scholarly journals Reduced Dosing Frequency Following a Switch to Rix-FP for the Treatment of Hemophilia B: Results from the Athn 2 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1039-1039
Author(s):  
Janna Journeycake ◽  
Dunlei Cheng ◽  
Tammuella Chrisentery-Singleton ◽  
Vidhi Desai ◽  
Annette von Drygalski ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Dose Interval ◽  
Hemophilia B ◽  
Dose Frequency ◽  
Advisory Committees ◽  
Dosing Frequency ◽  
Before And After ◽  
One Year

Abstract Introduction: The approval of extended half-life recombinant factor IX (rFIX) replacement products has expanded the range of therapeutic options available for the treatment of hemophilia B. Compared with standard half-life FIX, these products allow for extended dosing intervals while maintaining appropriate bleed control. One such extended half-life product is rIX-FP (IDELVION; CSL Behring), a recombinant fusion protein linking rFIX with recombinant albumin, offering the possibility of dosing up to every 21 days in adults. The ATHN 2: Factor Switching Study provides information on patient outcomes following a switch from a previous FIX product to rIX-FP. Methods: ATHN 2 was a factor-switching study sponsored by the American Thrombosis and Hemostasis Network (ATHN) conducted in participants across the US hemophilia treatment center (HTC) network. This was a multi-center, longitudinal, observational study with two arms: a prospective arm following participants for up to one year after switching factor replacement product, and a retrospective arm including participants who have switched products within the 50 weeks prior to enrollment with retrospective and/or prospective assessment for up to one year. Male and female children and adults (≥2 years) with FIX clotting activity ≤5% of normal who had previously been treated with plasma-derived or recombinant FIX for at least 50 exposure days were eligible for inclusion. Treatment was administered at the discretion of the participant's hemophilia caregiver. Data was collected at study/clinic visits, or via a telephone interview conducted every three months. Baseline demographic data was collected for all participants. The prescribed dosing frequency for each participant was collected before and after the switch to rIX-FP, including dosing frequency taken from the first and last treatment records taken during the study following the switch. Participants were also asked to rank their satisfaction with rIX-FP upon the completion or early termination of the study. Results: A total of 41 participants were included in this analysis; 27 in the prospective arm and 14 in the retrospective arm. The mean (SD) age across all participants was 22.5 (17.1) years, ranging from 2 to 71 years. The median age was 18 years old and most participants had severe hemophilia B (FIX activity <1%; n=26, 63%). Prior to the switch to rIX-FP, 76% (n=31) of participants were receiving prophylaxis and 24% (n=10) received episodic treatment. The majority of participants (62%) receiving prophylaxis were treated twice a week (Table 1). Following the treatment switch, 93% of participants were initially assigned to a once-weekly or less frequent dosing regimen. This proportion remained stable over the course of the study, with 89% of participants on once-weekly or less frequent prophylaxis by the time of the last record taken. Among 23 participants with complete data on their prophylaxis dose interval before and after treatment switch, 70% of the participants were able to extend their dose frequency and maintain the extended dose frequency through the study. Thirty-seven participants responded to the satisfaction survey, with the majority (n=33, 89%) being somewhat or very satisfied with rIX-FP treatment. Conclusions: Switching to rIX-FP allowed participants to extend their prophylaxis dosing interval and a majority of participants were able to maintain the extended dose interval through the study period. In addition, a majority of participants were satisfied with rIX-FP treatment, altogether suggesting that extended half-life factor replacement with rIX-FP offers a valuable treatment option for hemophilia B. Figure 1 Figure 1. Disclosures Journeycake: HEMA Biologics: Honoraria; LFB: Honoraria. Chrisentery-Singleton: Biomarin: Speakers Bureau; Kedrion: Consultancy; Takeda: Consultancy, Speakers Bureau; Spark: Consultancy, Research Funding; Sanofi: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Hema Biologics: Consultancy; Grifols: Consultancy; Genentech: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau. Desai: CSL Behring: Current Employment. von Drygalski: Pfizer: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Patel: CSL Behring: Current Employment. Raffini: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Bayer: Consultancy; XaTek: Consultancy. Recht: Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; CSL Behring: Consultancy; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment; Catalyst Biosciences: Consultancy. Sidinio: Biomarin: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Catalyst: Consultancy. Wang: Bayer: Consultancy; Biomarin: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Hema Biologics: Consultancy; Novo Nordisk: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; uniQure: Consultancy. Zhang: CSL Behring: Current Employment, Current holder of individual stocks in a privately-held company. Neufeld: Pfizer: Consultancy; Chiesi: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Octapharma: Consultancy, Research Funding; Acceleron Pharma: Consultancy; Baxter: Consultancy; Shire: Consultancy; Takeda: Consultancy; CSL: Consultancy; Biogen: Consultancy; Novo Nordisk: Consultancy; Bristol Myers-Squibb: Consultancy; ATHN: Research Funding; Celgene: Research Funding.

scholarly journals B Cell Receptor Signaling Drives APOBEC3 Expression Via Direct Enhancer Regulation in Chronic Lymphocytic Leukemia B Cells

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3313-3313
Author(s):  
Zhiquan Wang ◽  
Huihuang Yan ◽  
Justin C. Boysen ◽  
Charla R. Secreto ◽  
Esteban Braggio ◽  
...  
Keyword(s):  
B Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Chromatin Accessibility ◽  
S Phase ◽  
Advisory Committees ◽  
Bcr Signaling ◽  
Before And After ◽  
One Year ◽  
Apobec3 Expression

