Prompt Immune Tolerance Induction at Inhibitor Diagnosis Regardless of Titer May Increase Overall Success in Hemophilia A With Inhibitors: Experience of Two US Centers

Abstract Introduction Immune tolerance induction (ITI) for patients (pts) with hemophilia A with inhibitors is the only modality known to effectively eradicate inhibitors with an overall reported success of ∼60-80%. One debate concerns the optimal time to start ITI; recent guidelines recommend delaying ITI until inhibitor titer is <10 Bethesda units (BU). Aim We report results of an analytic project to determine the success of ITI relative to time from inhibitor detection to ITI initiation. Methods Data was collected retrospectively at 2 US hemophilia centers on pts with severe/moderate (≤5%) factor VIII (FVIII) deficiency undergoing ITI including time interval from inhibitor detection to ITI start, inhibitor titer and outcome. High-dose ITI was practiced by both centers (i.e. ≥100 IU/kg/day). Success, partial success and failure were defined practically with success as a negative inhibitor titer and ability to use FVIII concentrate routinely for treatment and prevention of bleeding; partial success was an inhibitor titer <5 BU with ability to use FVIII concentrate to treat bleeding episodes; failure as ongoing ITI >3 years without achieving success/partial success or discontinuation of ITI. IRB approvals were obtained at both centers for this data analysis. Pts were first divided into low responding inhibitor (LRI) and high responding inhibitor (HRI) based on peak inhibitor titer; the HRI subgroup was further subdivided based on time to start ITI, including within 1 month, 1-6 months and greater than 6 months. The HRI subgroup starting ITI within 1 month was analyzed based on pre-ITI inhibitor titer. Results Fifty eight male pts with adequate ITI history documentation were included; 55 (95%) were severe (<1%), 3 moderately deficient (1-3%). Forty-seven pts (48%) were Caucasian, 6 Hispanic, 2 African American, 2 Asian and 1 Native American. Outcome is summarized in Table 1. Overall, 49 of 58 pts (84%) underwent successful ITI. Low responding Inhibitors: Among 19 (33%) pts with LRI, ITI success was 100%. Most pts with LRI 15/19 (79%) started ITI within 1 month from inhibitor detection. High responding inhibitors: Among 39 (67%) pts with HRI, 30/39 (77%) achieved tolerance, 1 achieved partial success and continued ITI, 1 was ongoing, 7 pts failed. The 39 pts with HRI were further subdivided based on time to ITI start. ITI start within 1 month of detection: Twenty three pts started ITI within 1 month from detection; 21 achieved success (91%), 1 partially succeeded and 1 failed. Eight of 10 pts (80%) with a pre-ITI titer <10 BU achieved success, 1 partially succeeded and 1 failed. All 13 pts (100%) starting ITI with pre-ITI inhibitor titer ≥ 10 BU achieved success. ITI start > 6 months: Eleven pts had an interval > 6 months until ITI start; 7 (64%) achieved success and 4 (36%) failed. Conclusions These results suggest that the time interval from inhibitor detection to start of ITI may play a critical role in outcome. A titer ≥10 BU did not influence outcome in pts where ITI was utilized within 1 month, supporting this approach in contrast to the commonly accepted practice of delaying ITI start until a titer <10 BU is achieved. Pts may benefit from prompt ITI regardless of current inhibitor titer and are not subjected to wait periods where bleeding is more likely to occur. Prompt ITI should be considered a viable therapeutic option in newly identified inhibitor pts regardless of current inhibitor titer. Disclosures: Manco-Johnson: Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Eisai: Research Funding. Maahs:Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Biogen Idec: 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. Shapiro:Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novo Nordisck: Consultancy, 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; Biogen Idec: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Chugai Pharma: Consultancy; Kedrion Biopharma: Consultancy, Research Funding; Cangene Pharmaceuticals: Research Funding; CSL Behring: Research Funding; Octopharma: Research Funding; PTC Therapeutics: Research Funding; Eli Lilly: Research Funding.

Download Full-text

Immune Tolerance Induction (ITI) with a Plasma-Derived Factor VIII for Patients with Hemophilia a and Inhibitors: A Retrospective Study

Blood ◽

10.1182/blood-2019-122949 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4923-4923

Author(s):

Miguel A. Escobar ◽

Linda Shaffer ◽

Mark Holguin ◽

Timothy McCavit ◽

Sandeep K. Rajan ◽

...

