Bleeding Disorders

Concerns may be unfounded for risks of earlier-onset cardiovascular disease in men with hemophilia A, according to investigators.

Cardiovascular comorbidities between groups were generally comparable, regardless of hemophilia A status, reported lead author Thomas J. Humphries, MD, of Bayer, and his colleagues.

“To date, there have been conflicting data in the literature regarding the risks of [cardiovascular] comorbidities in patients with hemophilia A, compared with the general population,” the investigators wrote in Advances in Medical Sciences. “Some studies have reported lower mortality from [cardiovascular] diseases and/or decreased atherogenesis in patients with hemophilia … conversely, other reports indicate comparable or higher [cardiovascular] comorbidities in patients with hemophilia, compared with the general population.”

In two previous commercial database reviews conducted by Dr. Humphries and his colleagues, cardiovascular disease appeared to occur more commonly and at a younger age in men with hemophilia A. More concerning, patients aged under 40 years showed elevated incidence of stroke and thrombosis. The authors sought to clarify these findings in the present study.

The retrospective chart review involved 74 men with hemophilia A and 222 men without the condition, matched by study year, payer type, race, and age. Patients presented at any of 31 medical facilities within the Henry Ford Health System in Detroit. Diagnoses were made between Jan. 1, 1995, and Dec. 31, 2014.

For the most part there were no significant differences in cardiovascular disease prevalence between the two cohorts. Rates of hypertension, obesity, coronary artery disease, heart failure, stroke, venous and arterial thrombosis, ventricular arrhythmias, atrial fibrillation, and chronic renal disease were numerically higher in the control group, but those differences were not statistically significant. There were significantly higher prevalence rates for diabetes (P = .0108) and hyperlipidemia (P = .0001) in the control group versus patients with hemophilia A.

The investigators pointed out that meaningful statistical differences using standardized differences were not reached for venous and arterial thrombosis and atrial fibrillation.

“It is worth noting that in the hemophilia A group, hypertension appeared first in the 18- to 29-year age group, as did venous thrombosis,” the investigators wrote, suggesting that monitoring, starting in the late teens, may be warranted.

The investigators also noted multiple study limitations, notably the small sample size, compared with commercial databases that were reviewed in previous studies. Additionally, the severity of disease was unknown for some of the hemophilia A patients and the study only followed patients for 1 year.

“The results of this retrospective chart review did not confirm diffuse statistically significant differences in [cardiovascular] comorbidities and their earlier onset in hemophilia A versus controls,” the investigators concluded.

The study was funded by Bayer. Three of the authors were employed by Bayer when the study was conducted. Other authors reported employment with Xcenda and the Henry Ford Health System and research funding from Xcenda.

SOURCE: Humphries TJ et al. Adv Med Sci. 2018;63(2):329-33.

Concerns may be unfounded for risks of earlier-onset cardiovascular disease in men with hemophilia A, according to investigators.

Cardiovascular comorbidities between groups were generally comparable, regardless of hemophilia A status, reported lead author Thomas J. Humphries, MD, of Bayer, and his colleagues.

“To date, there have been conflicting data in the literature regarding the risks of [cardiovascular] comorbidities in patients with hemophilia A, compared with the general population,” the investigators wrote in Advances in Medical Sciences. “Some studies have reported lower mortality from [cardiovascular] diseases and/or decreased atherogenesis in patients with hemophilia … conversely, other reports indicate comparable or higher [cardiovascular] comorbidities in patients with hemophilia, compared with the general population.”

In two previous commercial database reviews conducted by Dr. Humphries and his colleagues, cardiovascular disease appeared to occur more commonly and at a younger age in men with hemophilia A. More concerning, patients aged under 40 years showed elevated incidence of stroke and thrombosis. The authors sought to clarify these findings in the present study.

The retrospective chart review involved 74 men with hemophilia A and 222 men without the condition, matched by study year, payer type, race, and age. Patients presented at any of 31 medical facilities within the Henry Ford Health System in Detroit. Diagnoses were made between Jan. 1, 1995, and Dec. 31, 2014.

For the most part there were no significant differences in cardiovascular disease prevalence between the two cohorts. Rates of hypertension, obesity, coronary artery disease, heart failure, stroke, venous and arterial thrombosis, ventricular arrhythmias, atrial fibrillation, and chronic renal disease were numerically higher in the control group, but those differences were not statistically significant. There were significantly higher prevalence rates for diabetes (P = .0108) and hyperlipidemia (P = .0001) in the control group versus patients with hemophilia A.

The investigators pointed out that meaningful statistical differences using standardized differences were not reached for venous and arterial thrombosis and atrial fibrillation.

“It is worth noting that in the hemophilia A group, hypertension appeared first in the 18- to 29-year age group, as did venous thrombosis,” the investigators wrote, suggesting that monitoring, starting in the late teens, may be warranted.