Abstract Introduction: CLL is the most common leukemia in the U.S. and characterized by constitutively activated BCR signaling pathway, which has a crucial role both in normal B cell development and B cell malignancies. The biological events controlled by BCR signaling in CLL are not fully understood. Active BCR signaling is mediated through activation of the downstream kinase Bruton tyrosine kinase (BTK), which has become a key therapeutic target to inhibit BCR signaling for the treatment of B cell malignancies. We reasoned that blood samples from CLL patients before and after Bruton's tyrosine kinase inhibitors (BTKi) treatment would provide a valuable resource in the study of BCR modulation of epigenetic machinery in leukemic B cells. Methods: We obtained blood samples from CLL patients before and after BTKi ibrutinib treatment and used them to study BCR signaling regulated genes (n = 8 patients, after one-year of continuous ibrutinib treatment). Gene expression profile of CLL B cells from patients before and after one-year ibrutinib treatment was analyzed by mRNA-seq seq. Genome wide Histone H3K4me1, H3K27ac, and H3K4me3 profile was determined by CUT&tag. Chromatin accessibility was determined by ATAC-seq. Putative enhancers were deleted by CRISPR-Cas9. Results: Notably BTKi treatment led to the reduction of expression in genes associated with single strand DNA deamination (Fig. 1A) The BTKi regulated genes involved in this process mainly contains the APOBEC3 family genes (APOBEC3C, APOBEC3D APOBEC3F, APOBEC3G, APOBEC3H), and their expression levels showed a consistent reduction in CLL B cells from ibrutinib treated patients (Fig. 1B). We then confirmed the reduction of APOBEC3 levels by western blot in CLL B cells from four patients before and after one-year of continuous ibrutinib treatment (Fig. 1C). We hypothesized that BCR signaling regulates APOBEC3 expression by modifying the local chromatin around the APOBEC3 gene cluster and performed CUT&Tag to map the histone marks including H3K4me1, H3K4me3, H3K27ac and ATAC-seq. This approach permitted us to examine the chromatin accessibility of the leukemic cells from CLL patients before and then after one-year of continuous ibrutinib treatment. We found that BTKi treatment caused reductions of H3K4me1, H3K27ac, and chromatin accessibility at these regions in ibrutinib treated patients ( 7 of the 8 samples tested), however, there was no change of the promoter marker H3K4me3 (Fig. 1D), which indicated that BTKi treatment leads to APOBEC3 genes expression change via the regulation of their enhancer regulation (APOBEC3 enhancers, AEs). Based on the enrichment of H3K4me1, H3K27ac and chromatin accessibility, AE regions of the ibrutinib native samples contain three active enhancer modules, we designated these modules as AE1, AE2, and AE3 (Fig. 1D). To assess the functional activity of these enhancers on the expression of APOBEC3 genes, we investigated the consequence of deletion of each one of these AEs in the MEC1 cell line by CRISPR-Cas9. PCR analysis showed very robust deletion of AE1, AE2, and AE3 (Fig. 1E). Both deletion of AE1 or AE2 reduced the expression of APOBEC3 genes, while AE3 deletion suppressed the expression of APBEC3C, APOBEC3D, APOBEC3F and APOBEC3G, but not APOBEC3H, which is in closest proximity to AE3 (Fig. 1F, G). Together, we identified the BCR signaling dependent enhancers that regulate APOBEC3 expression. Since APOBEC3 deaminates ssDNA, we reasoned that APOBEC3 in CLL B cells may also contribute to replication stress and DNA instability. We found that MEC1 cells have a high level of spontaneous DNA damage in the S phase cells (Fig. 1H). which is associated with replication stress. However, AE2 deleted MEC cells showed decreased γH2Ax in the S phase cells (Fig. 1H). Edu/PI assay showed that MEC1 cells had a fraction of S phase cells with low Edu incorporation during S phase, also indicating DNA replication stress (Fig. 1I); however, AE2 deletion greatly increased Edu incorporation (Fig. 1I). Taken together, these data suggest that increased expression of APOBEC3 may be involved in DNA replication stress and drives genomic instability in malignant B cells. Conclusion: We demonstrate a novel mechanism for BTKi suppression of APOBEC3 expression via direct enhancer regulation in CLL B cells, implicating BCR signaling as a potential regulator of leukemic genomic instability. Figure 1 Figure 1. Disclosures Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Kay: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Tolero Pharmaceuticals: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Real-World Data on the Use of rFIXFc in Subjects With Hemophilia B for Up to 3.7 Years Demonstrates Improved Bleed Control and Adherence With Reduced Treatment Burden

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2493-2493 ◽  
Author(s):  
Amy Shapiro ◽  
Ateefa Chaudhury ◽  
Nisha Jain ◽  
Elisa Tsao ◽  
Chris Barnowski ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
The United States ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Real World Data ◽  
Advisory Committees ◽  
Dosing Interval ◽  
Before And After

