of contamination of platelets and permit extension of platelet dating up to 7 days, including bacterial testing strategies using culture-based devices, rapid bacterial detection devices, and the implementation of pathogen reduction technology.

The recommendations in the draft guidance incorporate ideas put forth during a July 2018 meeting of the agency’s Blood Products Advisory Committee. Committee members were asked to discuss the advantages and disadvantages of various strategies to control the risk of bacterial contamination in platelets, including the scientific evidence and the operational considerations involved. Their comments have been incorporated into the new draft guidance document.

In late November 2018, the FDA held a public workshop to encourage a scientific discussion on a range of pathogen reduction topics, including the development of novel technologies. “The ideal pathogen reduction technology would: be relatively inexpensive, be simple to implement on whole blood, allow treated blood to subsequently be separated into components or alternatively could be performed on apheresis products, inactivate a broad range of pathogens, and would have no adverse effect on product safety or product yield,” the FDA noted in a statement.

[email protected]

The Food and Drug Administration is asking for comments on its newly released draft guidance on how industry can reduce the risk of bacterial contamination in platelets destined for transfusion, especially those stored at room temperature.

The draft document, “Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion,” will be open for public comment through Feb. 4, 2019.

It is the first update to the policy document since 2016.

In the draft guidance, the FDA recommended three strategies for platelets stored for 5 days from collection. For apheresis platelets and prestorage pools, the FDA suggested an initial primary culture followed by a secondary culture on day 3 or day 4 or an initial primary culture followed by secondary testing with a rapid test. The third strategy – for apheresis platelets – is pathogen reduction alone.

The FDA also outlined three strategies for testing platelets stored for 7 days, all of which apply to apheresis platelets. The methods include an initial primary culture followed by a secondary culture no earlier than day 4, using a device labeled as a safety measure; an initial primary culture followed by a secondary rapid test, labeled as a safety measure; or large volume delayed sampling.

The supply of blood and blood components in the United States is among the safest in the world, FDA Commissioner Scott Gottlieb, MD, said in a statement. The FDA’s continuously updated protocols are intended to keep it that way.

“Blood and blood components are some of the most critical medical products American patients depend upon,” Dr. Gottlieb wrote. “But there remains risk, albeit uncommon, of contamination with infectious diseases, particularly with blood products that are stored at room temperature. While we’ve made great strides in reducing the risk of blood contamination through donor screening and laboratory testing, we continue to support innovations and blood product alternatives that can better keep pace with emerging pathogens and reduce some of the logistical challenges and costs associated with ensuring the safety of blood products.”

Since the 2016 guidance document was issued, new strategies for bacterial detection have become available that could potentially reduce the risk of contamination of platelets and permit extension of platelet dating up to 7 days, including bacterial testing strategies using culture-based devices, rapid bacterial detection devices, and the implementation of pathogen reduction technology.

The recommendations in the draft guidance incorporate ideas put forth during a July 2018 meeting of the agency’s Blood Products Advisory Committee. Committee members were asked to discuss the advantages and disadvantages of various strategies to control the risk of bacterial contamination in platelets, including the scientific evidence and the operational considerations involved. Their comments have been incorporated into the new draft guidance document.

In late November 2018, the FDA held a public workshop to encourage a scientific discussion on a range of pathogen reduction topics, including the development of novel technologies. “The ideal pathogen reduction technology would: be relatively inexpensive, be simple to implement on whole blood, allow treated blood to subsequently be separated into components or alternatively could be performed on apheresis products, inactivate a broad range of pathogens, and would have no adverse effect on product safety or product yield,” the FDA noted in a statement.

[email protected]

The Food and Drug Administration is asking for comments on its newly released draft guidance on how industry can reduce the risk of bacterial contamination in platelets destined for transfusion, especially those stored at room temperature.

The draft document, “Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion,” will be open for public comment through Feb. 4, 2019.

It is the first update to the policy document since 2016.

In the draft guidance, the FDA recommended three strategies for platelets stored for 5 days from collection. For apheresis platelets and prestorage pools, the FDA suggested an initial primary culture followed by a secondary culture on day 3 or day 4 or an initial primary culture followed by secondary testing with a rapid test. The third strategy – for apheresis platelets – is pathogen reduction alone.

The FDA also outlined three strategies for testing platelets stored for 7 days, all of which apply to apheresis platelets. The methods include an initial primary culture followed by a secondary culture no earlier than day 4, using a device labeled as a safety measure; an initial primary culture followed by a secondary rapid test, labeled as a safety measure; or large volume delayed sampling.

The supply of blood and blood components in the United States is among the safest in the world, FDA Commissioner Scott Gottlieb, MD, said in a statement. The FDA’s continuously updated protocols are intended to keep it that way.

“Blood and blood components are some of the most critical medical products American patients depend upon,” Dr. Gottlieb wrote. “But there remains risk, albeit uncommon, of contamination with infectious diseases, particularly with blood products that are stored at room temperature. While we’ve made great strides in reducing the risk of blood contamination through donor screening and laboratory testing, we continue to support innovations and blood product alternatives that can better keep pace with emerging pathogens and reduce some of the logistical challenges and costs associated with ensuring the safety of blood products.”

Since the 2016 guidance document was issued, new strategies for bacterial detection have become available that could potentially reduce the risk of contamination of platelets and permit extension of platelet dating up to 7 days, including bacterial testing strategies using culture-based devices, rapid bacterial detection devices, and the implementation of pathogen reduction technology.