Keyword(s):

Board Of Directors ◽

Immune Tolerance ◽

Hemophilia A ◽

Tolerance Induction ◽

Advisory Committees ◽

Immune Tolerance Induction ◽

Off Label ◽

Inhibitor Titer ◽

Antihemophilic Factor ◽

Partial Success

Introduction: A serious complication in hemophilia A is the formation of inhibitors to clotting factors. The primary means for eradicating inhibitors is immune tolerance induction (ITI) therapy. Antihemophilic factor (human) (Koate®-DVI) is a purified dried concentrate indicated for the treatment of hemophilia A with insufficient activity of Factor VIII (FVIII). Although other plasma-derived concentrates containing von Willebrand factor have been utilized successfully for ITI, studies evaluating this product for ITI therapy have not been published. An evaluation of patient- and treatment-related factors associated with outcomes following primary or rescue ITI with antihemophilic factor (human) in patients with hemophilia A and inhibitors was conducted in this retrospective multicenter chart review project. Methods: An evaluation of medical records of 13 inhibitor patients treated with antihemophilic factor (human) for primary or rescue ITI therapy between January 1, 2012, and July 31, 2017, was conducted in five US hemophilia treatment centers. To be eligible for inclusion, patients were required to have a diagnosis of hemophilia A of any severity level, inhibitor to FVIII at the time of treatment initiation with antihemophilic factor (human), and ongoing treatment with antihemophilic factor (human) for primary or rescue ITI. Data were de-identified and analyzed descriptively. Outcome measures were defined, per the International Immune Tolerance consensus recommendations, as "complete success" (inhibitor titer <0.6 Bethesda Units [BU] at 33 months of ITI, FVIII recovery ≥66% and half-life ≥6 hours), "partial success" (a reduction in inhibitor titer to <5 BU mL with FVIII recovery <66% and/or FVIII half-life <6 hours associated with clinical response to FVIII therapy not followed by a treatment-limiting anamnestic rise in inhibitors to >5 BU mL), or "failure" (neither complete nor partial success). Results: All (N=13) patients who met the inclusion criteria were males with severe hemophilia, with the exception of one with moderate hemophilia. Six patients were African American, four were Hispanic, two Caucasian, and one was Asian. They were diagnosed with inhibitors between the ages of 8 months and 39 years and were 5 to 53 years old upon ITI with antihemophilic factor (human). Ten of 13 patients (76.9%) had successful ITI; seven with complete success and three with partial success (Table). Three patients failed ITI. As primary therapy, complete success was obtained with all but one of the six patients treated with antihemophilic factor (human). These six patients were all older than 7 at the initiation of ITI, a risk factor for poor ITI. Seven of the 13 total patients had a combined previous 12 attempts at ITI with other products (plasma derived and/or recombinant). Of these seven rescue patients, ITI with antihemophilic factor (human) was completely successful in two and partially successful in three. Adverse events reported once in separate patients during treatment with antihemophilic factor (human) included catheter infection, portal infection, bacteremia, peritonitis due to a ruptured appendix, and complications in treatment. One patient had several adverse events, including cellulitis at the port site, abdominal wall hematoma, right thumb fracture and hematoma, and left shoulder hemarthrosis. Conclusions: While retrospective data has limitations, real-world evidence demonstrates that ITI with antihemophilic factor (human) concentrate can be successful or partially successful in diverse populations of moderately complex patients with hemophilia A and inhibitors. The data suggest that antihemophilic factor (human) may be most appropriate for patients when used as primary ITI, as even patients older than 7 years achieved complete success. Additional patients need to be evaluated to make a definitive conclusion regarding the impact of age on success of ITI therapy in addition to other risk factors. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rajan:Bayer, Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Amega:Kedrion Biopharma: Employment. OffLabel Disclosure: Koate is not approved to treat vWD, nor, cTTP however, based on some published reports using kotae for these indications, we are anticipating those type of off label inquiries. I will clearly disclose to the participants that these are off label indications.

