Risk Factors for the Development of High-Titer Inhibitors in 260 Children with Severe Hemophilia a Born Between 1990 and 2009: The Remain Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3774-3774
Author(s):  
Maria Elisa Mancuso ◽  
Kathelijn Fischer ◽  
Elena Santagostino ◽  
Johannes Oldenburg ◽  
Helen Platokouki ◽  
...  
Keyword(s):  
Family History ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
History Of

Abstract The development of anti-FVIII antibodies (i.e., inhibitors) is the major side effect of severe hemophilia A treatment. Inhibitors mainly develop in children during the first 50 exposure days and are classified in low-and high-titer (i.e., peak titer < or > 5 UB/ml). High-titer inhibitors have the major clinical impact. At diagnosis however, the real nature of the antibody is not clear in all patients, since some low-titer inhibitors may progress to high-titer. The determinants of the evolution from low- to high-titer inhibitors are still unclear and the aim of the present study was to investigate potential risk factors associated with the progression from low- to high-titer inhibitors. This study is a follow-up study of the PedNet Registry and includes 260 children with severe hemophilia A and clinically relevant inhibitors, born between 1990 and 2009 and consecutively recruited from 31 hemophilia centers in 16 countries. Clinical and laboratory data were collected from the date of first positive inhibitor test and covered a minimum of 3-years follow-up. Factors potentially associated with progression from low- to high-titer inhibitor development were analyzed using univariate and multivariate logistic regression. F8 mutation type was known in 247 patients (95%), including 202 (82%) null mutations (i.e., large deletions, nonsense mutations and inversions). Positive family history of inhibitors was present in 37 of 99 (37%) with positive family history of hemophilia. At diagnosis 49% (n=127) had low-titer inhibitors, however, upon FVIII re-exposure, 50% of low-titer inhibitors progressed to high-titer and only 25% of patients (n=69) had persistent low-titer inhibitors. Within the first 3 years of follow-up, immune tolerance induction (ITI) was equally implemented in around 80% of low-and high-titer patients but it was started later in children with high-titers (median time to ITI start 4.5 vs 0.3 months; p<0.001) in whom daily regimens and high-dose FVIII were more frequently adopted (89, 67% vs 41, 50% and 98, 74% vs 35, 43%; p=0.01 and <0.001, respectively). Overall high-titer inhibitor development was associated with null F8 mutations (OR 2.8, 95%CI 1.4-5.5) and family history of inhibitors (OR 3.9, 95%CI 1.2-12.6). The progression from low- to high-titer inhibitors during follow up, was associated with the use of high-dose ITI regimens (i.e., >100 IU/kg/day) with an OR of 3.9 (95%CI 1.5-10.0), independent from the effects of F8 mutation type (adjusted OR 3.6, 95%CI 1.4-9.8) and family history of inhibitors (adjusted OR 6.7, 95%CI 1.1-42.6). No difference was found by comparing the use of daily versus non-daily ITI. In conclusion, in a cohort of 260 children with severe hemophilia A and inhibitors, 49% presented with low-titers at diagnosis and 46% of them progressed to high-titers during follow-up. Progression to high-titer inhibitors was associated with the use of high-dose ITI. These results suggest that intensive ITI should be avoided as initial strategy in low-titer inhibitor patients. Disclosures Mancuso: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Fischer:Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Santagostino:Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Sobi: Consultancy; Biogen Idec: Consultancy; Roche: Consultancy; Grifols: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Liesner:BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding.

Phase II Trial of Rituximab in the Treatment of Inhibitors in Congenital Hemophilia A: Results of the RICH Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 27-27 ◽  
Author(s):  
Cindy A. Leissinger ◽  
Rebecca Kruse-Jarres ◽  
Suzanne Granger ◽  
Barbara A Konkle ◽  
Margaret V. Ragni ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Null Hypothesis ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Minor Response ◽  
Inhibitor Titer