The recommendations in the draft guidance incorporate ideas put forth during a July 2018 meeting of the agency’s Blood Products Advisory Committee. Committee members were asked to discuss the advantages and disadvantages of various strategies to control the risk of bacterial contamination in platelets, including the scientific evidence and the operational considerations involved. Their comments have been incorporated into the new draft guidance document.

In late November 2018, the FDA held a public workshop to encourage a scientific discussion on a range of pathogen reduction topics, including the development of novel technologies. “The ideal pathogen reduction technology would: be relatively inexpensive, be simple to implement on whole blood, allow treated blood to subsequently be separated into components or alternatively could be performed on apheresis products, inactivate a broad range of pathogens, and would have no adverse effect on product safety or product yield,” the FDA noted in a statement.

[email protected]

A blood management initiative that reduced RBC transfusions in the hospital did not adversely impact long-term outcomes after discharge, a retrospective analysis of an extensive patient database suggested.

Vlad/Fotolia

Tolerating moderate in-hospital anemia did not increase subsequent RBC use, readmission, or mortality over the next 6 months, according to results of the study, which drew on nearly half a million patient records.

In fact, modest mortality decreases were seen over time for patients with moderate anemia, perhaps because of concomitant initiatives that targeted infectious and circulatory conditions, reported Nareg H. Roubinian, MD, of Kaiser Permanente Northern California in Oakland and the University of California, San Francisco, and coinvestigators.

“These data support the efficacy and safety of practice recommendations to limit red blood cell transfusion in patients with anemia during and after hospitalization,” Dr. Roubinian and colleagues wrote in their report, which appears in the Annals of Internal Medicine.

However, additional studies are needed to guide anemia management, they wrote, particularly since persistent anemia has impacts on quality of life that are “likely substantial” and linked to the severity of that anemia.

Dr. Roubinian and colleagues sought to evaluate the impact of blood management programs – initiated starting in 2010 – that included blood-sparing surgical and medical techniques, increased use of hemostatic and cell salvage agents, and treatment of suboptimal iron stores before surgery.

In previous retrospective cohort studies, the researchers had found that the blood conservation strategies did not impact in-hospital or 30-day mortality rates, which was consistent with short-term safety data from clinical trials and other observational studies.

Their latest report on longer-term outcomes was based on data from Kaiser Permanente Northern California for 445,371 adults who had 801,261 hospitalizations with discharges between 2010 and 2014. In this cohort, moderate anemia (hemoglobin between 7 g/dL and 10 g/dL) at discharge occurred in 119,489 patients (27%) and 187,440 hospitalizations overall (23%).

Over the 2010-2014 period, RBC transfusions decreased by more than 25% in the inpatient and outpatient settings; and in parallel, the prevalence of moderate anemia at hospital discharge increased from 20% to 25%.

However, the risks of subsequent RBC transfusions and rehospitalization after discharge with anemia decreased during the study period, and mortality rates stayed steady or decreased slightly.

Among patients with moderate anemia, the proportion with subsequent RBC transfusions within 6 months decreased from 18.9% in 2010 to 16.8% in 2014 (P less than .001), while the rate of rehospitalization within 6 months decreased from 36.5% to 32.8% over that same time period (P less than .001).

The adjusted 6-month mortality rate likewise decreased from 16.1% to 15.6% (P = .004) over that time period among patients with moderate anemia.

The study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Roubinian and several coauthors reported grants during the conduct of the study from the National Institutes of Health.

SOURCE: Roubinian NH et al. Ann Intern Med. 2018 Dec 18. doi: 10.7326/M17-3253.

A blood management initiative that reduced RBC transfusions in the hospital did not adversely impact long-term outcomes after discharge, a retrospective analysis of an extensive patient database suggested.

Vlad/Fotolia

Tolerating moderate in-hospital anemia did not increase subsequent RBC use, readmission, or mortality over the next 6 months, according to results of the study, which drew on nearly half a million patient records.

In fact, modest mortality decreases were seen over time for patients with moderate anemia, perhaps because of concomitant initiatives that targeted infectious and circulatory conditions, reported Nareg H. Roubinian, MD, of Kaiser Permanente Northern California in Oakland and the University of California, San Francisco, and coinvestigators.

“These data support the efficacy and safety of practice recommendations to limit red blood cell transfusion in patients with anemia during and after hospitalization,” Dr. Roubinian and colleagues wrote in their report, which appears in the Annals of Internal Medicine.

However, additional studies are needed to guide anemia management, they wrote, particularly since persistent anemia has impacts on quality of life that are “likely substantial” and linked to the severity of that anemia.

Dr. Roubinian and colleagues sought to evaluate the impact of blood management programs – initiated starting in 2010 – that included blood-sparing surgical and medical techniques, increased use of hemostatic and cell salvage agents, and treatment of suboptimal iron stores before surgery.

In previous retrospective cohort studies, the researchers had found that the blood conservation strategies did not impact in-hospital or 30-day mortality rates, which was consistent with short-term safety data from clinical trials and other observational studies.

Their latest report on longer-term outcomes was based on data from Kaiser Permanente Northern California for 445,371 adults who had 801,261 hospitalizations with discharges between 2010 and 2014. In this cohort, moderate anemia (hemoglobin between 7 g/dL and 10 g/dL) at discharge occurred in 119,489 patients (27%) and 187,440 hospitalizations overall (23%).