Download Full-text

Natural History Of Inhibitor Recurrence Following Successful Immune Tolerance Induction

Blood ◽

10.1182/blood.v122.21.1106.1106 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1106-1106 ◽

Cited By ~ 2

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.

Download Full-text

Low-Dose Immune Tolerance Induction for Hemophilia a Children with Poor-Risk High-Titer Inhibitors

Blood ◽

10.1182/blood-2019-132021 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1122-1122

Author(s):

Zekun Li ◽

Zhenping Chen ◽

Xiaoling Cheng ◽

Xinyi Wu ◽

Li Gang ◽

...

Keyword(s):

Success Rate ◽

Board Of Directors ◽

Immune Tolerance ◽

Low Dose ◽

Hemophilia A ◽

Tolerance Induction ◽

Advisory Committees ◽

Immune Tolerance Induction ◽

Inhibitor Titer

Background: Low-dose immune tolerance induction (ITI) +/- immunosuppression as a practical ITI strategy in China showed a relatively satisfactory success rate and economic advantages in pilot study. However, the outcome still needs to be verified by larger cohort. Aim: To report the efficacy of this low-dose ITI +/- immunosuppression strategy in hemophilia A children ≥ 10 BU. Methods: This was a single center, prospective study in 53 hemophilia A subjects from Sep 2016 to Apr 2019. All subjects having ≥ 10 BU receiving ~50IU/kg FVIII every other day using domestic intermediate purity pdFVIII/VWF products, either alone or in combination with rituximab and prednisone judging by inhibitors and ITI response. Results: Finally, 46 subjects received this strategy at a median of 3.2 (IQR, 2.3-6.5) years old, their pre-ITI inhibitor titer was median 30.0 (range, 10.1-416) BU. Analysis at median 15.1 (range 3.0-34.4) months follow-up, success (inhibitor <0.6BU) was achieved in 32 (69.6%) subjects, partial success (inhibitor <5BU but >0.6BU) in 11 (23.9%) subjects, and failure in 5 (10.9%) subjects. Between subjects administered ITI-alone and ITI- immunosuppression, no significant difference was observed in time to success (median 8.5; IQR 6.7-11.7 vs 10.2; IQR 5.1-25.1, P=0.164). The mean monthly bleeding rate on ITI was 0.49 which declined 59.3% compared with pre-ITI period. Subjects administered ITI-immunosuppression (0.54 ± 0.46) was higher than ITI-alone (0.42 ± 0.69) although with no significantly difference (P=0.089). Seven (21.9%) subjects experienced inhibitor recurrence, 4 subjects treated with ITI-alone, 3 with ITI-immunosuppression. Recurrence occurred at a median of 4.8 (range, 2.8-10.8) months after successful ITI with inhibitor titer transiently rising to median 0.7 (range, 0.7-1.5) BU. Conclusion: This low-dose ITI +/- immunosuppression therapy in subjects with pre-ITI inhibitor ≥ 10 BU showed a success rate similar to other high/intermediate-dose regimen for the whole inhibitor patients. The subjects treated with ITI-immunosuppression did not showed higher recurrence at present, while a longer time follow-up is still needed. Disclosures Poon: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; World Federation of Hemophilia: Other: Not-for-profit organization affiliation: volunteer ; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation in sponsored research; CSL-Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Immune Tolerance Induction Using Rfviiifc (Eloctate)

Blood ◽

10.1182/blood.v126.23.3531.3531 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3531-3531 ◽

Cited By ~ 2

Author(s):

Lynn M. Malec ◽

Margaret V Ragni ◽

Janna M. Journeycake ◽

Michelle Alabek

Keyword(s):

Board Of Directors ◽

Immune Tolerance ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Central Venous Access ◽