Abstract Introduction: Recombinant factor IX Fc fusion protein (rFIXFc) was the first extended half-life FIX product approved in the United States to treat children and adults with hemophilia B. Long-term data from clinical trials have demonstrated the safety and efficacy of rFIXFc as well as an extended dosing interval (once weekly or every 10‒14 days based on individual needs); however, real-world data are limited (Wang et al. Haemophilia, 2018; Buckley et al. AMCP NEXUS, 2015). We therefore performed a retrospective chart review to further understand the clinical experience and outcomes associated with real-world treatment of hemophilia B with rFIXFc. Methods: This retrospective chart review is being conducted at 6 sites across different regions of the United States and aims to include 70 patient charts. Data entry for 43 patient charts has been completed to date (cutoff: June 29, 2018). Data collection is ongoing. Inclusion criteria were diagnosis of hemophilia B and receipt of rFIXFc for ≥6 months. Subjects with other coagulation disorders or any record of positive FIX inhibitor titers were excluded. De-identified subject-level data were transcribed onto anonymous electronic case report forms. Endpoints included changes in FIX therapy dosing interval, factor consumption, bleed control, and patient adherence before and after rFIXFc initiation. Descriptive statistics were used to summarize the results. Results: For the 43 charts available for analysis, the duration of follow-up receiving rFIXFc ranged from 0.5 to 3.7 years. Of these, 58% of subjects (25/43) were >18 years of age, 77% (33/43) were of white race, and 51% (22/43) had severe hemophilia B (Table 1). The most common genotype was missense, occurring in 63% of subjects (27/43). Among subjects with comorbidity, 37% reported hemophilic arthropathy (16/43) and 28% had hepatitis C (12/43). All 22 subjects with severe hemophilia B were treated with rFIXFc prophylactically compared with 9/15 moderate and 3/6 mild cases. From the data collected thus far, 94% of prophylaxis subjects were on a dosing interval of weekly or longer (every 7 days, n=20; every 10 days, n=3; and every 14 days, n=9). The total weekly dose before and after switching to rFIXFc prophylaxis were available for 20 subjects. Of the 12 adults (9 severe, 2 moderate, and 1 mild), the median weekly factor consumption decreased from 111 IU/kg to 52.5 IU/kg. A similar pattern was observed for subjects who were 12-18 years of age (n=4). For subjects <12 years of age (n=4), 2 had reduced weekly consumption after switching to rFIXFc, whereas 2 (on plasma-derived product pre-rFIXFc) had an increase in weekly consumption. The annualized bleeding rates (ABRs), annualized spontaneous bleeding rates (AsBRs), and annualized joint bleeding rates (AjBRs) were available for 17 subjects treated with prophylaxis regimens pre- and post-rFIXFc (Table 2). Of these subjects, 11 had severe, 5 had moderate, and 1 had mild hemophilia B. Among 11 subjects with severe hemophilia B, median (interquartile range) ABRs decreased from 8.2 (4.4‒11.5) to 2.3 (0.6‒10.2), AsBR from 1.2 (0‒9.7) to 0.3 (0‒8.7), and AjBR from 2.3 (1.4‒8.2) to 0.7 (0‒6.9) before and after rFIXFc treatment. Subjects with moderate disease had a similar pattern (Table 2). The most common reason for switching to rFIXFc was to reduce the burden associated with therapy (21/43, 49%). No rationale for switching was documented in 40% (17/43) of subjects, and 7% (3/43) switched due to lack of efficacy with previous treatment. The other reasons, including difficult venous access, lack of adherence, and failure to reach desired trough were mentioned by <5% of subjects. No subject reported adherence issues while on rFIXFc. Conclusions: This real-world study of rFIXFc demonstrates improved bleed control, reduced overall consumption, and reduced frequency of injection for subjects with moderate and severe hemophilia B. The data also show that rFIXFc provides an opportunity to tailor dosing and improve adherence. These results echo the findings of the pivotal trials and add to the pool of evidence supporting rFIXFc in the treatment of hemophilia B. These data also reflect the use of rFIXFc for mild hemophilia patients in the real-world setting. Disclosures Shapiro: Kedrion Biopharma: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; BioMarin: Research Funding; Bio Products Laboratory: Consultancy; Octapharma: Research Funding; OPKO: Research Funding; Sangamo Biosciences: Consultancy; Daiichi Sankyo: Research Funding. Chaudhury:Bioverativ, a Sanofi Company: Consultancy, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees. Jain:Bioverativ: Employment. Tsao:Bioverativ: Employment. Barnowski:Bioverativ, a Sanofi Company: Employment. Feng:Bioverativ: Employment. Quon:Shire: Speakers Bureau; Genetech: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Bayer: Consultancy; Octapharma: Consultancy; Bioverativ, a Sanofi Company: Speakers Bureau.

Pharmacokinetics Of Recombinant Factor IX Fc Fusion Protein (rFIXFc) In Pediatric Subjects With Hemophilia B: An Interim Analysis Of The Kids B-LONG Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3599-3599
Author(s):  
Kathelijn Fischer ◽  
Roshni Kulkarni ◽  
Myles Bradbury ◽  
Margaret V. Ragni ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Half Life ◽  
Interim Analysis ◽  
Research Funding ◽  
Factor Ix ◽  
Hemophilia B ◽  
Employment Equity ◽  
Advisory Committees ◽  
Age Cohorts ◽  
Equity Ownership