Over the 2010-2014 period, RBC transfusions decreased by more than 25% in the inpatient and outpatient settings; and in parallel, the prevalence of moderate anemia at hospital discharge increased from 20% to 25%.

However, the risks of subsequent RBC transfusions and rehospitalization after discharge with anemia decreased during the study period, and mortality rates stayed steady or decreased slightly.

Among patients with moderate anemia, the proportion with subsequent RBC transfusions within 6 months decreased from 18.9% in 2010 to 16.8% in 2014 (P less than .001), while the rate of rehospitalization within 6 months decreased from 36.5% to 32.8% over that same time period (P less than .001).

The adjusted 6-month mortality rate likewise decreased from 16.1% to 15.6% (P = .004) over that time period among patients with moderate anemia.

The study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Roubinian and several coauthors reported grants during the conduct of the study from the National Institutes of Health.

SOURCE: Roubinian NH et al. Ann Intern Med. 2018 Dec 18. doi: 10.7326/M17-3253.

A blood management initiative that reduced RBC transfusions in the hospital did not adversely impact long-term outcomes after discharge, a retrospective analysis of an extensive patient database suggested.

Vlad/Fotolia

Tolerating moderate in-hospital anemia did not increase subsequent RBC use, readmission, or mortality over the next 6 months, according to results of the study, which drew on nearly half a million patient records.

In fact, modest mortality decreases were seen over time for patients with moderate anemia, perhaps because of concomitant initiatives that targeted infectious and circulatory conditions, reported Nareg H. Roubinian, MD, of Kaiser Permanente Northern California in Oakland and the University of California, San Francisco, and coinvestigators.

“These data support the efficacy and safety of practice recommendations to limit red blood cell transfusion in patients with anemia during and after hospitalization,” Dr. Roubinian and colleagues wrote in their report, which appears in the Annals of Internal Medicine.

However, additional studies are needed to guide anemia management, they wrote, particularly since persistent anemia has impacts on quality of life that are “likely substantial” and linked to the severity of that anemia.

Dr. Roubinian and colleagues sought to evaluate the impact of blood management programs – initiated starting in 2010 – that included blood-sparing surgical and medical techniques, increased use of hemostatic and cell salvage agents, and treatment of suboptimal iron stores before surgery.

In previous retrospective cohort studies, the researchers had found that the blood conservation strategies did not impact in-hospital or 30-day mortality rates, which was consistent with short-term safety data from clinical trials and other observational studies.

Their latest report on longer-term outcomes was based on data from Kaiser Permanente Northern California for 445,371 adults who had 801,261 hospitalizations with discharges between 2010 and 2014. In this cohort, moderate anemia (hemoglobin between 7 g/dL and 10 g/dL) at discharge occurred in 119,489 patients (27%) and 187,440 hospitalizations overall (23%).

Over the 2010-2014 period, RBC transfusions decreased by more than 25% in the inpatient and outpatient settings; and in parallel, the prevalence of moderate anemia at hospital discharge increased from 20% to 25%.

However, the risks of subsequent RBC transfusions and rehospitalization after discharge with anemia decreased during the study period, and mortality rates stayed steady or decreased slightly.

Among patients with moderate anemia, the proportion with subsequent RBC transfusions within 6 months decreased from 18.9% in 2010 to 16.8% in 2014 (P less than .001), while the rate of rehospitalization within 6 months decreased from 36.5% to 32.8% over that same time period (P less than .001).

The adjusted 6-month mortality rate likewise decreased from 16.1% to 15.6% (P = .004) over that time period among patients with moderate anemia.

The study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Roubinian and several coauthors reported grants during the conduct of the study from the National Institutes of Health.

SOURCE: Roubinian NH et al. Ann Intern Med. 2018 Dec 18. doi: 10.7326/M17-3253.

The Food and Drug Administration has approved romiplostim (Nplate) for pediatric patients aged 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The FDA based the approval on two trials in pediatric patients 1 year and older with ITP for at least 6 months duration.

In the first trial, 62 patients were randomized 2:1 to receive romiplostim or placebo; differences in durable platelet response, overall platelet response, and duration of response were all statistically significant, with P values less than .05.

Durable platelet response (at least 6 weekly platelet counts greater than or equal to 50 × 10⁹/L during weeks 18 through 25 of treatment) was achieved in 22 patients (52%) who received romiplostim and 2 (10%) who received placebo. Overall platelet response was achieved in 30 (71%) and 4 (20%) patients, respectively. Patients who received romiplostim had platelet counts greater than or equal to 50 x 10⁹/L for a median of 12 weeks, compared with 1 week in patients who received placebo, the FDA said in a statement.

In the second randomized trial, 22 patients were randomized 3:1 to receive romiplostim or placebo; 15 patients in the romiplostim arm achieved a platelet count greater than or equal to 50 x 10⁹/L for 2 consecutive weeks and an increase in platelet count of greater than or equal to 20 × 10⁹/L above baseline for 2 consecutive weeks during the treatment period (88%; 95% confidence interval, 64%-99%), compared with 0 patients in the placebo arm.

The most common adverse reactions observed in children receiving romiplostim include contusion, upper respiratory tract infection, and oropharyngeal pain.