Tolerance Induction ◽

Severe Hemophilia ◽

Advisory Committees ◽

Immune Tolerance Induction

Abstract Introduction: Inhibitor formation affects approximately 30% of individuals with severe hemophilia A. The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy, although typically requires daily high-dose factor VIII via a port for up to a year. Extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc, Eloctate¨) has a half-life extension 1.5-fold longer than standard recombinant FVIII (rFVIII), reducing treatment frequency, and also induces regulatory T cell response to FVIII in animal models. We hypothesized that rFVIIIFc would provide more effective ITI, specifically shortening ITI, than rFVIII. We describe ITI with rFVIIIFc in three patients with severe hemophilia A. Methods: Immune tolerance induction was initiated with rFVIIIFc (Eloctate) in three children with severe hemophilia A and an anti-FVIII inhibitor. Dosing was per MD discretion with family agreement, and performed by central venous access device or intravenous infusion via heplock. Follow-up was scheduled every 6-8 weeks, with planned determination of FVIII half-life once the anti-FVIII fell to <0.6 B.U. Tolerance was a priori defined as achieving anti-FVIII <0.6 B.U. and half-life, t½ >6 hours. FVIII half-life was determined by one-stage FVIII:C assay on citrate samples drawn pre- and 10 minutes, 1, 2, 4, and 6 hours post-infusion of a single dose of rFVIIIFc. Once a t½ >6 hours was documented, incremental reduction to 50 IU/kg every other day or three times weekly, once there was evidence of maintenance of inhibitor neutralization and a >6 hour FVIII:C half-life. Results: Immune tolerance induction was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc via central venous access device every other day or three times weekly per MD discretion in three children with severe hemophilia A and in anti-FVIII inhibitor > 5 B.U. (Table 1). Two patients had F8 genetic testing. In two patients, Pt 1 and Pt 3, this was the initial ITI course, and in the third child (Pt 2) this was salvage ITI after failing to achieve tolerance due to noncompliance with daily rFVIII ITI taper regimen. In two rFVIIIFc ITI was begun when anti-FVIII was < 10 B.U. Historic peak titers were 16-422 B.U. The time to anti-FVIII tolerance was 4-12 weeks Discussion: Immune tolerance induction was successful in three children with inhibitors using rFVIIIFc, including a child previously failing rFVIII ITI. The time to anti-FVIII=0 was 4-12 weeks, significantly shorter than with current rFVIII ITI. There were no adverse effects. These data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in children with inhibitors. Whether ITI may be accomplished more rapidly with rFVIIIFc, and the optimal dose for ITI will require prospective studies. A prospective observational study of rFVIIIFc ITI pre- and post-ITI T cell responses in children with hemophilia and inhibitors, the H emophilia I nhibitor R esponse to E loctate (HIRE) Study, is underway. Table 1. Immune Tolerance Induction with rFVIIIFc in Hemophilia A Inhibitor Patients Patient (Pt) Hemophilia Severity F8 Gene Mutation Age at Anti-FVIII Detection Peak Anti-FVIII Titer Initial ITI Dose Time toAnti-FVIII = 0 Current Anti-FVIII 1 <0.01 IU/ml Intron 22 inversion 13 months 32 B.U. 200 IU/kg QOD 12 weeks 0 B.U. 2 < 0.01 IU/ml Exon 18 nonsense variant 9 months 422 B.U. 200 IU/kg 3x/week 4 weeks 0 B.U. 3 <0.01 IU/ml Not available 10 years 16 B.U. 100 IU/kg QOD 11 weeks 0 B.U. Disclosures Malec: Baxter: Research Funding; Biogen: Research Funding. Ragni:Pfizer: Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Dimension: Research Funding; Vascular Medicine Institute: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; SPARK: Research Funding; Biomarin: Research Funding; Genentech Roche: Research Funding; Bayer: Research Funding; Biogen: Research Funding; Alnylam: Research Funding. Journeycake:CSL, Baxalta, NovoNordisk: Consultancy; ATHN: Research Funding; Biogen: Speakers Bureau; ATHN: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

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

Blood ◽

10.1182/blood.v118.21.27.27 ◽

2011 ◽

Vol 118 (21) ◽

pp. 27-27 ◽

Cited By ~ 1

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.