The investigators also noted multiple study limitations, notably the small sample size, compared with commercial databases that were reviewed in previous studies. Additionally, the severity of disease was unknown for some of the hemophilia A patients and the study only followed patients for 1 year.

“The results of this retrospective chart review did not confirm diffuse statistically significant differences in [cardiovascular] comorbidities and their earlier onset in hemophilia A versus controls,” the investigators concluded.

The study was funded by Bayer. Three of the authors were employed by Bayer when the study was conducted. Other authors reported employment with Xcenda and the Henry Ford Health System and research funding from Xcenda.

SOURCE: Humphries TJ et al. Adv Med Sci. 2018;63(2):329-33.

Concerns may be unfounded for risks of earlier-onset cardiovascular disease in men with hemophilia A, according to investigators.

Cardiovascular comorbidities between groups were generally comparable, regardless of hemophilia A status, reported lead author Thomas J. Humphries, MD, of Bayer, and his colleagues.

“To date, there have been conflicting data in the literature regarding the risks of [cardiovascular] comorbidities in patients with hemophilia A, compared with the general population,” the investigators wrote in Advances in Medical Sciences. “Some studies have reported lower mortality from [cardiovascular] diseases and/or decreased atherogenesis in patients with hemophilia … conversely, other reports indicate comparable or higher [cardiovascular] comorbidities in patients with hemophilia, compared with the general population.”

In two previous commercial database reviews conducted by Dr. Humphries and his colleagues, cardiovascular disease appeared to occur more commonly and at a younger age in men with hemophilia A. More concerning, patients aged under 40 years showed elevated incidence of stroke and thrombosis. The authors sought to clarify these findings in the present study.

The retrospective chart review involved 74 men with hemophilia A and 222 men without the condition, matched by study year, payer type, race, and age. Patients presented at any of 31 medical facilities within the Henry Ford Health System in Detroit. Diagnoses were made between Jan. 1, 1995, and Dec. 31, 2014.

For the most part there were no significant differences in cardiovascular disease prevalence between the two cohorts. Rates of hypertension, obesity, coronary artery disease, heart failure, stroke, venous and arterial thrombosis, ventricular arrhythmias, atrial fibrillation, and chronic renal disease were numerically higher in the control group, but those differences were not statistically significant. There were significantly higher prevalence rates for diabetes (P = .0108) and hyperlipidemia (P = .0001) in the control group versus patients with hemophilia A.

The investigators pointed out that meaningful statistical differences using standardized differences were not reached for venous and arterial thrombosis and atrial fibrillation.

“It is worth noting that in the hemophilia A group, hypertension appeared first in the 18- to 29-year age group, as did venous thrombosis,” the investigators wrote, suggesting that monitoring, starting in the late teens, may be warranted.

The investigators also noted multiple study limitations, notably the small sample size, compared with commercial databases that were reviewed in previous studies. Additionally, the severity of disease was unknown for some of the hemophilia A patients and the study only followed patients for 1 year.

“The results of this retrospective chart review did not confirm diffuse statistically significant differences in [cardiovascular] comorbidities and their earlier onset in hemophilia A versus controls,” the investigators concluded.

The study was funded by Bayer. Three of the authors were employed by Bayer when the study was conducted. Other authors reported employment with Xcenda and the Henry Ford Health System and research funding from Xcenda.

SOURCE: Humphries TJ et al. Adv Med Sci. 2018;63(2):329-33.

Photo from Bayer

Health Canada has approved Jivi^® (antihemophilic factor [recombinant, B-domain deleted, PEGylated]) for use in patients with hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate developed by Bayer.

Health Canada has approved Jivi for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in previously treated hemophilia A patients age 12 and older.

Jivi is also approved for the control and prevention of episodic bleeding and for perioperative management of bleeding.

The recommended initial dosing for Jivi as prophylaxis is twice weekly, with the ability to dose every 5 days and further adjust dosing based on bleeding episodes.

Health Canada’s approval of Jivi is based on the PROTECT VIII trial. Results from this trial are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A. In part B, Jivi was used for perioperative management of bleeding.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

Health Canada has approved Jivi^® (antihemophilic factor [recombinant, B-domain deleted, PEGylated]) for use in patients with hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate developed by Bayer.

Health Canada has approved Jivi for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in previously treated hemophilia A patients age 12 and older.

Jivi is also approved for the control and prevention of episodic bleeding and for perioperative management of bleeding.

The recommended initial dosing for Jivi as prophylaxis is twice weekly, with the ability to dose every 5 days and further adjust dosing based on bleeding episodes.