The recommended initial romiplostim dose for pediatric patients is 1 mcg/kg based on actual body weight and administered as a weekly subcutaneous injection. Dose should be adjusted in increments of 1 mcg/kg until the patient achieves a platelet count greater than or equal to 50 x 10⁹/L. Body weight should be reassessed every 12 weeks, according to the FDA announcement.

[email protected]

The Food and Drug Administration has approved romiplostim (Nplate) for pediatric patients aged 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The FDA based the approval on two trials in pediatric patients 1 year and older with ITP for at least 6 months duration.

In the first trial, 62 patients were randomized 2:1 to receive romiplostim or placebo; differences in durable platelet response, overall platelet response, and duration of response were all statistically significant, with P values less than .05.

Durable platelet response (at least 6 weekly platelet counts greater than or equal to 50 × 10⁹/L during weeks 18 through 25 of treatment) was achieved in 22 patients (52%) who received romiplostim and 2 (10%) who received placebo. Overall platelet response was achieved in 30 (71%) and 4 (20%) patients, respectively. Patients who received romiplostim had platelet counts greater than or equal to 50 x 10⁹/L for a median of 12 weeks, compared with 1 week in patients who received placebo, the FDA said in a statement.

In the second randomized trial, 22 patients were randomized 3:1 to receive romiplostim or placebo; 15 patients in the romiplostim arm achieved a platelet count greater than or equal to 50 x 10⁹/L for 2 consecutive weeks and an increase in platelet count of greater than or equal to 20 × 10⁹/L above baseline for 2 consecutive weeks during the treatment period (88%; 95% confidence interval, 64%-99%), compared with 0 patients in the placebo arm.

The most common adverse reactions observed in children receiving romiplostim include contusion, upper respiratory tract infection, and oropharyngeal pain.

The recommended initial romiplostim dose for pediatric patients is 1 mcg/kg based on actual body weight and administered as a weekly subcutaneous injection. Dose should be adjusted in increments of 1 mcg/kg until the patient achieves a platelet count greater than or equal to 50 x 10⁹/L. Body weight should be reassessed every 12 weeks, according to the FDA announcement.

[email protected]

The Food and Drug Administration has approved romiplostim (Nplate) for pediatric patients aged 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

The FDA based the approval on two trials in pediatric patients 1 year and older with ITP for at least 6 months duration.

In the first trial, 62 patients were randomized 2:1 to receive romiplostim or placebo; differences in durable platelet response, overall platelet response, and duration of response were all statistically significant, with P values less than .05.

Durable platelet response (at least 6 weekly platelet counts greater than or equal to 50 × 10⁹/L during weeks 18 through 25 of treatment) was achieved in 22 patients (52%) who received romiplostim and 2 (10%) who received placebo. Overall platelet response was achieved in 30 (71%) and 4 (20%) patients, respectively. Patients who received romiplostim had platelet counts greater than or equal to 50 x 10⁹/L for a median of 12 weeks, compared with 1 week in patients who received placebo, the FDA said in a statement.

In the second randomized trial, 22 patients were randomized 3:1 to receive romiplostim or placebo; 15 patients in the romiplostim arm achieved a platelet count greater than or equal to 50 x 10⁹/L for 2 consecutive weeks and an increase in platelet count of greater than or equal to 20 × 10⁹/L above baseline for 2 consecutive weeks during the treatment period (88%; 95% confidence interval, 64%-99%), compared with 0 patients in the placebo arm.

The most common adverse reactions observed in children receiving romiplostim include contusion, upper respiratory tract infection, and oropharyngeal pain.

The recommended initial romiplostim dose for pediatric patients is 1 mcg/kg based on actual body weight and administered as a weekly subcutaneous injection. Dose should be adjusted in increments of 1 mcg/kg until the patient achieves a platelet count greater than or equal to 50 x 10⁹/L. Body weight should be reassessed every 12 weeks, according to the FDA announcement.

[email protected]

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim (NPlate®) is now approved by the U.S. Food and Drug Administration (FDA) to treat pediatric patients 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have not responded sufficiently to corticosteroids, immunoglobulins, or splenectomy.

Romiplostim was originally FDA-approved in 2008 to treat adult patients with chronic ITP who had an insufficient response to the same treatments.

Romiplostim is manufactured by Amgen, Inc.

The FDA based its approval on two double-blind, placebo-controlled clinical trials.

NCT01444417

The phase 3 study (NCT01444417) enrolled 62 pediatric patients 1 year and older who had ITP for at least 6 months. They were refractory to or relapsed after at least one prior therapy.

Investigators randomized them 2:1 to receive romiplostim (n=42) or placebo (n=20).

The starting dose was 1 μg/kg weekly for all ages. The dose was titrated up over a 24-week period to a maximum of 10 μg/kg weekly.

Patients were a median age of 9.5 years (range, 3–17), and 57% were female. A little over half (58%) had baseline platelet counts of 20 x 10⁹/L or less, which was similar in both treatment arms.

Eighty-one percent of romiplostim-treated patients had at least two prior ITP therapies, compared with 70% in the placebo group. One patient in each group had undergone splenectomy.

Twenty-two (52%) of the romiplostim-treated patients had durable platelet responses of 50 x 10⁹/L or greater for at least six weekly assessments during weeks 18 through 25 of treatment. Two (10%) patients in the placebo arm achieved durable platelet responses.