Download Full-text

Treatment Of Serious Bleeds With a B-Domain Deleted Recombinant Porcine Sequence Factor VIII (OBI-1) In Patients With Acquired Hemophilia A: A Prospective Clinical Trial

Blood ◽

10.1182/blood.v122.21.206.206 ◽

2013 ◽

Vol 122 (21) ◽

pp. 206-206 ◽

Cited By ~ 1

Author(s):

Rebecca Kruse-Jarres ◽

Jean St. Louis ◽

Anne Greist ◽

Amy D. Shapiro ◽

Hedy Smith ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Positive Response ◽

Acquired Hemophilia A ◽

Advisory Committees ◽

Baxter Healthcare ◽

Bayer Healthcare ◽

Travel Grant

Abstract Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder, resulting from auto-antibodies to human factor VIII (hFVIII). The challenges created by the management of AHA and the co-morbidities present in this typically elderly population, can be managed by a recombinant, highly pure, B-domain deleted, porcine sequence FVIII (OBI-1) that is not generally susceptible to the inhibitory activity of anti-human FVIII antibodies. Treatment with OBI-1 allows for monitoring of FVIII levels which provides a reproducible and objective surrogate predictor of hemostasis. Eradication of hFVIII inhibitors with immunosuppressive therapy is critical for disease management. During immunosuppression, the patient transitions from a bleeding state at initial presentation to a relative hypercoagulable state which can be an issue in patients who are susceptible to thromboembolic events due to their comorbidities. This transition period is of most concern especially when using traditionally utilized bypassing agents that cannot be monitored. OBI-1 enables measurement of FVIII levels, guiding dosing and enhancing treatment safety during this critical period. Methods This global, prospective, multi-center phase 2/3 open label clinical trial investigates the efficacy and safety of OBI-1 in the treatment of serious bleeds in adults with AHA conducted under ICH guidelines and local IRB/Ethics Committee oversight. Primary efficacy endpoint was assessed at 24 hours (eg. effective, partially effective). All subjects (N= 18) presented with a serious bleed and were treated with an initial dose of OBI-1 (200 U/kg), followed by additional doses based on the subject's target factor VIII levels, anti-OBI-1 titer, and clinical factors. Results In all 18 subjects, a positive response (14 effective/4 partially effective) to treatment was observed at 24 hours. This positive response to OBI-1 treatment was seen by 8 hours in 14/18 of the subjects and at 16 hours in 16/18 of the subjects. Median total exposure to OBI-1 per subject was 1782.5 U/kg. The median total first dose was 14,000 U. For subjects who received additional doses of OBI-1, the median dose was reduced from the initial dose, but did not differ considerably over subsequent doses (9180 to 13561 U; median 11000 U). The majority of subjects (17/18) received concomitant immunosuppressive therapies. No related serious adverse reactions occurred. Non-serious adverse events related to treatment were noted in 5/18 (27.8%) subjects. One subject had mild tachycardia, hypotension and constipation. One subject had 2 instances of mild PICC line occlusion. One subject had a mild hypofibrogenemia. All of these adverse effects completely resolved. Three subjects developed anti-porcine inhibitors after infusion of study drug (range 8-108 BU) and two were discontinued from treatment. Anti-porcine inhibitors were detected prior to infusion in 6/18 patients (range 0.8-29 BU). All of these subjects had a favorable clinical response at 24 hours post-OB-1 infusions. Conclusions Data from this prospective study demonstrate OBI-1 as a safe and effective treatment of bleeding episodes in patients with AHA, with the added advantage over other bypass therapies of allowing FVIII monitoring throughout treatment and healing phase. Disclosures: Kruse-Jarres: Baxter Healthcare: Consultancy; Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy. St. Louis:CSL Behring: Research Funding; Octapharma: Consultancy, Research Funding; Baxter: Consultancy; Novo Nordisk: Honoraria. Shapiro:Kedrion Biopharma: Consultancy; Chugai Pharma USA: Consultancy; Biogen IDEC: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Baxter Healthcare: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Chowdary:Baxter Healthcare: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel grant Other; Novo Nordisk: Honoraria, Research Funding, Travel grant, Travel grant Other; Bayer HealthCare: Honoraria, Travel grant, Travel grant Other; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; CSL Behring: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel grant Other; Biogen IDEC: Honoraria, Travel, Travel Other. Drebes:Octapharma: Travel grant Other; CSL Behring: Travel grant, Travel grant Other; Leo-pharma: Travel grant, Travel grant Other; Bayer Healthcare: Consultancy, Honoraria. Gomperts:Baxter Healthcare: Consultancy; Asklepios Biopharmaceutoicals Inc: Consultancy; Cangene Inc: Consultancy. Chapman:Baxter Healthcare: Employment. Mo:Baxter Healthcare: Employment. Novack:Baxter Healthcare: Employment. Farin:Baxter Healthcare: Employment.