Abstract Abstract 27 Antibodies (inhibitors) to exogenously administered factor VIII (FVIII) develop in as many as 30 – 40% of patients with severe hemophilia A. Patients with persistent inhibitors are at increased risk of serious, poorly controlled bleeding which results in significant morbidity and in some cases early death. Rituximab, a chimeric murine/human monoclonal antibody directed against CD20, suppresses circulating and tissue B cells and pre-B cells and has been used in the treatment of a variety of autoimmune and alloimmune disorders. The primary objective of this NHLBI Transfusion Medicine Hemostasis network-sponsored study was to evaluate the role of rituximab as an approach to inhibit the production of FVIII antibodies in patients with severe congenital hemophilia A and high titer inhibitors. Methods: This was a prospective, multi-institution, single-arm, open-label Phase II trial. Eligible subjects were males over 18 months of age with severe hemophilia A and a history of an inhibitor ≥5 Bethesda units (BU). Individuals who were HIV positive, undergoing immune tolerance, or receiving immune modulating therapies were excluded. Following a challenge dose of recombinant FVIII (rAHF-PFM) at 50 IU/kg, and evidence of an inhibitor titer ≥ 5 BU at 5 – 14 days after the challenge dose, subjects received rituximab 375 mg/m2 weekly for 4 weeks. Starting two weeks after the fourth rituximab treatment, inhibitor titers were drawn every 4 weeks. A major response was defined as a fall in the inhibitor titer to < 5 BU at any time up to and including week 22, with the titer remaining < 5 BU following re-challenge with FVIII. A minor response was defined as inhibitor falling to < 5 BU at any time up to and including week 22, with the anamnestic peak following re-challenge with FVIII between 5–10 BU and less than 50% of the original anamnestic peak. The null hypothesis was that no more than 5% of subjects treated with rituximab would be major responders. Results: A total of 23 subjects were enrolled; 21 received the initial FVIII challenge. Of these, 4 subjects did not meet the criteria to receive rituximab treatment, and 1 subject withdrew consent. A total of 16 subjects received at least one dose of rituximab and are included in this analysis. The median age was 14 y (range 4 – 38 y). Three subjects (18.8%) had a major response. If the null hypothesis were true, the probability of 3 or more major responses in 16 subjects would be 0.043, so the null hypothesis was rejected. One subject (6.2%) had a minor response to treatment. All 4 responders and 8 non-responders had a baseline inhibitor titer < 20 BU, resulting in a response rate of 33% in that group vs. 0% in the 4 subjects with a baseline inhibitor titer ≥ 20 BU. Discussion: Infusion of rituximab 375 mg/m2 once per week for four weeks was effective in reducing the anamnestic inhibitor response in 25% of severe hemophilia A subjects with inhibitors who were not receiving concurrent immune tolerance therapy. Those who responded tended to have lower baseline inhibitor levels compared to the group that did not meet the criteria for response. This Phase II study, designed as a proof of concept, demonstrated that rituximab may be useful in lowering inhibitor levels and anamnesis in some patients with inhibitors, but that the effect as a solo treatment strategy is modest, and possibly restricted to patients with inhibitor titers under 20 BU. Further studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerization strategies. Acknowledgments: The authors acknowledge the support of Genentech for the provision of rituximab and partial financial support for the study. The authors also acknowledge Baxter Healthcare Corporation for donating the recombinant FVIII used in the trial. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab, a drug approved for use in treating lymphoma, was studied for its efficacy in suppressing inhibitors against factor VIII in patients with hemophilia and high titer inhibitors. Kruse-Jarres:Baxter: Consultancy, Honoraria; Bayer:; Griforls: Consultancy, Honoraria; Inspiration: Consultancy, Honoraria; NovoNordisk: Consultancy, Honoraria. Konkle:Baxter Corporation: Consultancy, Research Funding; Bayer Corp: Consultancy; Inspiration Biopharmaceuticals: Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees. Neufeld:Genentech: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Bennett:Biogen IDEC: Honoraria. Valentino:Baxter Bioscience, Bayer Healthcare, GTC Biotherapeutics, NovoNordisk, Pfizer, CSL Behring, Inspiration Bioscience, and Biogen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals 99.3% of Inhibitors in Severe Hemophilia a Develop before Exposure Day 75. Time to Change Definition of Previously Treated Patients; Data from 1038 Patients with Severe Hemophilia a of the Pednet Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2472-2472
Author(s):  
Marijke Van den Berg ◽  
Kathelijn Fischer ◽  
Elena Santagostino ◽  
Herve Chambost ◽  
Karin Kurnik ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Definition Of