Abstract Introduction Prophylaxis with factor IX (FIX) is the optimal treatment for patients with hemophilia B; however, due to the short half-life of currently available FIX products, frequent injections may be required to prevent bleeding episodes. To prolong half-life and reduce injection frequency, a long-acting recombinant FIX Fc fusion protein (rFIXFc) consisting of one rFIX molecule covalently linked to the Fc domain of immunoglobulin G1 (IgG1) was developed. In a phase 3 study in adults and adolescents, rFIXFc had a 2.43-fold increase in half-life and 50% reduction in clearance (CL) compared with FIX (BeneFIX®) (J Thromb Haemost. 2013;11[2]:241). The Kids B-LONG study (NCT01440946) was designed to evaluate the pharmacokinetics (PK), safety, and efficacy of rFIXFc prophylaxis in previously treated pediatric subjects with hemophilia B. The objective of this planned interim analysis was to determine the PK parameters of rFIXFc in subjects enrolled in Kids B-LONG and compare these parameters to their pre-study FIX PK parameters. Methods This multicenter, open-label, phase 3 study is currently enrolling previously treated subjects aged<12 years with severe hemophilia B (≤2 IU/dL endogenous FIX), at least 50 exposure days (EDs) to FIX products, and no inhibitors to FIX. Subjects are stratified into two age cohorts (<6 and 6 to<12 years of age). A weekly prophylactic regimen of 50-60 IU/kg of rFIXFc is administered to all subjects, with subsequent dose and interval adjustments based upon PK data and bleeding frequency. Subjects will continue treatment until they achieve 50 EDs. The primary endpoint is the incidence of inhibitor formation. A sequential PK analysis is performed to compare the PK parameters of rFIXFc with that of pre-study FIX products. PK sampling of pre-study FIX occurs at baseline prior to first dose of FIX (50 IU/kg) and at 5 additional time points through 48 hours. PK sampling of rFIXFc occurs prior to first dose of 50 IU/kg rFIXFc and at 7 additional time points through 168 hours following the first dose; a washout period of 96 hours is required before the first dose of both pre-study FIX and rFIXFc. Plasma FIX activity is measured using the one-stage clotting assay calibrated against a commercially available FIX plasma standard and the FIX activity-over-time profiles are analyzed by non-compartmental analysis (NCA) using the PK data analysis software Phoenix™ WinNonlin 6.2.1.51. A data cut-off date of 23 April 2013 was used to report PK data in this interim analysis. Results At the time of this interim analysis, 24 subjects were enrolled and had received at least one dose of pre-study FIX and/or rFIXFc. Of 18 subjects with evaluable PK profiles, 15 had complete PK profiles for both pre-study FIX (BeneFIX®, Haemosolvex®, or Alphanine®) and rFIXFc. A comparison of PK parameters for rFIXFc versus FIX for both age cohorts is presented in Table 1. rFIXFc had a more than 3-fold prolongation in half-life and a more than 60% reduction in CL compared to the FIX products. Conclusion In comparison to currently available FIX products, rFIXFc had a prolonged half-life and reduced CL in pediatric subjects, which was similar to previous observations in adults and adolescents. The final analysis of the Kids B-LONG study will provide further PK information and evaluate the safety and efficacy of rFIXFc in children. Disclosures: Fischer: Biogen Idec, Baxter, Novo Nordisk, Bayer: Membership on an entity’s Board of Directors or advisory committees; Baxter, Bayer, Novo Nordisk, Pfizer: Research Funding. Kulkarni:Biogen Idec, Novo Nordisk, Baxter : Membership on an entity’s Board of Directors or advisory committees. Ragni:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb, Smith Kline Glaxo, Tacere Benitec: Consultancy; Baxter, Bayer, Biogen Idec, Bristol Myers Squibb, CSL Behring, Merck, Novo Nordisk, Pfizer, Smith Kline Glaxo: Research Funding. Rangarajan:Baxter, Pfizer: Research Funding; Biogen Idec : Membership on an entity’s Board of Directors or advisory committees. Dong:Biogen Idec: Employment, Equity Ownership. Li:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment, Equity Ownership. Nugent:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Allen:Biogen Idec: Employment, Equity Ownership.

scholarly journals Adoption of Prophylaxis in the United States in the Era of Extended Half-Life Factor Concentrates

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2467-2467
Author(s):  
Lynn M. Malec ◽  
Gilbert C. White ◽  
Stacy E. Croteau ◽  
Dunlei Cheng ◽  
Margaret V. Ragni
Keyword(s):  
United States ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Number Of Patients

Abstract Background: Use of prophylaxis is the evidence-based strategy to prevent joint bleeds and reduce arthropathy for patients with severe hemophilia however, prophylaxis has not been universally adopted in the United States. Amongst patients with severe hemophilia enrolled in the ATHNdataset, the largest database of patients with disorders of hemostasis and thrombosis in the United States, as of 2015, 37% of patients with hemophilia A, and 45% of patients with hemophilia B do not receive prophylaxis. With the approval of extended half-life (EHL) factor products, patients and providers have options for less treatment-intense and burdensome prophylaxis. With the changing landscape of available hemophilia products, we aimed to quantify the number of patients treated at U.S. HTCs on prophylaxis utilizing the ATHNdataset with the objective determining the impact of EHL products on the proportion of patients with severe hemophilia receiving prophylaxis and to characterize use of prophylaxis according to age, race and ethnicity, geographic region, and payer. Methods: The ATHNdataset, a HIPAA compliant limited dataset sponsored by the American Thrombosis and Hemostasis Network (ATHN), was accessed as of June 30, 2018. The proportion of subjects with severe hemophilia on prophylaxis were compared to those on demand by age cohort. The proportion of subjects on prophylaxis was analyzed by race, ethnicity, insurance status, and hemophilia treatment center region. For each group receiving prophylaxis, the product (EHL versus standard half-life (SHL)), dose and frequency of treatment was analyzed. Results: ATHNdataset included 6,160 severe hemophilia patients using factor replacements, 5,234 individuals with hemophilia A and 926 individuals with hemophilia B. Overall, 76.0% (n=4,864) of patients with severe hemophilia are on prophylaxis whereas 24.0% (n=1426) are on demand; this included a total of 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B on prophylaxis. Treatment type (prophylaxis or not) had significant associations with age (p-value <0.001), ethnicity (p<0.001), race (p=0.005), hemophilia treatment center (HTC) region (p<0.001), and hemophilia type (p=0.015) (Table 1). Prophylaxis was not significantly correlated with payer (p=0.847) with a similar number of patients with Medicare/Medicaid or private insurance receiving prophylaxis. Among patients on prophylaxis, 30.8% (n=1,462) are prescribed EHL products including 27.4% of patients with hemophilia A and 50.4% with hemophilia B. In terms of dosing frequency (n=758), 73.8% of hemophilia A patients on prophylaxis receive EHL two times per week while 73.7% (n=1,906) receive SHL every other day (Table 2). Of hemophilia B patients using EHL products, 63.3% of patients receive prophylaxis once weekly, 12.7% every 10 days, and 15.0% every 2 weeks (Table 2). Discussion: The ATHNdataset highlights increased use of prophylaxis over the past 3 years in the U.S. with 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B currently receiving prophylactic therapy as compared to 63% and 55% of patients, respectively, in 2015. Further, the majority (83.7%) of patients are beginning prophylaxis according to the World Federation of Haemophilia recommendation to initiate prophylaxis by three years of age. There has been an uptake of the use of EHL factor products including a majority of patients (50.4%) with severe hemophilia B. Although not captured in the ATHNdataset, a plausible reason for the increased uptake of EHL in the hemophilia B population includes the data that 91% of patients are able to dose between weekly or less frequently. As the hemophilia treatment landscape continues to evolve, it is important to continue to understand the adoption of these new products into practice and to examine their real-world impact. Disclosures Malec: Shire: Consultancy; Bioverativ: Consultancy; Bayer: Consultancy; Bioverativ: Research Funding. White:Biomarin: Other: DSMB; Bioverativ: Other: DSMB; Bayer: Other: GRAC; Shire: Other: Physician Leadership Group; Novo Nordisk: Consultancy; Asklepios: Other: Scientific Advisory Board; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Croteau:Biomarin: Consultancy; Bioveritiv: Consultancy; Catalyst Biosciences: Consultancy; CSL-Behring: Consultancy; Genetech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Ragni:Sangamo: Research Funding; CSL Behring: Research Funding; Bioverativ: Consultancy, Research Funding; SPARK: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Shire: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