Download Full-text

Early Prophylaxis Provides Continued Joint Protection in Severe Hemophilia A: Results of the Joint Outcome Continuation Study

Blood ◽

10.1182/blood-2018-99-117413 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 382-382 ◽

Cited By ~ 3

Author(s):

Beth Boulden Warren ◽

Dianne Thornhill ◽

Jill Stein ◽

Michael Fadell ◽

Sharon Funk ◽

...

Keyword(s):

Soft Tissue ◽

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Joint Damage ◽

Severe Hemophilia ◽

Advisory Committees ◽

Episodic Treatment ◽

Bayer Healthcare

Abstract Background: The Joint Outcome Study (JOS) was a randomized controlled trial showing that, in severe hemophilia A, prophylactic factor VIII every other day starting prior to age 30 months leads to better joint outcomes at age 6 years than enhanced episodic treatment with factor VIII for bleeding1. After conclusion of the JOS, all participants were encouraged to continue on, or to transition to, prophylaxis. Here we describe the results of the Joint Outcome Continuation Study (JOS-C), which followed the participants of the JOS to age 18 years. Methods: All participants of the JOS were eligible for the JOS-C. MRIs of 6 index joints (right and left ankles, knees, and elbows), index joint physical exam scores using the Colorado Haemophilia Paediatric Joint Physical Examination Scale2 , estimates of joint bleeding episodes, and surgery information were collected. The primary endpoint, as in the initial JOS analysis, was evidence of hemophilia-related osteochondral joint damage on MRI, scored using the extended MRI scale3. Results: Of the 65 previous participants of the JOS, 37 gave informed consent for the JOS-C study, including 18 initially randomized to prophylaxis prior to age 30 months ("early prophylaxis"), and 19 initially randomized to enhanced episodic treatment who started prophylaxis at a mean age of 7.5 years (median 6.1, range 2.7-17.1, "delayed prophylaxis"). All initially on prophylaxis in the JOS continued on prophylaxis through the JOS-C. One participant (early prophylaxis arm) failed to complete an MRI, and four others (2 early and 2 delayed prophylaxis) had their MRIs excluded for technical reasons. Four participants (3 early prophylaxis and 1 delayed prophylaxis) developed high titer inhibitors during or shortly after the JOS and were analyzed separately. Osteochondral joint damage was defined as evidence of osteochondral damage on MRI or a need for joint surgery. The relative risk of osteochondral damage in those on delayed prophylaxis as compared to those on early prophylaxis was 6.5 (95% CI 1.3, 33.6; p=0.029). At age 18, 67% of those on early prophylaxis, and only 24% of those on delayed prophylaxis had zero index joints with osteochondral damage (Figure 1). Twenty-five percent of early prophylaxis and 47% of delayed prophylaxis participants had osteochondral damage to more than one joint. Most participants had some soft tissue changes on MRI, defined as effusion, synovial hypertrophy, or hemosiderin deposition. There was no difference in risk of soft tissue damage between initial treatment groups (p=0.48). Osteochondral damage scores were available for 3 patients with inhibitors: two with refractory inhibitors had osteochondral changes on at least one joint, and one with an inhibitor that tolerized within 3 months had no osteochondral damage. Total physical exam scores were also higher in the delayed prophylaxis arm (mean 22.6, standard deviation (SD) 15.5) than in the early prophylaxis arm (mean 16.2, SD 10.5), but this difference was not statistically significant (p=0.19). Conclusion: The JOS-C demonstrates that, in severe hemophilia A, initiation of prophylaxis prior to age 30 months provides continued protection against joint damage throughout childhood. Those who started on prophylaxis later in childhood had higher risk of joint damage at age 18. Initiation of factor VIII prophylaxis in the toddler years is critical to preventing osteochondral joint damage and should not be delayed. ReferencesManco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.Hacker MR, Funk SM, Manco-Johnson MJ. The Colorado Haemophilia Paediatric Joint Physical Examination Scale: normal values and interrater reliability. Haemophilia. 2007;13(1):71-78.Hong W, Raunig D, Lundin B. SPINART study: validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data. Haemophilia. 2016;22(6):e519-e526. Figure 1: Percentage of participants with zero joints with osteochondral damage at JOS exit (age 6 years) and JOS-C exit (age 18 years), excluding participants with inhibitors. Disclosures Warren: Bayer Healthcare: Research Funding; HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program Fellowship Project Award: Research Funding; CSL Behring Heimburger Award: Research Funding. Shapiro:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Prometic Life Sciences: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; OPKO: Research Funding; BioMarin: Research Funding. Recht:Shire: Research Funding; Biogen: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Bayer AG: Honoraria, Research Funding; Novo Nordisk: Honoraria; Biogentek: Honoraria; CSL Behring: Honoraria; Baxalta, now part of Shire: Honoraria.