Thirty (71%) romiplostim-treated patients achieved an overall platelet response, defined as a durable or transient platelet response. This compared with four (20%) patients in the placebo group.

Romiplostim-treated patients had platelet counts of at least 50 x 10⁹/L for a median of 12 weeks, compared to 1 week for patients in the placebo arm.

All response endpoints were significant at P<0.05.

NCT00515203

The phase 1/2 study (NCT00515203) enrolled 22 patients who had ITP for at least 6 months prior to study enrollment and were relapsed from or refractory to prior treatment.

Investigators randomized the patients 3:1 to romiplostim (n=17) or placebo (n=5).

Patients were a median age of 10 years (range, 1–17), and 27.3% were female.

Approximately 82% of patients had baseline platelet counts of 20 x 10⁹/L or less, which was similar between the treatment arms.

Eighty-eight percent of patients in the romiplostim arm had at least two prior ITP therapies, as did 100% in the placebo group.

Six patients in the romiplostim group and two in the placebo group had undergone splenectomy.

Of the 17 patients treated with romiplostim, 15 (88.2%) achieved a platelet count of 50 x 10⁹/L or great for 2 consecutive weeks.

The same 15 patients also achieved an increase in platelet count of 20 x 10⁹/L or greater above baseline for 2 consecutive weeks during the treatment period.

None of the placebo-treated patients achieved either endpoint.

The adverse events profile in pediatric patients was compiled from the two trials and reflects a median drug exposure of 168 days for 59 patients.

The most common adverse events, occurring in 25% or more of romiplostim-treated patients, were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). These occurred with an incidence at least 5% higher than in the placebo group.

Dosing

The recommended starting dose for pediatric patients is 1 µg/kg based on actual body weight and administered as a weekly subcutaneous injection.

The dose should be adjusted in increments of 1 µg/kg until the patient achieves a platelet count of 50 x 10⁹/L or greater.

The prescribing information recommends reassessing patients’ body weight every 12 weeks. 

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim (NPlate®) is now approved by the U.S. Food and Drug Administration (FDA) to treat pediatric patients 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have not responded sufficiently to corticosteroids, immunoglobulins, or splenectomy.

Romiplostim was originally FDA-approved in 2008 to treat adult patients with chronic ITP who had an insufficient response to the same treatments.

Romiplostim is manufactured by Amgen, Inc.

The FDA based its approval on two double-blind, placebo-controlled clinical trials.

NCT01444417

The phase 3 study (NCT01444417) enrolled 62 pediatric patients 1 year and older who had ITP for at least 6 months. They were refractory to or relapsed after at least one prior therapy.

Investigators randomized them 2:1 to receive romiplostim (n=42) or placebo (n=20).

The starting dose was 1 μg/kg weekly for all ages. The dose was titrated up over a 24-week period to a maximum of 10 μg/kg weekly.

Patients were a median age of 9.5 years (range, 3–17), and 57% were female. A little over half (58%) had baseline platelet counts of 20 x 10⁹/L or less, which was similar in both treatment arms.

Eighty-one percent of romiplostim-treated patients had at least two prior ITP therapies, compared with 70% in the placebo group. One patient in each group had undergone splenectomy.

Twenty-two (52%) of the romiplostim-treated patients had durable platelet responses of 50 x 10⁹/L or greater for at least six weekly assessments during weeks 18 through 25 of treatment. Two (10%) patients in the placebo arm achieved durable platelet responses.

Thirty (71%) romiplostim-treated patients achieved an overall platelet response, defined as a durable or transient platelet response. This compared with four (20%) patients in the placebo group.

Romiplostim-treated patients had platelet counts of at least 50 x 10⁹/L for a median of 12 weeks, compared to 1 week for patients in the placebo arm.

All response endpoints were significant at P<0.05.

NCT00515203

The phase 1/2 study (NCT00515203) enrolled 22 patients who had ITP for at least 6 months prior to study enrollment and were relapsed from or refractory to prior treatment.

Investigators randomized the patients 3:1 to romiplostim (n=17) or placebo (n=5).

Patients were a median age of 10 years (range, 1–17), and 27.3% were female.

Approximately 82% of patients had baseline platelet counts of 20 x 10⁹/L or less, which was similar between the treatment arms.

Eighty-eight percent of patients in the romiplostim arm had at least two prior ITP therapies, as did 100% in the placebo group.

Six patients in the romiplostim group and two in the placebo group had undergone splenectomy.

Of the 17 patients treated with romiplostim, 15 (88.2%) achieved a platelet count of 50 x 10⁹/L or great for 2 consecutive weeks.

The same 15 patients also achieved an increase in platelet count of 20 x 10⁹/L or greater above baseline for 2 consecutive weeks during the treatment period.

None of the placebo-treated patients achieved either endpoint.

The adverse events profile in pediatric patients was compiled from the two trials and reflects a median drug exposure of 168 days for 59 patients.

The most common adverse events, occurring in 25% or more of romiplostim-treated patients, were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). These occurred with an incidence at least 5% higher than in the placebo group.

Dosing

The recommended starting dose for pediatric patients is 1 µg/kg based on actual body weight and administered as a weekly subcutaneous injection.

The dose should be adjusted in increments of 1 µg/kg until the patient achieves a platelet count of 50 x 10⁹/L or greater.

The prescribing information recommends reassessing patients’ body weight every 12 weeks. 