Abstract Introduction.In patients with hemophilia treated with factor VIII products, the development of inhibitory antibodies poses the largest safety risk. Especially during the first 50 exposure days (EDs), up to 37% of patients with severe hemophilia A have been reported to develop an inhibitor. To study neo-immunogenicity of products and new treatment strategies, patients have been distinguished into previously untreated (PUPs) and previously treated patients (PTPs); the latter defined as patients treated for more than 150 EDs. The number of 150 EDs was established in the eighties during a time when most patients received on-demand treatment and testing for inhibitors was not frequently performed. More recent studies on inhibitor incidence in PUPs with severe hemophilia A report that 50% of inhibitors develop within 14-15 EDs, however the cut-off number of EDs for a PUP to become a PTP is not well defined. The aim of this study was to define the number of EDs for PUPs to become PTPs based on long-term follow-up of patients with severe hemophilia A Methods.All patients with severe hemophilia A born after January 1, 2000, treated for at least 1 ED and followed prospectively until inhibitor development or the number of EDs at last follow-up, were included. The number of EDs at inhibitor development is the last exposure day before the first positive titer was reported. An inhibitor was defined as positive when at least two positive inhibitor titers were measured. Positivity was defined according to the cut-off level in each individual center's laboratory. Results.Of 1,038 PUPs with severe hemophilia A, 930 (89.6%) were followed until 75 EDs, 429 until 500 EDs and 212 until 1000 EDs. In total, 300 inhibitors developed, of which 298 (99.3%) within the first 75 EDs. Thereafter only two inhibitors developed, both low titer: after 249 and 264 EDs. Conclusion.Almost all inhibitors develop during the first 75 EDs. Patients with severe hemophilia A can be defined as PTP after 75 instead of 150 exposure days. A change of definition of PTP will increase the number of severe hemophilia A patients eligible for new therapies. Disclosures Santagostino: Bioverativ: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Male:SOBI: Speakers Bureau; Shire: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Speakers Bureau; Novo Nordisk: Speakers Bureau; Biotest: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oldenburg:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liesner:Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Sobi: Speakers Bureau; Bayer: Consultancy, Research Funding; Roche: Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau. Carcao:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nolan:CSL Behring: Research Funding; Sobi: Research Funding; Bayer: Research Funding. Álvarez-Roman:Shire: Consultancy; NovoNordisk: Consultancy; SOBI: Consultancy. Koenigs:Gilead: Research Funding; CSL Behring: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Intersero: Research Funding; Bioverativ: Consultancy; Roche/Chugai: Consultancy; EU (IMI, FP7): Research Funding; Sobi: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding; Novo Nordisk: Consultancy, Speakers Bureau; Biotest: Research Funding, Speakers Bureau; Jansen: Research Funding.

scholarly journals BIVV001: The First Investigational Factor VIII Therapy to Break Through the VWF Ceiling in Hemophilia A, with Potential for Extended Protection for One Week or Longer

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 636-636 ◽  
Author(s):  
Barbara A Konkle ◽  
Amy Shapiro ◽  
Doris Quon ◽  
Janice Staber ◽  
Takashi Suzuki ◽  
...  
Keyword(s):  
Single Dose ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
High Dose ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Dose Cohort