Health Canada’s approval of Jivi is based on the PROTECT VIII trial. Results from this trial are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A. In part B, Jivi was used for perioperative management of bleeding.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

Health Canada has approved Jivi^® (antihemophilic factor [recombinant, B-domain deleted, PEGylated]) for use in patients with hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate developed by Bayer.

Health Canada has approved Jivi for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in previously treated hemophilia A patients age 12 and older.

Jivi is also approved for the control and prevention of episodic bleeding and for perioperative management of bleeding.

The recommended initial dosing for Jivi as prophylaxis is twice weekly, with the ability to dose every 5 days and further adjust dosing based on bleeding episodes.

Health Canada’s approval of Jivi is based on the PROTECT VIII trial. Results from this trial are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A. In part B, Jivi was used for perioperative management of bleeding.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Single-nucleotide polymorphisms linked to increased bleeding risk have been identified in patients of African descent taking warfarin, investigators have reported.

Four single-nucleotide polymorphisms (SNPs) were associated with increased major bleeding risk in African Americans at an international normalized ratio (INR) of less than 4, according to results of their preliminary, retrospective study.

The preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University, Chicago, and her coauthors.

“Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population,” Dr. Perera and her colleagues wrote in JAMA.

Most prior studies looking at warfarin-related bleeding risk have included predominantly white patients and don’t account for differences in warfarin responsiveness between ethnic groups, they wrote.

Moreover, bleeding-associated SNPs have been identified, but in populations of European ancestry, they added.

The report covered results of a discovery cohort based on African American patients from a genome-wide study conducted at the University of Chicago, and a replication cohort based on patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her coinvestigators found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding, including rs115112393, rs16871327, rs78132896, and rs114504854. In particular, the rs78132896 SNP was found in 35.5% of cases (n = 11) and just 4.9% of controls (n = 9), with an odds ratio of 8.31 (95% confidence interval, 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. That SNP was similarly found in 35.0% of cases (n = 14) and 4.8% of controls (n = 7), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” said the investigators, who reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription, results of gene assay analyses further showed.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” they said.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

SOURCE: Perera MA et al. JAMA. 2018 Oct 23. doi: 10.1001/jama.2018.14955.

Single-nucleotide polymorphisms linked to increased bleeding risk have been identified in patients of African descent taking warfarin, investigators have reported.

Four single-nucleotide polymorphisms (SNPs) were associated with increased major bleeding risk in African Americans at an international normalized ratio (INR) of less than 4, according to results of their preliminary, retrospective study.

The preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University, Chicago, and her coauthors.

“Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population,” Dr. Perera and her colleagues wrote in JAMA.

Most prior studies looking at warfarin-related bleeding risk have included predominantly white patients and don’t account for differences in warfarin responsiveness between ethnic groups, they wrote.

Moreover, bleeding-associated SNPs have been identified, but in populations of European ancestry, they added.

The report covered results of a discovery cohort based on African American patients from a genome-wide study conducted at the University of Chicago, and a replication cohort based on patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her coinvestigators found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding, including rs115112393, rs16871327, rs78132896, and rs114504854. In particular, the rs78132896 SNP was found in 35.5% of cases (n = 11) and just 4.9% of controls (n = 9), with an odds ratio of 8.31 (95% confidence interval, 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. That SNP was similarly found in 35.0% of cases (n = 14) and 4.8% of controls (n = 7), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” said the investigators, who reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription, results of gene assay analyses further showed.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” they said.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

SOURCE: Perera MA et al. JAMA. 2018 Oct 23. doi: 10.1001/jama.2018.14955.

Single-nucleotide polymorphisms linked to increased bleeding risk have been identified in patients of African descent taking warfarin, investigators have reported.

Four single-nucleotide polymorphisms (SNPs) were associated with increased major bleeding risk in African Americans at an international normalized ratio (INR) of less than 4, according to results of their preliminary, retrospective study.

The preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University, Chicago, and her coauthors.

“Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population,” Dr. Perera and her colleagues wrote in JAMA.

Most prior studies looking at warfarin-related bleeding risk have included predominantly white patients and don’t account for differences in warfarin responsiveness between ethnic groups, they wrote.

Moreover, bleeding-associated SNPs have been identified, but in populations of European ancestry, they added.

The report covered results of a discovery cohort based on African American patients from a genome-wide study conducted at the University of Chicago, and a replication cohort based on patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her coinvestigators found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding, including rs115112393, rs16871327, rs78132896, and rs114504854. In particular, the rs78132896 SNP was found in 35.5% of cases (n = 11) and just 4.9% of controls (n = 9), with an odds ratio of 8.31 (95% confidence interval, 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. That SNP was similarly found in 35.0% of cases (n = 14) and 4.8% of controls (n = 7), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” said the investigators, who reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription, results of gene assay analyses further showed.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” they said.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

SOURCE: Perera MA et al. JAMA. 2018 Oct 23. doi: 10.1001/jama.2018.14955.