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim (NPlate®) is now approved by the U.S. Food and Drug Administration (FDA) to treat pediatric patients 1 year and older who have had immune thrombocytopenia (ITP) for at least 6 months and have not responded sufficiently to corticosteroids, immunoglobulins, or splenectomy.

Romiplostim was originally FDA-approved in 2008 to treat adult patients with chronic ITP who had an insufficient response to the same treatments.

Romiplostim is manufactured by Amgen, Inc.

The FDA based its approval on two double-blind, placebo-controlled clinical trials.

NCT01444417

The phase 3 study (NCT01444417) enrolled 62 pediatric patients 1 year and older who had ITP for at least 6 months. They were refractory to or relapsed after at least one prior therapy.

Investigators randomized them 2:1 to receive romiplostim (n=42) or placebo (n=20).

The starting dose was 1 μg/kg weekly for all ages. The dose was titrated up over a 24-week period to a maximum of 10 μg/kg weekly.

Patients were a median age of 9.5 years (range, 3–17), and 57% were female. A little over half (58%) had baseline platelet counts of 20 x 10⁹/L or less, which was similar in both treatment arms.

Eighty-one percent of romiplostim-treated patients had at least two prior ITP therapies, compared with 70% in the placebo group. One patient in each group had undergone splenectomy.

Twenty-two (52%) of the romiplostim-treated patients had durable platelet responses of 50 x 10⁹/L or greater for at least six weekly assessments during weeks 18 through 25 of treatment. Two (10%) patients in the placebo arm achieved durable platelet responses.

Thirty (71%) romiplostim-treated patients achieved an overall platelet response, defined as a durable or transient platelet response. This compared with four (20%) patients in the placebo group.

Romiplostim-treated patients had platelet counts of at least 50 x 10⁹/L for a median of 12 weeks, compared to 1 week for patients in the placebo arm.

All response endpoints were significant at P<0.05.

NCT00515203

The phase 1/2 study (NCT00515203) enrolled 22 patients who had ITP for at least 6 months prior to study enrollment and were relapsed from or refractory to prior treatment.

Investigators randomized the patients 3:1 to romiplostim (n=17) or placebo (n=5).

Patients were a median age of 10 years (range, 1–17), and 27.3% were female.

Approximately 82% of patients had baseline platelet counts of 20 x 10⁹/L or less, which was similar between the treatment arms.

Eighty-eight percent of patients in the romiplostim arm had at least two prior ITP therapies, as did 100% in the placebo group.

Six patients in the romiplostim group and two in the placebo group had undergone splenectomy.

Of the 17 patients treated with romiplostim, 15 (88.2%) achieved a platelet count of 50 x 10⁹/L or great for 2 consecutive weeks.

The same 15 patients also achieved an increase in platelet count of 20 x 10⁹/L or greater above baseline for 2 consecutive weeks during the treatment period.

None of the placebo-treated patients achieved either endpoint.

The adverse events profile in pediatric patients was compiled from the two trials and reflects a median drug exposure of 168 days for 59 patients.

The most common adverse events, occurring in 25% or more of romiplostim-treated patients, were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%). These occurred with an incidence at least 5% higher than in the placebo group.

Dosing

The recommended starting dose for pediatric patients is 1 µg/kg based on actual body weight and administered as a weekly subcutaneous injection.

The dose should be adjusted in increments of 1 µg/kg until the patient achieves a platelet count of 50 x 10⁹/L or greater.

The prescribing information recommends reassessing patients’ body weight every 12 weeks. 

SAN DIEGO – An inexpensive, rapid, and easy-to-use blood test was more than 99% accurate in detecting sickle cell disease in young children in sub-Saharan Africa, according to research reported at the annual meeting of the American Society of Hematology.

Courtesy American Society of Hematology

The test, called HemoTypeSC, uses monoclonal antibodies to detect hemoglobins A, S, and C in a drop of whole blood, said investigator Erik Serrao, PhD, of Silver Lake Research in Azusa, Calif.

Findings from the diagnostic accuracy trial, which included 1,000 children in Uganda, suggest that the immunoassay is a promising tool to enable newborn and general population screening in resource-constrained regions of high prevalence, such as Africa and India.

“Early screening plus treatment plus counseling equals saving millions of lives over the coming decades, and we believe HemoTypeSC can form an integral part of the initial part of this equation,” Dr. Serrao said during a late-breaking abstract session at the meeting.

Each test kit costs less than $2 to the end user; requires no electricity, special equipment, or training; and delivers results in about 10 minutes, he added.


Of all the late-breaking abstracts at ASH this year, the study by Dr. Serrao and his colleagues is the one with the potential to save the most lives, said Mark Crowther, MD, of McMaster University, Hamilton, Ont.

“The ability to diagnose sickle cell disease early and intervene early will result in potentially thousands of infants, who would otherwise die in infancy or early childhood, surviving into adulthood,” Dr. Crowther said during a press briefing.

Using current gold standard methods for diagnosing sickle cell disease is, at minimum, challenging and “frankly impossible” in many low-resource settings, because of the cost and the requirement for sophisticated equipment and reliable electricity, Dr. Crowther added.