Abstract Introduction: The standard of care for patients with severe hemophilia A is prophylactic factor VIII (FVIII) replacement. Conventional recombinant FVIII products are efficacious but require frequent administration because of their short half-life, which reflects the dependence of FVIII on von Willebrand factor (VWF). Recombinant FVIII Fc fusion protein (rFVIIIFc) provides an extended dosing interval, as well as joint protection and improved quality of life (Oldenburg et al, Haemophilia, 2018; Wang et al, Blood, 2016), with a well-characterized safety profile. While rFVIIIFc reduces the required administration frequency, longer prophylactic dosing intervals that also offer maximum overall protection are still an unmet need for patients with severe hemophilia A. Increasing the half-life of rFVIII is ultimately dependent upon decoupling FVIII and endogenous VWF. BIVV001 (rFVIII-VWF-XTEN) is a novel investigational rFVIII therapy with single-chain FVIII, the Fc domain of human immunoglobulin G1, 2 XTEN polypeptides, and the FVIII-binding D′D3 domain of VWF, designed to circulate in plasma independently of VWF, thereby breaking the VWF half-life ceiling. Here, we present the low-dose cohort results of EXTEN-A, a Phase 1/2a study assessing the safety and tolerability of a single dose of BIVV001, and the pharmacokinetic (PK) characteristics of a single dose of BIVV001 compared with rFVIII. Methods: EXTEN-A (NCT03205163) is an open-label, dose-escalation, multicenter study. Previously treated adult males with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII activity) with ≥150 exposure days to FVIII products were included. Patients were assigned to either the low-dose cohort (25 IU/kg of rFVIII and 25 IU/kg of BIVV001; n≥6) or the high-dose cohort (65 IU/kg of rFVIII and 65 IU/kg of BIVV001; n≥8). Escalation from the low-dose cohort, and enrolment of patients to the high-dose cohort was undertaken after assessment of available data from the low-dose cohort. After a screening and washout period of up to 28 days, patients received a single dose (25 or 65 IU/kg) of rFVIII. After a 3- to 4-day washout period, patients received a single dose of BIVV001 at the same dose level as rFVIII. Blood samples for PK analysis were collected for 3 days after dosing of rFVIII and up to 14 days after dosing of BIVV001. Inhibitor testing was performed 14 and 28 days following BIVV001 administration. Adverse events, clinical abnormalities in laboratory tests (including inhibitor development), and PK parameters were assessed. An interim analysis is planned, including the first 2 patients of the high-dose cohort. Results: Out of 7 patients enrolled in the low-dose cohort (25 IU/kg), 6 patients were dosed with BIVV001. Patients in this group were primarily white, with 1 patient of Asian descent, and 1 of Hispanic/Latino ethnicity. Patient ages ranged from 19 to 60 years. Low-dose BIVV001 was well tolerated and no inhibitors were detected through 28 days after BIVV001 dosing. Low-dose BIVV001 demonstrated an extended half-life of 37.6 hours, compared with a 12.1-hour half-life for rFVIII. Average FVIII activity post-infusion of BIVV001 was 12.2% at 5 days and 5.3% at 7 days. At least 8 patients will be enrolled in the high-dose cohort (65 IU/kg); preliminary data for the first 2 patients will be reported. Conclusions: BIVV001 was well tolerated in 6 patients with severe hemophilia A who were treated with a single low dose (25 IU/kg). No patient developed an inhibitor to FVIII. Low-dose cohort data demonstrated a breakthrough in the half-life of rFVIII therapy, with BIVV001 providing sustained FVIII levels that could potentially allow for more optimal, extended protection for patients. Disclosures Konkle: Genentech: Consultancy; Spark: Consultancy, Research Funding; Pfizer: Research Funding; Gilead: Consultancy; CSL Behring: Consultancy; Bioverativ: Research Funding; BioMarin: Consultancy; Sangamo: Research Funding; Shire: Research Funding. Shapiro:Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioMarin: Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo Biosciences: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; OPKO: Research Funding; Octapharma: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Daiichi Sankyo: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding. Quon:Bioverativ, a Sanofi Company: Speakers Bureau; Octapharma: Consultancy; Genetech: Consultancy, Speakers Bureau; Bayer: Consultancy; NovoNordisk: Consultancy, Speakers Bureau; Shire: Speakers Bureau. Staber:uniQure: Honoraria; NovoNordisk: Consultancy; Bayer: Honoraria. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Poloskey:Bioverativ: Employment. Rice:Bioverativ: Employment. Katragadda:Bioverativ: Employment. Rudin:Bioverativ: Employment, Equity Ownership. Fruebis:Bioverativ: Employment, Other: Clinical Development.

scholarly journals Incidence of Inhibitors in a Previously Untreated Patients with Severe Hemophilia Α Cohort Treated with a Single Third-Generation Recombinant Factor VIII Concentrate

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1211-1211
Author(s):  
Alessandra N L Prezotti ◽  
Monica H Cerqueira ◽  
Marilia Renni ◽  
Clarissa Ferreira ◽  
Ieda S. Pinto ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Bleeding ◽  
Third Generation ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
African Descendants