Image from Graham Beards

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to PRN1008 for the treatment of patients with immune thrombocytopenia (ITP).

PRN1008 is an oral, reversible, covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed by Principia Biopharma, Inc.

Principia is conducting a phase 1/2 trial (NCT03395210) to evaluate the safety and efficacy of PRN1008 in patients with ITP.

Results of preclinical research with PRN1008 in ITP were presented at the 2017 ASH Annual Meeting.

There, researchers reported that PRN1008 significantly reduced platelet loss in a mouse model of ITP.

The team found the BTK inhibitor could diminish platelet loss in two ways:

• By reducing platelet destruction via inhibition of autoantibody/FcγR signaling in splenic macrophages
• By reducing autoantibody generation through inhibition of B-cell activation and maturation.

The researchers also assessed the effects of PRN1008 and ibrutinib on platelet function in samples from healthy volunteers and ITP patients.

Samples were treated with one of the two BTK inhibitors, and platelet aggregation was induced by platelet agonists.

Unlike ibrutinib, PRN1008 did not impact platelet aggregation in healthy volunteer or ITP patient samples.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image from Graham Beards

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to PRN1008 for the treatment of patients with immune thrombocytopenia (ITP).

PRN1008 is an oral, reversible, covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed by Principia Biopharma, Inc.

Principia is conducting a phase 1/2 trial (NCT03395210) to evaluate the safety and efficacy of PRN1008 in patients with ITP.

Results of preclinical research with PRN1008 in ITP were presented at the 2017 ASH Annual Meeting.

There, researchers reported that PRN1008 significantly reduced platelet loss in a mouse model of ITP.

The team found the BTK inhibitor could diminish platelet loss in two ways:

• By reducing platelet destruction via inhibition of autoantibody/FcγR signaling in splenic macrophages
• By reducing autoantibody generation through inhibition of B-cell activation and maturation.

The researchers also assessed the effects of PRN1008 and ibrutinib on platelet function in samples from healthy volunteers and ITP patients.

Samples were treated with one of the two BTK inhibitors, and platelet aggregation was induced by platelet agonists.

Unlike ibrutinib, PRN1008 did not impact platelet aggregation in healthy volunteer or ITP patient samples.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image from Graham Beards

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to PRN1008 for the treatment of patients with immune thrombocytopenia (ITP).

PRN1008 is an oral, reversible, covalent Bruton’s tyrosine kinase (BTK) inhibitor being developed by Principia Biopharma, Inc.

Principia is conducting a phase 1/2 trial (NCT03395210) to evaluate the safety and efficacy of PRN1008 in patients with ITP.

Results of preclinical research with PRN1008 in ITP were presented at the 2017 ASH Annual Meeting.

There, researchers reported that PRN1008 significantly reduced platelet loss in a mouse model of ITP.

The team found the BTK inhibitor could diminish platelet loss in two ways:

• By reducing platelet destruction via inhibition of autoantibody/FcγR signaling in splenic macrophages
• By reducing autoantibody generation through inhibition of B-cell activation and maturation.

The researchers also assessed the effects of PRN1008 and ibrutinib on platelet function in samples from healthy volunteers and ITP patients.

Samples were treated with one of the two BTK inhibitors, and platelet aggregation was induced by platelet agonists.

Unlike ibrutinib, PRN1008 did not impact platelet aggregation in healthy volunteer or ITP patient samples.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Photo by Bill Branson

The European Medicine’s Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of the marketing authorization for the recombinant factor VIIa product eptacog alfa (NovoSeven).

The recommendation is to expand the approved use of eptacog alfa in patients with Glanzmann’s thrombasthenia.

Eptacog alfa is already approved by the European Commission (EC) for use in patients with Glanzmann’s thrombasthenia with antibodies to glycoprotein IIb/IIIa and/or human leukocyte antigen who have past or present refractoriness to platelet transfusions.

Now, the CHMP has recommended expanding the use of eptacog alfa to include situations in which patients are not refractory to platelet transfusions but platelets are not readily available.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

If the EC follows the CHMP’s recommendation for eptacog alfa, the product will be approved for the treatment of bleeding episodes and for the prevention of bleeding in those undergoing surgery or invasive procedures in the following patient groups:

• Patients with congenital hemophilia with inhibitors to coagulation factors VIII or IX > 5 Bethesda units
• Patients with congenital hemophilia who are expected to have a high anamnestic response to factor VIII or factor IX administration
• Patients with acquired hemophilia
• Patients with congenital FVII deficiency
• Patients with Glanzmann’s thrombasthenia with antibodies to glycoprotein IIb/IIIa and/or human leukocyte antigen and past or present refractoriness to platelet transfusions, or where platelets are not readily available.