In the study, investigators compared results of the HemoTypeSC test with hemoglobin electrophoresis for detection of the phenotypes HbAA (normal), HbAS (sickle cell trait), and HbSS (sickle cell disease). They compared these two testing methods in 1,000 children between the ages of 1 month and 5 years who were prospectively recruited from hospital wards and outpatient clinics in Uganda.

The immunoassay had an overall accuracy of 99.8%, correctly identifying 998 of 1,000 phenotypes as initially determined by electrophoresis. Specifically, the test correctly identified 100% of the 720 HbAA specimens, 100% of 182 HbAS specimens, and 98% of HbSS, or 96 of 98 specimens, leaving just 2 discordant samples, both of which HemoTypeSC identified as HbAS.

Investigators subsequently discovered that both of the individuals with the discordant samples had previously been diagnosed with sickle cell disease and had received recent transfusions. Both cases were subsequently confirmed as HbSS in review of previous diagnostic result reports, bringing the accuracy rate up to 100% in a secondary analysis also reported at the meeting.

Although this particular study excluded newborns, a different study of the immunoassay, recently published in the American Journal of Hematology, demonstrated 100% accuracy across multiple phenotypes in the setting of newborn screening (2018 Oct 5. doi: 10.1002/ajh.25305).

Sickle cell disease screening programs have been projected to be cost effective in Africa, Dr. Serrano said, and could even save money for governments over time as budgets are reallocated toward screening, with less money needed for treatment of patients presenting with severe complications in hospitals.

Dr. Serrao reported that he is an employee of Silver Lake Research, which funded the study, approved the study design, and donated HemoTypeSC tests.

On March 11, 2019, the editors of Blood, an ASH journal, retracted the abstract for this study. The second listed author on the abstract said that it was submitted without his consent or approval. The retraction makes no statement on the underlying science of the study, the editors noted.

This article was updated on 3/14/2019.

SOURCE: Serrao E et al. ASH 2018, Abstract LBA-3.

SAN DIEGO – An inexpensive, rapid, and easy-to-use blood test was more than 99% accurate in detecting sickle cell disease in young children in sub-Saharan Africa, according to research reported at the annual meeting of the American Society of Hematology.

Courtesy American Society of Hematology

The test, called HemoTypeSC, uses monoclonal antibodies to detect hemoglobins A, S, and C in a drop of whole blood, said investigator Erik Serrao, PhD, of Silver Lake Research in Azusa, Calif.

Findings from the diagnostic accuracy trial, which included 1,000 children in Uganda, suggest that the immunoassay is a promising tool to enable newborn and general population screening in resource-constrained regions of high prevalence, such as Africa and India.

“Early screening plus treatment plus counseling equals saving millions of lives over the coming decades, and we believe HemoTypeSC can form an integral part of the initial part of this equation,” Dr. Serrao said during a late-breaking abstract session at the meeting.

Each test kit costs less than $2 to the end user; requires no electricity, special equipment, or training; and delivers results in about 10 minutes, he added.


Of all the late-breaking abstracts at ASH this year, the study by Dr. Serrao and his colleagues is the one with the potential to save the most lives, said Mark Crowther, MD, of McMaster University, Hamilton, Ont.

“The ability to diagnose sickle cell disease early and intervene early will result in potentially thousands of infants, who would otherwise die in infancy or early childhood, surviving into adulthood,” Dr. Crowther said during a press briefing.

Using current gold standard methods for diagnosing sickle cell disease is, at minimum, challenging and “frankly impossible” in many low-resource settings, because of the cost and the requirement for sophisticated equipment and reliable electricity, Dr. Crowther added.

In the study, investigators compared results of the HemoTypeSC test with hemoglobin electrophoresis for detection of the phenotypes HbAA (normal), HbAS (sickle cell trait), and HbSS (sickle cell disease). They compared these two testing methods in 1,000 children between the ages of 1 month and 5 years who were prospectively recruited from hospital wards and outpatient clinics in Uganda.

The immunoassay had an overall accuracy of 99.8%, correctly identifying 998 of 1,000 phenotypes as initially determined by electrophoresis. Specifically, the test correctly identified 100% of the 720 HbAA specimens, 100% of 182 HbAS specimens, and 98% of HbSS, or 96 of 98 specimens, leaving just 2 discordant samples, both of which HemoTypeSC identified as HbAS.

Investigators subsequently discovered that both of the individuals with the discordant samples had previously been diagnosed with sickle cell disease and had received recent transfusions. Both cases were subsequently confirmed as HbSS in review of previous diagnostic result reports, bringing the accuracy rate up to 100% in a secondary analysis also reported at the meeting.

Although this particular study excluded newborns, a different study of the immunoassay, recently published in the American Journal of Hematology, demonstrated 100% accuracy across multiple phenotypes in the setting of newborn screening (2018 Oct 5. doi: 10.1002/ajh.25305).

Sickle cell disease screening programs have been projected to be cost effective in Africa, Dr. Serrano said, and could even save money for governments over time as budgets are reallocated toward screening, with less money needed for treatment of patients presenting with severe complications in hospitals.

Dr. Serrao reported that he is an employee of Silver Lake Research, which funded the study, approved the study design, and donated HemoTypeSC tests.

On March 11, 2019, the editors of Blood, an ASH journal, retracted the abstract for this study. The second listed author on the abstract said that it was submitted without his consent or approval. The retraction makes no statement on the underlying science of the study, the editors noted.

This article was updated on 3/14/2019.

SOURCE: Serrao E et al. ASH 2018, Abstract LBA-3.