Abstract Introduction: One of the most important complications in the treatment of patients with hemophilia A is the formation of neutralizing antibodies (inhibitors) interfering in the coagulant activity of factor VIII (FVIII). The presence of inhibitor causes a direct impact on mortality and morbidity in these patients and considerably increases the cost of treatment. Among the non-genetic risk factors for inhibitor development, the influence of the type of factor concentrate used in replacement therapy (recombinant or plasma-derived) remains controversial. Thus, the evaluation of an additional population in the real world setting may contribute to elucidate this problem. Since August 2013, almost all previously untreated patients (PUPs) with hemophilia A in Brazil have been receiving exclusively the same third-generation recombinant FVIII (rFVIII) (Advate®, Shire). Objective: The aim of this study is to evaluate the immunogenicity of rFVIII (Advate®). In this context, we analyzed the occurrence of inhibitor among severe and moderately severe hemophilia A PUPs during the first 50 exposure days (EDs) to Advate®. Methods: This is an open-label, multicenter, prospective/retrospective, uncontrolled, observational study conducted in eight reference hemophilia treatment centers from distinct geographic areas in Brazil. The inclusion criteria were (a) diagnosis of severe or moderately severe hemophilia A (FVIII:C <2 IU/dL), (b) absence of previous exposure to other FVIII concentrates, except a maximum of 5 previous exposures to any blood components (whole blood, fresh-frozen plasma, packed red cells, platelets, or cryoprecipitate), and (c) exclusive treatment with Advate® until the 50th ED or until inhibitor development (primary endpoint). Positive inhibitor was defined as at least two consecutive plasma samples with Bethesda-Nijmegen assay results ≥0.60 BU/mL. Patients were considered as having low-titer inhibitors when peak titers were <5 BU/mL, and high-titer inhibitors if inhibitor titer was ≥5 BU/mL on at least one occasion. Any clinical information considered relevant for the risk of inhibitor development was analyzed when available, and included family history of inhibitor, F8 genotype, ethnicity (defined according physical traits and ancestry ethnic background in the last three generations), age at first rFVIII exposure, treatment regimens (prophylaxis or episodic), doses, occurrence of a severe bleeding episode, surgery, and use of FVIII concentrate simultaneously to infection or vaccination. Results: So far, 122 patients were enrolled, and 100 patients reached the 50th ED to rFVIII or developed inhibitor. Twenty-two are still on Advate® and have not achieved 50EDs (7 patients: 20 to 50EDs; 15 patients: <20ED). Overall, the median age at first exposure to Advate® was 11.9 months (interquartile range (IQR): 7.5-16.7), and most patients were African-descendants (48%), followed by Caucasians (45%). Positive inhibitor was detected in 35 of the 100 patients (35%), and 71% occurred during the first 20EDs. Most inhibitors were detected during prophylactic treatment (29 of 35; 82.9%). Twenty-five (25%) patients had high-titer inhibitor. Although not statistically significant, 19/48 (39.6%) of the African-descendants patients developed inhibitor, in contrast to 15/45 (33%) of the Caucasians. Interestingly, inhibitor was detected in only 1/7 (14.6%) of the patients with the indigenous background (native population). The influence of other risk factors, as severe bleeding episodes, presence of infection, surgery and history of blood transfusion, were not statistically significant. Conclusions: Overall inhibitor development in this cohort is consistent with results reported in other PUP studies with recombinant products. The majority of inhibitors developed during the first 20EDs. However, no other risk factor as intensive treatment was statistically significant, due to the small number of events observed. Although observational studies have limitations to assess the immunogenicity of FVIII products, our study contributes to this knowledge, since it evaluates a single third-generation rFVIII in a distinct population, with similar access to factor concentrate and same treatment regimen. Disclosures Prezotti: Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bioverative: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Medina:Shire: Speakers Bureau. Ozelo:Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; BioMarin: Honoraria, Speakers Bureau; Shire: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Honoraria, Research Funding; Grifols: Honoraria.

scholarly journals Outcomes of Severe Hemophilia a Patients on Continuous Prophylaxis Relative to Inhibitor Status in the Community Counts Registry

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1405-1405
Author(s):  
Marilyn J. Manco-Johnson ◽  
Vanessa R. Byams ◽  
Roshni Kulkarni ◽  
Brandi Dupervil ◽  
Becky Dudley ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Bleeding Disorders ◽  
Severe Hemophilia ◽  
Opioid Use ◽  
Advisory Committees ◽  
Active Inhibitor ◽  
History Of ◽  
Bypassing Agents