Photo by Bill Branson

The European Medicine’s Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of the marketing authorization for the recombinant factor VIIa product eptacog alfa (NovoSeven).

The recommendation is to expand the approved use of eptacog alfa in patients with Glanzmann’s thrombasthenia.

Eptacog alfa is already approved by the European Commission (EC) for use in patients with Glanzmann’s thrombasthenia with antibodies to glycoprotein IIb/IIIa and/or human leukocyte antigen who have past or present refractoriness to platelet transfusions.

Now, the CHMP has recommended expanding the use of eptacog alfa to include situations in which patients are not refractory to platelet transfusions but platelets are not readily available.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

If the EC follows the CHMP’s recommendation for eptacog alfa, the product will be approved for the treatment of bleeding episodes and for the prevention of bleeding in those undergoing surgery or invasive procedures in the following patient groups:

• Patients with congenital hemophilia with inhibitors to coagulation factors VIII or IX > 5 Bethesda units
• Patients with congenital hemophilia who are expected to have a high anamnestic response to factor VIII or factor IX administration
• Patients with acquired hemophilia
• Patients with congenital FVII deficiency
• Patients with Glanzmann’s thrombasthenia with antibodies to glycoprotein IIb/IIIa and/or human leukocyte antigen and past or present refractoriness to platelet transfusions, or where platelets are not readily available.

Photo by Bill Branson

The European Medicine’s Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of the marketing authorization for the recombinant factor VIIa product eptacog alfa (NovoSeven).

The recommendation is to expand the approved use of eptacog alfa in patients with Glanzmann’s thrombasthenia.

Eptacog alfa is already approved by the European Commission (EC) for use in patients with Glanzmann’s thrombasthenia with antibodies to glycoprotein IIb/IIIa and/or human leukocyte antigen who have past or present refractoriness to platelet transfusions.

Now, the CHMP has recommended expanding the use of eptacog alfa to include situations in which patients are not refractory to platelet transfusions but platelets are not readily available.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

If the EC follows the CHMP’s recommendation for eptacog alfa, the product will be approved for the treatment of bleeding episodes and for the prevention of bleeding in those undergoing surgery or invasive procedures in the following patient groups:

• Patients with congenital hemophilia with inhibitors to coagulation factors VIII or IX > 5 Bethesda units
• Patients with congenital hemophilia who are expected to have a high anamnestic response to factor VIII or factor IX administration
• Patients with acquired hemophilia
• Patients with congenital FVII deficiency
• Patients with Glanzmann’s thrombasthenia with antibodies to glycoprotein IIb/IIIa and/or human leukocyte antigen and past or present refractoriness to platelet transfusions, or where platelets are not readily available.

The Food and Drug Administration has approved ID CORE XT, a molecular-based assay that uses DNA to test for non-ABO red blood cell types for use in transfusion.

It’s the second molecular test for blood compatibility but the first to report genotype in its results, according to an announcement from the agency.

The test is important because it evaluates patients – especially those who receive repeated blood transfusions for conditions such as sickle cell anemia – for non-ABO antigens, but it does so without using antisera, which is sometimes unavailable.

A study found comparable performance between the ID CORE XT, licensed serologic reagents, and DNA sequencing tests, according to the FDA.

The ID CORE XT test is marketed by Progenika Biopharma, a Grifols company.

More information can be found in the full FDA press announcement.

[email protected]

The Food and Drug Administration has approved ID CORE XT, a molecular-based assay that uses DNA to test for non-ABO red blood cell types for use in transfusion.

It’s the second molecular test for blood compatibility but the first to report genotype in its results, according to an announcement from the agency.

The test is important because it evaluates patients – especially those who receive repeated blood transfusions for conditions such as sickle cell anemia – for non-ABO antigens, but it does so without using antisera, which is sometimes unavailable.

A study found comparable performance between the ID CORE XT, licensed serologic reagents, and DNA sequencing tests, according to the FDA.

The ID CORE XT test is marketed by Progenika Biopharma, a Grifols company.

More information can be found in the full FDA press announcement.

[email protected]

The Food and Drug Administration has approved ID CORE XT, a molecular-based assay that uses DNA to test for non-ABO red blood cell types for use in transfusion.

It’s the second molecular test for blood compatibility but the first to report genotype in its results, according to an announcement from the agency.

The test is important because it evaluates patients – especially those who receive repeated blood transfusions for conditions such as sickle cell anemia – for non-ABO antigens, but it does so without using antisera, which is sometimes unavailable.

A study found comparable performance between the ID CORE XT, licensed serologic reagents, and DNA sequencing tests, according to the FDA.

The ID CORE XT test is marketed by Progenika Biopharma, a Grifols company.