Long-Term Outcome Following B-Cell Depletion Therapy with Rituximab In Children and Adults with Immune Thrombocytopenia (ITP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 72-72 ◽  
Author(s):  
Vivek L. Patel ◽  
Matthieu Mahévas ◽  
Roberto Stasi ◽  
Susanna Cunningham-Rundles ◽  
Bertrand Godeau ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Initial Response ◽  
Response Rates ◽  
Advisory Committees ◽  
Term Outcome ◽  
Long Term Outcome ◽  
One Year

Abstract Abstract 72 Background: Studies of B-cell depletion using Rituximab in adults with ITP report responses lasting at least one year in almost all of the 30–40% of patients with complete responses (CR: platelet count >150 × 109/l) and also a small fraction of patients with partial responses (PR: platelet count 50–150 × 109/l). However data describing patients with ITP who are relapse-free and off-treatment beyond 1–2 years from initial Rituximab are almost entirely anecdotal and comparable response data are even less available for children. This study assessed the duration of unmaintained platelet response following rituximab treatment in 72 adults and 66 children with ITP, all of whom had had at least an initial response to rituximab. Long-term outcome was estimated from these data. Methods: Seventeen published studies including 486 patients, 376 adults and 110 children, were used to obtain the initial response rates to standard-dose rituximab treatment (375mg/m2 weekly for 4 weeks) in adults and children. Only 1 included study did not use the standard dose of rituximab. The Godeau study (Blood, 2008) was used to estimate the one-year response rate in adults with ITP. Only those adults whose responses persisted at least one year had follow up assessed whereas children who demonstrated even ephemeral responses were included. Only verified counts were used in this IRB-approved multicenter study. Results: 138 subjects with CR's or PR's after rituximab were included. All patients had starting platelet counts <30×109/l and 131 (95%) had ITP of > 6 months duration. Thirty-three (24%) had undergone splenectomy. Using the data from prior publications to obtain the initial response rates, children had a 56% initial response rate to rituximab treatment and adults had a 57% rate. Taking initial responders and then using the Godeau data for adults and Kaplan-Meier analysis of our data for children, 38% one-year response rates were obtained for both children and adults treated with rituximab. Both age groups also showed remarkable similarity at two years with 30% relapse-free response rates. However, all of the 26 eligible children maintained their response beyond two years whereas adults continued to relapse. Therefore the five-year response rate was 30% for children and only 21% for adults. Sex, duration of ITP, and age among adults did not affect long-term outcome. The rate of relapse was almost identical for splenectomized patients and non-splenectomized ones but the splenectomized patients appeared to relapse sooner (Figure). Patients with CR's (55 of the 72 adults with responses lasting at least one year were CR's) had better long-term outcomes than did patients with PR's even more than one year from initial treatment. B-cells returned significantly sooner to higher levels in subjects who relapsed compared to those whose responses were ongoing. No clinical long-term toxicity was observed but 2 patients were identified to have mild hypogammaglobulinemia > 30 months from initial treatment. Conclusions: In summary, only approximately 1 in 5 adults treated with rituximab will have an at least five-year relapse-free response rate which is disappointingly low; children have only a slightly higher five-year relapse-free response rate. A pilot study to improve outcomes using either R-CVP or double dose rituximab was unsuccessful (Hasan, Am J Hematol,2009) Current efforts to improve long-term response rates have focused on the combination of high dose dexamethasone and rituximab (or even by providing maintenance treatment with rituximab). A better understanding of the mechanism of effect of rituximab in patients with ITP might allow an improved treatment strategy to be developed. Fortunately, the toxicity of rituximab treatment in patients with uncomplicated ITP appears to be low; however, yearly testing for immunoglobulins for a minimum of five years might be appropriate. Disclosures: Neufeld: Novartis. Inc: Research Funding. Shenoy:Novartis Oncology: Honoraria. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy.