Abstract Background: Continuous prophylaxis, or the routine replacement of deficient clotting factor, is the standard of care therapy for individuals with severe hemophilia A and joint bleeding. In the United States (US), the majority of eligible patients are prescribed continuous prophylaxis, including approximately 75% of children < 20 years of age. However, up to 30% of severe hemophilia A patients develop neutralizing alloantibodies that render factor replacement ineffective requiring inhibitor eradication through induction of immune tolerance (ITI) therapy. Tolerized patients demonstrate successful elimination of inhibitors and normal response to FVIII concentrates. Non-tolerized patients can also be treated on prophylaxis using bypassing agents. Aim: This analysis used national surveillance data to compare joint and other outcomes in persons with severe hemophilia A on continuous prophylaxis in three groups: no history of an inhibitor, likely tolerized inhibitor and active (non-tolerized) inhibitor. Methods: The Community Counts bleeding disorders surveillance project is funded by the Centers for Disease Control and Prevention (CDC) through a cooperative agreement awarded to the American Thrombosis and Hemostasis Network (ATHN) in partnership with the US Hemophilia Treatment Center Network (USHTCN). The Registry for Bleeding Disorders Surveillance component collects detailed medical information on patients with bleeding disorders who receive treatment within the USHTCN. Likely tolerized inhibitors were defined as having a history of a previous inhibitor and currently being treated with FVIII concentrate; active inhibitors were defined as having a history of a previous inhibitor and being treated with bypassing agents. Using the Registry component, the following data elements, stratified by age and inhibitor status, were extracted from the initial visit form: demographics, treatment regimen, mobility, cumulative joint bleeding, invasive joint procedures, pain and opioid use. Results: Data on 1,300 persons with severe hemophilia A were analyzed including: 739 with a negative inhibitor history; 410 likely tolerized inhibitor patients; and 151 with an active inhibitor. The 410 patients represented 73% of participants with a positive inhibitor history, similar to the North American Inhibitor Registry (DiMichele D, Haemophilia 2009;15:320-8). Participants with likely tolerized inhibitors were treated using continuous prophylaxis in similar proportion to participants with no history of inhibitor (83% vs 78%, respectively), and more often than participants with active inhibitor (83% vs 65%); however outcomes of participants on continuous prophylaxis were similar in all three groups (Table 1). Patients < 20 years of age had less disability, and fewer joint bleeds, invasive procedures, pain and opioid use compared with adult participants. Conclusions: Improved outcomes on preventive strategies may be best determined prospectively in younger patients due to the lesser degree of established morbidity. Persons with severe hemophilia A on continuous prophylaxis with likely tolerized inhibitors (using FVIII) or with active inhibitors (using bypassing agents) demonstrate outcomes similar to those without inhibitors. However, more age- and treatment regimen- stratified analysis is needed for more precise comparisons. Future findings may contribute to the perspective that prophylaxis should be the standard of care for all hemophilia patients regardless of inhibitor status. Disclosures Manco-Johnson: Bayer: Honoraria, Research Funding; Baxalta: Honoraria; NovoNordisk: Honoraria; BiogenIdec: Honoraria; CSL Behring: Honoraria. Kulkarni:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; BPL: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding, Speakers Bureau. Buckner:Novo Nordisk: Consultancy; Genentech: Consultancy; Baxalta: Consultancy.

scholarly journals U.S. Cohort Study of Previously Untreated Patients with Congenital Hemophilia (ATHN 8: PUPs Study): Association between Family History and Age of Diagnosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Courtney D Thornburg ◽  
Kenneth D Friedman ◽  
Michael F Guerrera ◽  
Chunla He ◽  
Lynn M Malec ◽  
...  
Keyword(s):  
Family History ◽  
Board Of Directors ◽  
Interim Analysis ◽  
Research Funding ◽  
Hemophilia A ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Age Of Diagnosis