More information can be found in the full FDA press announcement.

[email protected]

Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.

Gio_tto/Thinkstock

Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.

“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”

MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).

Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.

To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.

Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.

Gio_tto/Thinkstock

Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.

“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”

MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).

Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.

To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.

Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.

Gio_tto/Thinkstock

Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.

“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”

MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.

This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.

By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.

The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.

Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).

Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.

To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.

The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.

SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Image by Spencer Phillips

DUBROVNIK, CROATIA—New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL¹ and autoimmune diseases² in patients from Northwest Europe.

However, a study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

Therefore, she and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients—168 with CLL, 66 with AIHA, and 86 with ITP—and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

1. Hebbring S et al. Blood. 2013 121:237-238; doi: https://doi.org/10.1182/blood-2012-08-450221

2. Burb GL et al. FEBS Lett. 2011 Dec 1;585(23):3689-98. doi: 10.1016/j.febslet.2011.04.032

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) approved emicizumab-kxwh (Hemlibra) for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients, including newborns, with hemophilia A with or without factor VIII (FVIII) inhibitors.

Emicizumab is a humanized bispecific factor IXa- and factor X-directed antibody for patients with congenital FVIII deficiency.

It was first approved in 2017 for hemophilia A patients with FVIII inhibitors.

The current approval expands the indication to include patients without FVIII inhibitors and provides new dosing regimens.

The FDA based the current approval on the HAVEN 3 and HAVEN 4 trials.

HAVEN 3 (NCT02847637)

This multicenter trial randomized 89 patients with severe hemophilia A without FVIII inhibitors to receive emicizumab prophylaxis at one of 3 dose levels: 1.5 mg/kg once weekly (ARM A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C). Patients had previously received on-demand treatment with FVIII.

Before the start of the trial, investigators stratified patients by 24-week bleed rate—fewer than 9 bleeds and 9 or more bleeds.

Patients were treated with emicizumab for a minimum of 24 weeks.

Patients in Arm A experienced a 96% reduction in annualized bleed rate (ABR) compared to patients with no prophylaxis (ABR ratio=0.04; P<0.0001).

Patients in Arm B had a 97% reduction in ABR compared to patients with no prophylaxis (ABR ratio=0.03; P<0.0001).

The trial met all bleed-related secondary endpoints, such as all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds.

HAVEN 4 (NCT03020160)

This was a single-arm multicenter trial in 48 adult and adolescent males with hemophilia A with or without FVIII inhibitors. The patients had previously received on-demand or prophylactic treatment with FVIII or bypassing agents.

The study was conducted in two parts: a run-in of 7 patients to determine the pharmacokinetics after a single 6 mg/kg dose in four weeks. This was followed by the same dose once every four weeks for at least 24 weeks.

The second part was an expansion cohort of 41 patients who received emicizumab at 3 mg/kg once weekly for the first four weeks followed by 6 mg/kg once every four weeks for at least 24 weeks.

The ABR for treated bleeds was 2.4 (95% CI: 1.38, 4.28) and the median ABR was 0.0 (interquartile range: 0.00, 2.08).

The recommended loading dose is 3 mg/kg once weekly for the first four weeks for all prophylactic regimens.

Safety

The prescribing information for emicizumab includes a warning about thrombotic microangiopathy and thromboembolism.

These events were reported on average when a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab prophylaxis.

According to the warning box, patients should be monitored for these events if aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab dosing suspended.

The most common adverse reactions reported for emicizumab with an incidence ≥10% were injection site reactions (22%), headache (15%), and arthralgia (15%).

Emicizumab is manufactured by Genentech, Inc., a member of the Roche Group.

Additional data on emicizumab can be found in an earlier Roche media release. 

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) approved emicizumab-kxwh (Hemlibra) for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients, including newborns, with hemophilia A with or without factor VIII (FVIII) inhibitors.

Emicizumab is a humanized bispecific factor IXa- and factor X-directed antibody for patients with congenital FVIII deficiency.

It was first approved in 2017 for hemophilia A patients with FVIII inhibitors.

The current approval expands the indication to include patients without FVIII inhibitors and provides new dosing regimens.

The FDA based the current approval on the HAVEN 3 and HAVEN 4 trials.

HAVEN 3 (NCT02847637)

This multicenter trial randomized 89 patients with severe hemophilia A without FVIII inhibitors to receive emicizumab prophylaxis at one of 3 dose levels: 1.5 mg/kg once weekly (ARM A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C). Patients had previously received on-demand treatment with FVIII.

Before the start of the trial, investigators stratified patients by 24-week bleed rate—fewer than 9 bleeds and 9 or more bleeds.

Patients were treated with emicizumab for a minimum of 24 weeks.