Outcome and Prognostic Factors in Patients with Mantle Cell Lymphoma Relapsing After Autologous Stem Cell Transplantation: A Retrospective Study of the EBMT

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 474-474 ◽  
Author(s):  
Sascha Dietrich ◽  
Herve Finel ◽  
Ariane Boumendil ◽  
Irit Avivi ◽  
Liisa Volin ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Mantle Cell ◽  
One Year

Abstract Abstract 474 BACKGROUND: Autologous stem cell transplantation (autoSCT) is considered as standard treatment for non-frail patients with mantle cell lymphoma (MCL). However, little is known about outcome of MCL recurrence after autoSCT. We therefore conducted a retrospective analysis of patients with MCL who failed autoSCT using the EBMT database. PRIMARY OBJECTIVE was to analyse outcome and prognostic factors after relapse following autoSCT for MCL in the rituximab era. PRIMARY ENDPOINT was overall survival (OS) from relapse. ELIGIBLE were patients aged 18 years or more who relapsed following an autoSCT for MCL performed between 2000 and 2010 and who were registered with the EBMT. Centres were contacted to provide additional information on relapse treatment. STATISTICAL ANALYSIS was based on log-rank comparisons and multivariable testing using Cox regression models. RESULTS: 1054 patients meeting the eligibility criteria could be identified in the EBMT registry. Of these, a full data set could be retrieved for 382 patients. Sixteen patients had to be excluded due to loss of follow up (n=7), wrong diagnosis (n=6), or falsely reported relapse (n=3). Median age at autoSCT of 366 evaluable patients was 59 years (range: 37 to 76), 290 patients (79%) were men. 64% had undergone autoSCT as part of 1st-line therapy; 68% and 49% had documented exposure to rituximab (RTX) and high-dose ara-C (HA) before autoSCT; and 12% had had refractory disease at autoSCT. Median time from autoSCT to relapse was 20 months (range: 0.4 to 117). 21 relapses (6%) occurred beyond 5 years after autoSCT. With a median observation time of 37 months (95% CI 32–43), median OS after relapse of the whole study group was 20 months. By univariate analysis, a long (>12mo) interval between autoSCT and relapse (p<0.001; HR 0.26; Figure 1A), 1st-line autoSCT (p=0.006; HR 0.7) refractory disease at autoSCT (p<0.001, HR 2.0) and more recent year of relapse (p<0.001, HR per year 0.9) significantly influenced OS from relapse, whereas age, gender, RTX and HA exposure did not. By multivariate analysis refractory disease at autoSCT (p<0.001, HR=2.14), remission duration after autoSCT (p<0.001 HR per 3 months 0.88) and calendar year of relapse (p<0.03, HR per year 0.93) were confirmed to be predictors for OS. In addition, HA exposure prior autoSCT adversely affected OS from relapse (p=0.06, HR 1.38). Salvage chemotherapy after relapse resulted in only 31% complete responses and 29% partial responses, whereas 40% of patients have been refractory to first salvage chemotherapy. 83 patients (23%) received an allogeneic SCT (alloSCT), whereas only 7 patients (2%) received a second autoSCT after relapse. Median time after relapse to second SCT was 7 months (range: 1 to 40). Survival after relapse for patients who received a second autoSCT was poor with no long-term survivor. AlloSCT performed for late relapse (>12mo) after autoSCT was associated with superior OS compared to patients who received an allograft upon a shorter remission duration after autoSCT (5-year OS from alloSCT 50% vs 0%; p=0.001; Figure 1B). Achievement of CR before alloSCT (p=0.05 HR=0.5), but not donor source, T-cell depletion or conditioning intensity affected OS after alloSCT. CONCLUSIONS: Patients with MCL who relapse within one year after autoSCT have an extremely dismal outcome even with alloSCT. In contrast, about half of the patients who have MCL recurrence beyond one year after autoSCT and can undergo salvage alloSCT enjoy long-term survival. It remains to be shown if a similarly good outcome can be achieved without alloSCT in this favourable selection of patients. A 2nd autoSCT does not appear to be a promising option in patients with MCL failing a 1st autoSCT. Disclosures: Walewski: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Cephalon: Research Funding.

Hypercholesterolemia In Imatinib Intolerant/Resistant CML-CP Patients Treated With Nilotinib: A Retrospective Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1503-1503 ◽  
Author(s):  
Devendra K. Hiwase ◽  
David T Yeung ◽  
Lisa Carne ◽  
David Ross ◽  
Andrew Grigg ◽  
...  
Keyword(s):  
Risk Factors ◽  
Lipid Profile ◽  
Retrospective Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Lipid Profiles ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Advisory Committees ◽  
Before And After