Introduction: ATHN 8: U.S. Cohort Study of Previously Untreated Patients (PUPs) with Congenital Hemophilia is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at ATHN-affiliated sites in the United States. The ATHN 8: PUPs Study collects detailed demographic, diagnosis, treatment, bleed, and inhibitor data on children with moderate and severe hemophilia born on or after January 1, 2010 and followed at an ATHN-affiliated hemophilia treatment center (HTC). The endpoint for the overall study is inhibitor development or achieving 50 exposure days. A confirmed inhibitor is defined as two consecutive positive inhibitor titers (&gt;0.5 Nijmegen Bethesda Units (BU) for hemophilia A and &gt;0.3 Nijmegen BU for hemophilia B) which results in change in treatment. Available family history is also collected. For this interim analysis, we hypothesized that children with severe hemophilia A (HA) and a family history (FH) of hemophilia would have earlier age of diagnosis. Methods: Available data through April 30, 2020 were analyzed for participants with severe HA (factor VIII &lt;1%) born between January 1, 2010 and December 31, 2019. Diagnostic history, circumcision, and bleeding and treatment within the first 30 days of life were compared between participants with and without a known FH. Results: Twenty-six HTCs have enrolled 112 male participants with severe HA. FH regarding hemophilia is known in 94 (84%) and positive in 60 (64%). Patients with a positive FH compared to patients without a positive FH were diagnosed significantly earlier and were less likely to have circumcision (Table 1). Bleeding rate and factor exposure rate was similar within the first 30 days of life. Among 46 subjects who bled within the first 30 days of life, 6 (13.0%) bled due to circumcision (2 have a positive family history, and 4 have a negative family history); 34/46 (74%) had other bleeding events within the first 30 days. Conclusions: The interim analysis of PUPs born with severe HA between 2010-2019 demonstrates a majority have a FH of HA which is associated with an earlier age at diagnosis compared to those without a FH. Those without a FH of HA have higher rates of circumcision. Earlier identification of hemophilia could result in perinatal management strategies and avoidance of procedures such as circumcision that could result in bleeding. Disclosures Thornburg: NovoNordisk: Research Funding; Genentech: Speakers Bureau; American Thrombosis and Hemostasis Network: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharmaceuticals: Research Funding; Spark Therapeutics: Consultancy; Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; Bluebird Bio: Consultancy; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; Biomarin: Consultancy, Speakers Bureau. Friedman:Alexion: Speakers Bureau; Instrumentation Laboratories: Consultancy; Alexion: Consultancy; Bayer: Consultancy. Guerrera:NovoNordisk: Consultancy, Speakers Bureau; Kedrion: Consultancy; Biomarin: Speakers Bureau; Sanofi Genzyme: Speakers Bureau; Takeda: Consultancy. Malec:SOBI: Consultancy; Bayer: Consultancy; CSL: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau. Simpson:HEMA Biologics: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; CSL Behring: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Bioverativ/Sanofi: Research Funding. Tarantino:Spark: Membership on an entity's Board of Directors or advisory committees; HRSA: Membership on an entity's Board of Directors or advisory committees; CDC: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other; NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees. Carpenter:Novo Nordisk: Honoraria; Shire: Research Funding; Genentech, Inc.: Honoraria; Kedrion: Honoraria; CSL Behring: Research Funding; Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees.

Inhibitor Development in Previously Untreated Patients with Severe Hemophilia a Treated with Nuwiq®, a New Generation Recombinant FVIII of Human Origin

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 327-327 ◽  
Author(s):  
Raina Liesner ◽  
Marina Abashidze ◽  
Olga Aleinikova ◽  
Carmen Altisent ◽  
Mark J. Belletrutti ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Recombinant Fviii ◽  
New Generation