SAN DIEGO – An inexpensive, rapid, and easy-to-use blood test was more than 99% accurate in detecting sickle cell disease in young children in sub-Saharan Africa, according to research reported at the annual meeting of the American Society of Hematology.

Courtesy American Society of Hematology

The test, called HemoTypeSC, uses monoclonal antibodies to detect hemoglobins A, S, and C in a drop of whole blood, said investigator Erik Serrao, PhD, of Silver Lake Research in Azusa, Calif.

Findings from the diagnostic accuracy trial, which included 1,000 children in Uganda, suggest that the immunoassay is a promising tool to enable newborn and general population screening in resource-constrained regions of high prevalence, such as Africa and India.

“Early screening plus treatment plus counseling equals saving millions of lives over the coming decades, and we believe HemoTypeSC can form an integral part of the initial part of this equation,” Dr. Serrao said during a late-breaking abstract session at the meeting.

Each test kit costs less than $2 to the end user; requires no electricity, special equipment, or training; and delivers results in about 10 minutes, he added.


Of all the late-breaking abstracts at ASH this year, the study by Dr. Serrao and his colleagues is the one with the potential to save the most lives, said Mark Crowther, MD, of McMaster University, Hamilton, Ont.

“The ability to diagnose sickle cell disease early and intervene early will result in potentially thousands of infants, who would otherwise die in infancy or early childhood, surviving into adulthood,” Dr. Crowther said during a press briefing.

Using current gold standard methods for diagnosing sickle cell disease is, at minimum, challenging and “frankly impossible” in many low-resource settings, because of the cost and the requirement for sophisticated equipment and reliable electricity, Dr. Crowther added.

In the study, investigators compared results of the HemoTypeSC test with hemoglobin electrophoresis for detection of the phenotypes HbAA (normal), HbAS (sickle cell trait), and HbSS (sickle cell disease). They compared these two testing methods in 1,000 children between the ages of 1 month and 5 years who were prospectively recruited from hospital wards and outpatient clinics in Uganda.

The immunoassay had an overall accuracy of 99.8%, correctly identifying 998 of 1,000 phenotypes as initially determined by electrophoresis. Specifically, the test correctly identified 100% of the 720 HbAA specimens, 100% of 182 HbAS specimens, and 98% of HbSS, or 96 of 98 specimens, leaving just 2 discordant samples, both of which HemoTypeSC identified as HbAS.

Investigators subsequently discovered that both of the individuals with the discordant samples had previously been diagnosed with sickle cell disease and had received recent transfusions. Both cases were subsequently confirmed as HbSS in review of previous diagnostic result reports, bringing the accuracy rate up to 100% in a secondary analysis also reported at the meeting.

Although this particular study excluded newborns, a different study of the immunoassay, recently published in the American Journal of Hematology, demonstrated 100% accuracy across multiple phenotypes in the setting of newborn screening (2018 Oct 5. doi: 10.1002/ajh.25305).

Sickle cell disease screening programs have been projected to be cost effective in Africa, Dr. Serrano said, and could even save money for governments over time as budgets are reallocated toward screening, with less money needed for treatment of patients presenting with severe complications in hospitals.

Dr. Serrao reported that he is an employee of Silver Lake Research, which funded the study, approved the study design, and donated HemoTypeSC tests.

On March 11, 2019, the editors of Blood, an ASH journal, retracted the abstract for this study. The second listed author on the abstract said that it was submitted without his consent or approval. The retraction makes no statement on the underlying science of the study, the editors noted.

This article was updated on 3/14/2019.

SOURCE: Serrao E et al. ASH 2018, Abstract LBA-3.

SAN DIEGO – Therapeutic expression of factor IX remains stable with no late toxicities occurring at up to 8.6 years after a single infusion of a novel gene therapy in patients with severe hemophilia B, according to interim follow-up data from a phase 1/2 dose-escalation study.

The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.

However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.

At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 10¹¹, 6 x 10¹¹, or 2 x 10¹² vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.

“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.

The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.

“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”

Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”

Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.

“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.

Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.

“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.

Dr. Reiss reported having no relevant disclosures

[email protected]

SOURCE: Reiss UM et al. ASH 2018, Abstract 491.

SAN DIEGO – Therapeutic expression of factor IX remains stable with no late toxicities occurring at up to 8.6 years after a single infusion of a novel gene therapy in patients with severe hemophilia B, according to interim follow-up data from a phase 1/2 dose-escalation study.

The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.

However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.

At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 10¹¹, 6 x 10¹¹, or 2 x 10¹² vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.

“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.

The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.

“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”

Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”

Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.

“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.

Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.

“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.

Dr. Reiss reported having no relevant disclosures

[email protected]

SOURCE: Reiss UM et al. ASH 2018, Abstract 491.

SAN DIEGO – Therapeutic expression of factor IX remains stable with no late toxicities occurring at up to 8.6 years after a single infusion of a novel gene therapy in patients with severe hemophilia B, according to interim follow-up data from a phase 1/2 dose-escalation study.

The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.

However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.

At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 10¹¹, 6 x 10¹¹, or 2 x 10¹² vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.

“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.

The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.

“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”

Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”

Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.

“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.

Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.

“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.

Dr. Reiss reported having no relevant disclosures

[email protected]

SOURCE: Reiss UM et al. ASH 2018, Abstract 491.