Abstract Background CML patients (pts) enjoy prolonged leukaemia-free survival with tyrosine kinase inhibitor (TKI) treatment. Addressing common non-CML causes of morbidity and mortality such as cardiovascular disease (CVD) and its associated risk factors is therefore increasingly important. Anecdotal evidence suggests a possible association between nilotinib (NIL) therapy and vascular events though there is little good quality evidence in this regard. The incidence of hyperlipidaemia and hyperglycaemia is higher in NIL-treated pts compared to imatinib- (IM) treated pts; conversely IM treatment may retard development of dyslipidaemia and hyperglycaemia. This retrospective analysis assessed the lipid profile of CML-CP pts before and after changing from IM to NIL therapy. Method Plasma lipid profile (total cholesterol, LDL, HDL and triglycerides), TKI exposure, and CVD risk factors before and after switchover to NIL of chronic phase CML pts were analysed. Baseline measurements were done during IM treatment or within 2 weeks of changing from IM to NIL. Follow-up results were obtained at least 1 month after starting NIL. Results Thirty-one CML pts were switched to NIL (median dose 400mg bd) after a median of 27 (1-96) months of IM therapy, predominantly for intolerance (16/31, 52%) or for failure to achieve deep molecular responses (13/31, 42%). Median age at NIL start was 51 (17-80) years (Table I). After switching to NIL, three pts had new onset PVD/IHD and one patient had multiple recurrences of PVD. Antihypertensive and hypoglycaemic medications were started in one additional patient each after switching over to NIL. Three pts were excluded from further analysis because of lack of data (n=2) or pre-existing dyslipidemia (n=1). The remaining pts had 90 TC assays, 72 of which were full lipid profiles whilst on NIL. Observations were censored at the time of statin commencement. Median time to 1st lipid measurement on NIL was 108 days (28-633) after switching. Median TC on IM was 4.7mM (2.1-6.4), compared to 6.1mM on NIL (3.1-8.5). Median peak TC on NIL was 6.8mM. Full fasting lipid profiles available for 11 pts before and after switching showed significantly increased LDL to be the major contributor to the increase in TC (Fig. 2). Thirteen pts had a fasting TC >5.5 mM (210 mg/dL) whilst on NIL, peaking at 312 days (medians). Eight of 13 pts started statins treatment for dyslipidemia whilst on NIL; (all retrospectively confirmed to be appropriate according to Australian National Heart Foundation guidelines, using a composite measure of CVD risk); whilst the other 5 were offered lifestyle modifications only. Of note, 2 pts had dyslipidaemia prior to starting IM treatment, discontinued statins whilst on IM, and had recurrence of dyslipidaemia after switching to NIL necessitating resumption of statin treatment. In addition, the 2 pts with PVD were also offered statins (total starting statin n=10) Discussion This retrospective analysis showed a high incidence of dyslipidemia in a cohort of CML pts treated with second-line NIL after IM therapy; 10/31 pts required lipid lowering agent. While the epidemiological association between nilotinib and CVD remains controversial, the increase in TC may have a contributing effect. Monitoring lipid levels in NIL-treated pts is prudent, along with screening for and minimisation of concomitant CVD risk factors, especially in pts previous treated with IM which may mask underlying metabolic syndromes. # DKH DTY and LC contributed equally to this work. Disclosures: Hiwase: Novartis Pharmaceuticals: Research Funding. Yeung:Novartis: Honoraria, Research Funding; BMS: Honoraria. Hughes:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Natural History Of Inhibitor Recurrence Following Successful Immune Tolerance Induction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1106-1106 ◽  
Author(s):  
Ana G. Antun ◽  
Paul Monahan ◽  
Marilyn J. Manco-Johnson ◽  
Michael Callaghan ◽  
Guy Young ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Immune Tolerance ◽  
Half Life ◽  
Research Funding ◽  
Tolerance Induction ◽  
Advisory Committees ◽  
Immune Tolerance Induction ◽  
Baxter Healthcare ◽  
Inhibitor Titer

Abstract Introduction The formation of Factor VIII (FVIII) inhibitory antibodies is a major complication of hemophilia A. Currently immune tolerance induction (ITI) is successful in up to 70% of patients. Outside of the International Immune Tolerance Registry, where 6 of 128 patients had a recurrent inhibitor between 1 and 6 years, little is known about the probability of inhibitor recurrence following successful ITI. Objective To determine the probability of inhibitor recurrence and the influence of adherence to post-ITI prophylaxis on inhibitor recurrence following successful ITI. Methods All persons with hemophilia A (FVIII level < 50%) who completed ITI (defined as inhibitor titer <0.6 BU/ml) between 1/1/1998 and 8/15/2010 at 12 U.S. Hemophilia Treatment Centers were identified. Demographic and clinical characteristics were obtained through review of subject medical records and included age at start of ITI, race, ethnicity, hemophilia severity, peak inhibitor titer prior to the start of ITI and ITI regimen. For those subjects where tolerance was confirmed with measurement of FVIII half-life > 6 hours and/or FVIII recovery > 66% in addition to inhibitor titer < 0.6 BU/ml, information was also collected on post-ITI prophylaxis regimen, adherence to post-ITI prophylaxis, and the presence of a recurrent inhibitor titer (≥ 0.6 BU/ml) or last inhibitor titer prior to 8/15/2011. Adherence during the 6 months prior to inhibitor recurrence or last inhibitor titer was determined by review of pharmacy and infusion logs compared with prescribed treatment regimen. Follow-up time started when the subject was considered tolerized (normalized half-life or recovery if half-life not performed) and ended at the time of inhibitor recurrence or the last recorded inhibitor titer. Estimates of the probability of remaining inhibitor-free at 1, 3 and 5 years were calculated with the Kaplan-Meier method. The association between adherence (completing >80% of prescribed infusions vs. < 80% of prescribed infusions) and inhibitor recurrence was assessed using the chi-square test. Results Eighty-three male subjects were enrolled. The median age at start of ITI was 3.3 years (range: 0.08 - 39). The majority of the subjects were white (73%) and non-Hispanic (73.5%). Seventy-one (85.6%) had severe hemophilia. The median peak inhibitor titer was 8.5 BU/ml (range: 0.6 - 950). Four subjects (5%) had a prior unsuccessful course of ITI. FVIII alone was used in 85% of subjects. Sixty-seven (80.7%) met criteria for tolerance and 64 had follow-up data available, with a median follow up time of 3.4 years (range: 0.08-12.4). Forty-four subjects (68.7%) remained tolerant without a recurrent inhibitor titer after a median 4.7 years (range: 0.25-12.4) of follow-up. Twenty subjects (31.3%) had at least one inhibitor titer ≥ 0.6 BU/ml after a median of 1.6 years (range 0.08-5.7). The probability of recurrent inhibitor at 1 year is 0.15 (95% CI: [0.05, 0.20]); at 3 years is 0.30 (95% CI: [0.2, 0.4]) and 5 years is 0.35 (95% CI: [0.2, 0.5]) (Figure 1). Four subjects discontinued post-ITI prophylaxis anywhere from 6 months to greater than 6 years after tolerance was achieved, of whom 2 (50%) developed a recurrent inhibitor. Of those that remained on post-ITI prophylaxis, 41 subjects (64.1%) were adherent (took >80% of prescribed infusions) to their post-ITI prophylaxis regimen, of whom 13 (31.7%) developed a recurrent inhibitor. Twenty-three (35.9%) who were non-adherent (took <80% of the prescribed infusions) of which 7 (30.4%) subjects developed a recurrent inhibitor; no statistically significant association was found between adherence and inhibitor-free status (p=0.92). Conclusion ITI is currently the most effective treatment to eradicate FVIII inhibitors, however 5 years after completion, 30-35% of patients will have at least one inhibitor titer ≥ 0.6 BU/ml. A recurrent inhibitor is unlikely after 5 years. Adherence to post-ITI prophylaxis does not appear to be a major driver of inhibitor recurrence. It is imperative to elucidate the factors that influence the durability of successful ITI to improve quality of life and cost of treatment in these patients. Disclosures: Monahan: Baxter: Consultancy, Honoraria, Research Funding, travel support, travel support Other; Bayer: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Prolor Biotech: Research Funding; Asklepios: Consultancy, Research Funding, travel support Other. Manco-Johnson:Eisai: Research Funding; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Carpenter:Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding. Kruse-Jarres:Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy; Baxter Healthcare: Consultancy. Ragni:Novo Nordisk: Research Funding; Merck: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Tacere Benitec: Consultancy; Smith Kline Glaxo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Kempton:Novo Nordisk: Research Funding; Baxter Healthcare: Membership on an entity’s Board of Directors or advisory committees.

Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3778-3778
Author(s):  
Amy L. Dunn ◽  
Alexis A. Thompson ◽  
Werner Engl ◽  
Marlies Sharkhawy ◽  
Brigitt E. Abbuehl
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Point Estimate ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

scholarly journals Spontaneous Bleeding and Poor Bleeding Response with Extended Half-Life Factor IX Products: A Survey of Select US and Canadian Hemophilia Treatment Centers

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2407-2407 ◽  
Author(s):  
Lynn M Malec ◽  
Stacy E. Croteau ◽  
Michael Callaghan ◽  
Davide Matino ◽  
Kenneth Dale Friedman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Factor Ix ◽  
Hemophilia B ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Spontaneous Bleeding ◽  
Recombinant Factor Ix ◽  
Traumatic Bleeding ◽  
Hemophilia Treatment Centers

Background: Factor IX (FIX) has distinct pharmacokinetic properties compared to factor VIII including significant distribution to the extravascular space. Extravascular distribution and binding to type IV collagen is important in hemostasis but not readily measureable in clinical practice for patients with hemophilia B receiving factor products. We previously reported data regarding use of EHL-FIX products in a cohort of patients who demonstrated issues with spontaneous bleeding and poorly controlled bleeding events; we now report data from an expanded cohort including performance of all EHL-FIX products available in US and Canada. Aims: To characterize the use and performance of EHL-FIX in clinical practice at six hemophilia treatment centers (HTCs). Methods: An electronic survey regarding center specific use of EHL-FIX amongst patients with severe hemophilia B (HB) was sent in summer 2019, including 4 previously surveyed centers and 2 additional centers. Providers were asked if patients utilizing EHL-FIX for prophylaxis had experienced 1) spontaneous/minimally traumatic bleeding events at factor levels >10% or 2) poorly controlled bleeding events requiring more frequent/higher doses of EHL-FIX than anticipated in addition to patterns of EHL-FIX product switching. Results: Surveyed HTCs cared for 90 patients with HB including 67 (74%) who utilized EHL-FIX, including 26 (39%) recombinant factor IX (FIX) albumin fusion protein (rFIX-FP), 37 (55%) recombinant factor IX Fc fusion protein (rFIXFc), and 4 (6%) received glycopegylated recombinant FIX (rFIX-GP). All patients had severe hemophilia B with the exception of one smaller center also contributing data regarding moderate HB patients on prophylaxis. All centers reported having patients with unexpected spontaneous/minimally traumatic bleeding and poorly controlled bleeding which did not seem to be dependent on age (median age 14.5 years, range 1.4-44). This occurred in 18 patients on prophylaxis, including 16 of 26 (62%) patients using rFIX-FP, and 2 of 4 (50%) of patients using rFIX-GP. Conclusions: Although plasma FIX activity levels have driven prophylaxis and bleed management decisions, clinical experience suggests novel properties of EHL-FIX may impact hemostasis. Although achieving seemingly adequate FIX plasma troughs (>10%), limited clinical experience suggests patients with SHB may have a differential response to EHL-FIX, noted in our cohort with FIX-FP and rFIX-GP. Successful bleed prevention or control in SHB may be predicted by the distribution of FIX in circulation and extravascular space, and the presence of FIX in tissues at time of injury. These data demonstrate the importance of real-world monitoring of efficacy of new FIX products and suggest the need for more robust mechanisms to understand the hemostatic performance of products. Disclosures Malec: Bayer: Honoraria; Spark: Honoraria; CSL: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria. Croteau:Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Octapharma: Honoraria; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Callaghan:Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Alnylum: Equity Ownership; Bayer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Global Blood Therapeutics: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy; Pfizer: Research Funding; Roche: Research Funding; Shire/Takeda: Speakers Bureau; Roche/Genentech: Speakers Bureau. Matino:Bayer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Bioviiix: Honoraria; Sanofi: Honoraria. Friedman:CSL: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Instrumentation Laboratory: Consultancy; Siemens: Consultancy. Sidonio:Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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