Abstract Background Studies have shown that the incidence of inhibitor development varies between FVIII concentrates, with some suggesting that recombinant FVIII (rFVIII) concentrates produced in hamster cell lines pose a greater risk of inhibitor development than plasma-derived (pd) von Willebrand factor (VWF)-containing FVIII (pdFVIII/VWF) products. In the SIPPET study, the cumulative incidence of high-titer inhibitorswith hamster-cell derived rFVIII products was 28.4% vs 18.6% for pdFVIII/VWF (Peyvandi F et al. N Engl J Med 2016; 374:2054-2064). These studies did not include new generation rFVIII products produced in human cell lines. Nuwiq® (Human-cl rFVIII) is the first and only new-generation rFVIII produced in human cells without chemical modification or protein fusion. The pharmacokinetics, efficacy and safety of Nuwiq® have been examined in previously treated patients (PTPs) with severe hemophilia A, and no inhibitors have been reported in 201 PTPs. The immunogenicity, efficacy and safety of Nuwiq® in previously untreated patients (PUPs) with severe hemophilia A is currently being assessed in the ongoing NuProtect study. Methods The NuProtect study was initiated in 2013 and is being conducted in 17 countries and 38 centers worldwide. One hundred evaluable (110 enrolled) male PUPs of all ages and ethnicities are being studied for 100 exposure days (EDs) or a maximum study participation of 5 years. The patients were to have received no treatment with FVIII concentrates or other blood products containing FVIII prior to study entry. The primary objective of the NuProtect study is to assess the immunogenicity of Nuwiq® by determining inhibitor activity (≥0.6 BU) using the Nijmegen modified Bethesda assay in a central laboratory. Intensive screening for inhibitors is scheduled every 3-4 EDs until 20 EDs, then every 10-12 EDs until 100 EDs, and every 3 months until study completion. Secondary endpoints include assessment of hemostatic efficacy in prophylaxis, in the treatment of bleeds and in surgical prophylaxis, as well as safety and tolerability. All patients undergo F8 gene mutation analysis. Results Data from 85 treated PUPs have been included in the first pre-planned interim analysis (May 2016) of which 66 PUPs had ≥20 EDs (by which time the majority of inhibitors are likely to have arisen). The median age at first treatment was 13 months (range: 3-135). Of the 59 patients with available F8 gene mutation analysis, 1 (1.7%) had no identifiable mutation, 44 (74.6%) had mutations conferring a high risk of inhibitor development and 47 (81.0%) had null mutations. Data analysis in May 2016 showed that only 8 of the 66 PUPs treated with Nuwiq® for ≥20 EDs had developed a high-titer inhibitor after a median of 11.5 EDs (range 6-24). Five of the 66 PUPs developed a low-titer inhibitor, 4 (80%) of which were transient. Only 2 patients developed an inhibitor (1 high-titer) after 20 EDs. The cumulative incidence of high-titer inhibitors in PUPs treated with Nuwiq® is 12.8% (95% CI: 4.49-21.15) (Figure 1). The cumulative incidence of low-titer inhibitors was 8.4% (95% CI: 1.28-15.59) and of all inhibitors was 20.8% (95% CI: 10.68-30.95). No patient developed an inhibitor after 25 EDs. The incidence has remained consistent since the start of the study in 2013. Twelve of 13 patients who developed inhibitors had the causative F8 gene mutation detected, all of which were null, and all but one were high-risk. Conclusions PUPs treated with Nuwiq® for ≥20 EDs had 12.8% cumulative incidence of high-titer inhibitorsat the time of interim analysis (8 of 66 PUPs) despite the fact that 81% of patients had gene mutations known to be associated with increased inhibitor risk (e.g. null mutations). These interim data support the low rate of inhibitor development in PUPs treated with Nuwiq® - a human-cell derived (not chemically modified or protein fused) recombinant FVIII. Final data from the NuProtect study are expected in 2018 and will provide further insights into the development of inhibitors in PUPs with severe hemophilia A. Figure 1. Cumulative incidence of inhibitor development Figure 1. Cumulative incidence of inhibitor development Disclosures Liesner: CSL Behring: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Altisent:Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Pfizer: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Octapharma: Consultancy. Belletrutti:Shire Pharmaceuticals (formerly Baxalta): Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; NovoNordisk: Other: Travel support. Borel-Derlon:LFB: Other: Reference expert and national coordinator for VWD; Shire - Baxalta: Research Funding; Octapharma: Research Funding; NovoNordisk: Other: Expert for scientific committee. Ducore:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Octapharama: Membership on an entity's Board of Directors or advisory committees; Baxalta (Shire): Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Sigaud:Shire - Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 2) ◽  
pp. LBA-5-LBA-5
Author(s):  
Lynn Malec ◽  
An Van Damme ◽  
Anthony Chan ◽  
Mariya Spasova ◽  
Nisha Jain ◽  
...  
Keyword(s):  
Half Life ◽  
Stock Options ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Severe Hemophilia ◽  
First Time ◽  
Inhibitor Titer ◽  
Privately Held

Abstract Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer &lt;0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR &gt;66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

scholarly journals Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1589-1589
Author(s):  
Fabian Frontzek ◽  
Marita Ziepert ◽  
Maike Nickelsen ◽  
Bettina Altmann ◽  
Bertram Glass ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
High Dose ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1126-1126
Author(s):  
Karen L. Zimowski ◽  
Glaivy M. Batsuli ◽  
Paulette Bryant ◽  
Jenny McDaniel ◽  
Kelly Tickle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Bleeding ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Acute Bleeding ◽  
Fviii Activity ◽  
Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio: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; Grifols: 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; 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; Kedrion: Research Funding.

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