Patients in Arm A experienced a 96% reduction in annualized bleed rate (ABR) compared to patients with no prophylaxis (ABR ratio=0.04; P<0.0001).

Patients in Arm B had a 97% reduction in ABR compared to patients with no prophylaxis (ABR ratio=0.03; P<0.0001).

The trial met all bleed-related secondary endpoints, such as all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds.

HAVEN 4 (NCT03020160)

This was a single-arm multicenter trial in 48 adult and adolescent males with hemophilia A with or without FVIII inhibitors. The patients had previously received on-demand or prophylactic treatment with FVIII or bypassing agents.

The study was conducted in two parts: a run-in of 7 patients to determine the pharmacokinetics after a single 6 mg/kg dose in four weeks. This was followed by the same dose once every four weeks for at least 24 weeks.

The second part was an expansion cohort of 41 patients who received emicizumab at 3 mg/kg once weekly for the first four weeks followed by 6 mg/kg once every four weeks for at least 24 weeks.

The ABR for treated bleeds was 2.4 (95% CI: 1.38, 4.28) and the median ABR was 0.0 (interquartile range: 0.00, 2.08).

The recommended loading dose is 3 mg/kg once weekly for the first four weeks for all prophylactic regimens.

Safety

The prescribing information for emicizumab includes a warning about thrombotic microangiopathy and thromboembolism.

These events were reported on average when a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab prophylaxis.

According to the warning box, patients should be monitored for these events if aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab dosing suspended.

The most common adverse reactions reported for emicizumab with an incidence ≥10% were injection site reactions (22%), headache (15%), and arthralgia (15%).

Emicizumab is manufactured by Genentech, Inc., a member of the Roche Group.

Additional data on emicizumab can be found in an earlier Roche media release. 

Photo from Business Wire

The U.S. Food and Drug Administration (FDA) approved emicizumab-kxwh (Hemlibra) for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients, including newborns, with hemophilia A with or without factor VIII (FVIII) inhibitors.

Emicizumab is a humanized bispecific factor IXa- and factor X-directed antibody for patients with congenital FVIII deficiency.

It was first approved in 2017 for hemophilia A patients with FVIII inhibitors.

The current approval expands the indication to include patients without FVIII inhibitors and provides new dosing regimens.

The FDA based the current approval on the HAVEN 3 and HAVEN 4 trials.

HAVEN 3 (NCT02847637)

This multicenter trial randomized 89 patients with severe hemophilia A without FVIII inhibitors to receive emicizumab prophylaxis at one of 3 dose levels: 1.5 mg/kg once weekly (ARM A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C). Patients had previously received on-demand treatment with FVIII.

Before the start of the trial, investigators stratified patients by 24-week bleed rate—fewer than 9 bleeds and 9 or more bleeds.

Patients were treated with emicizumab for a minimum of 24 weeks.

Patients in Arm A experienced a 96% reduction in annualized bleed rate (ABR) compared to patients with no prophylaxis (ABR ratio=0.04; P<0.0001).

Patients in Arm B had a 97% reduction in ABR compared to patients with no prophylaxis (ABR ratio=0.03; P<0.0001).

The trial met all bleed-related secondary endpoints, such as all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds.

HAVEN 4 (NCT03020160)

This was a single-arm multicenter trial in 48 adult and adolescent males with hemophilia A with or without FVIII inhibitors. The patients had previously received on-demand or prophylactic treatment with FVIII or bypassing agents.

The study was conducted in two parts: a run-in of 7 patients to determine the pharmacokinetics after a single 6 mg/kg dose in four weeks. This was followed by the same dose once every four weeks for at least 24 weeks.

The second part was an expansion cohort of 41 patients who received emicizumab at 3 mg/kg once weekly for the first four weeks followed by 6 mg/kg once every four weeks for at least 24 weeks.

The ABR for treated bleeds was 2.4 (95% CI: 1.38, 4.28) and the median ABR was 0.0 (interquartile range: 0.00, 2.08).

The recommended loading dose is 3 mg/kg once weekly for the first four weeks for all prophylactic regimens.

Safety

The prescribing information for emicizumab includes a warning about thrombotic microangiopathy and thromboembolism.

These events were reported on average when a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving emicizumab prophylaxis.

According to the warning box, patients should be monitored for these events if aPCC is administered. If symptoms occur, aPCC should be discontinued and emicizumab dosing suspended.

The most common adverse reactions reported for emicizumab with an incidence ≥10% were injection site reactions (22%), headache (15%), and arthralgia (15%).

Emicizumab is manufactured by Genentech, Inc., a member of the Roche Group.

Additional data on emicizumab can be found in an earlier Roche media release. 

The Food and Drug Administration has approved emicizumab-kxwh (Hemlibra) for subcutaneous prophylactic treatment in hemophilia A without factor VIII inhibitors.

Genentech announced the new approval on Oct. 4 of this year. In 2017, the bispecific antibody, which targets both factors IXa and X, was approved for patients as young as newborns who had factor VIII inhibitors; the latest approval allows it to be used for patients without inhibitors as well.

The approval is based on a pair of trials. HAVEN 3 (NCT02847637) is a phase 3 trial in which investigators looked at emicizumab prophylaxis weekly or every other week, versus on-demand factor VIII treatment in patients without inhibitors. The study included 152 patients aged 12 years and older who were previously treated with factor VIII therapy.

Compared with patients not receiving prophylactic treatments, those receiving weekly doses had a 96% reduction in treated bleeds, and those receiving doses every other week saw a 97% reduction. Investigators also found that 55.6% of patients treated every week, 60% of those treated every other week, and 0% of those treated with no prophylaxis experienced zero bleeds; similarly, 91.7%, 94.3%, and 5.6% experienced three or fewer bleeds.

The single-arm HAVEN 4 (NCT03020160) trial evaluated dosing patients every 4 weeks among 48 patients aged 12 years and older, with or without inhibitors, and results showed that even that dosing regimen could lead to a clinically meaningful control of bleeds: 56.1% had no bleeds, and 90.2% had three or fewer bleeds.

The most common adverse reactions were joint pain, headache, and injection-site reaction. When emicizumab-kxwh is used with activated prothrombin complex concentrate, there’s a risk of thrombotic microangiopathy and thrombotic events. Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved emicizumab-kxwh (Hemlibra) for subcutaneous prophylactic treatment in hemophilia A without factor VIII inhibitors.

Genentech announced the new approval on Oct. 4 of this year. In 2017, the bispecific antibody, which targets both factors IXa and X, was approved for patients as young as newborns who had factor VIII inhibitors; the latest approval allows it to be used for patients without inhibitors as well.

The approval is based on a pair of trials. HAVEN 3 (NCT02847637) is a phase 3 trial in which investigators looked at emicizumab prophylaxis weekly or every other week, versus on-demand factor VIII treatment in patients without inhibitors. The study included 152 patients aged 12 years and older who were previously treated with factor VIII therapy.

Compared with patients not receiving prophylactic treatments, those receiving weekly doses had a 96% reduction in treated bleeds, and those receiving doses every other week saw a 97% reduction. Investigators also found that 55.6% of patients treated every week, 60% of those treated every other week, and 0% of those treated with no prophylaxis experienced zero bleeds; similarly, 91.7%, 94.3%, and 5.6% experienced three or fewer bleeds.

The single-arm HAVEN 4 (NCT03020160) trial evaluated dosing patients every 4 weeks among 48 patients aged 12 years and older, with or without inhibitors, and results showed that even that dosing regimen could lead to a clinically meaningful control of bleeds: 56.1% had no bleeds, and 90.2% had three or fewer bleeds.

The most common adverse reactions were joint pain, headache, and injection-site reaction. When emicizumab-kxwh is used with activated prothrombin complex concentrate, there’s a risk of thrombotic microangiopathy and thrombotic events. Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved emicizumab-kxwh (Hemlibra) for subcutaneous prophylactic treatment in hemophilia A without factor VIII inhibitors.

Genentech announced the new approval on Oct. 4 of this year. In 2017, the bispecific antibody, which targets both factors IXa and X, was approved for patients as young as newborns who had factor VIII inhibitors; the latest approval allows it to be used for patients without inhibitors as well.

The approval is based on a pair of trials. HAVEN 3 (NCT02847637) is a phase 3 trial in which investigators looked at emicizumab prophylaxis weekly or every other week, versus on-demand factor VIII treatment in patients without inhibitors. The study included 152 patients aged 12 years and older who were previously treated with factor VIII therapy.

Compared with patients not receiving prophylactic treatments, those receiving weekly doses had a 96% reduction in treated bleeds, and those receiving doses every other week saw a 97% reduction. Investigators also found that 55.6% of patients treated every week, 60% of those treated every other week, and 0% of those treated with no prophylaxis experienced zero bleeds; similarly, 91.7%, 94.3%, and 5.6% experienced three or fewer bleeds.

The single-arm HAVEN 4 (NCT03020160) trial evaluated dosing patients every 4 weeks among 48 patients aged 12 years and older, with or without inhibitors, and results showed that even that dosing regimen could lead to a clinically meaningful control of bleeds: 56.1% had no bleeds, and 90.2% had three or fewer bleeds.

The most common adverse reactions were joint pain, headache, and injection-site reaction. When emicizumab-kxwh is used with activated prothrombin complex concentrate, there’s a risk of thrombotic microangiopathy and thrombotic events. Full prescribing information can be found on the FDA website.

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