Download Full-text

Breakthrough Bleeding in Hemophilia a Patients on Prophylaxis

Blood ◽

10.1182/blood.v128.22.2581.2581 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2581-2581 ◽

Cited By ~ 2

Author(s):

Beth Boulden Warren ◽

Taylor Blades ◽

Natalie L Smith ◽

Michael Wang ◽

Marilyn J. Manco-Johnson

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Tolerance Induction ◽

Severe Hemophilia ◽

Advisory Committees ◽

Breakthrough Bleeding ◽

University Of Colorado ◽

The University

Abstract Background: Patients with severe hemophilia A (factor VIII (FVIII)<1%), as well as many patients with moderate hemophilia A (FVIII 1-5%), are treated intravenously with FVIII prophylaxis to prevent bleeding. However, breakthrough bleeding occurs in many patients. Methods: To better understand breakthrough bleeding, we evaluated the effect of hemophilia severity, prophylaxis adherence, and replacement FVIII utilization on bleeding rates in patients with hemophilia A on prophylaxis. Data on hemophilia severity and bleeding rates were collected from subjects with hemophilia A, ages 2-30 years, treated at the University of Colorado for hemophilia A, using the University of Colorado Clinical Research Bleeding Disorders Database (UCBDD). Adherence and FVIII utilization data were collected from a subset of subjects with hemophilia A on prophylaxis without active inhibitors who participated in the Centers for Disease Control/American Thrombosis and Hemostasis Network Community Counts (CDCCC) registry between December 2013 and June 2016, which surveyed participants about their estimated percentage of missed prophylaxis doses. The CDCCC registry was also used to corroborate bleeding rates. The effect of hemophilia severity and missed prophylaxis doses (percentage of prescribed doses) on bleeding rates were analyzed using logistic regression, with bleeding rates dichotomized as high or low relative to study population median bleeding rates. The relationship between weekly factor utilization and annualized bleeding rates was evaluated using Pearson's correlation. Results: Of 89 patients with severe hemophilia A in the UCBDD, 86.5% of patients were on continuous prophylaxis, with an additional 7.9% on immune tolerance induction. The 5.6% of patients with severe hemophilia on episodic treatment had been encouraged to use prophylaxis but had declined. Of 37 patients with moderate hemophilia A, 48.7% were on continuous prophylaxis. Sixty-nine subjects on prophylaxis had data in the UCBDD and the CDCCC registry collected during the defined time period. Bleeding rates are shown in Table 1. Prophylaxis doses in this population had an interquartile range of 74.3 to 120 units/kg/week (mean 96.9 units/kg/week), dosed 2-7 times per week depending on activities and historic bleeding patterns. Eighty-two percent of patients rated their percentage of missed prophylaxis doses at <10%, 11.6% rated their missed doses at 10-20%, 2.9% rated their missed doses at 21-50%, and 2.9% rated missed doses at >50%. There was not a statistically significant relationship between any bleeding rate and percentage of missed doses, hemophilia severity, or factor utilization, as shown graphically in figures 1 and 2. Conclusion: Although prophylaxis usage and adherence were excellent, breakthrough bleeding was common, with breakthrough joint bleeding occurring in 36% of subjects, and was not related to FVIII dose per week. Prospective studies are needed to better determine individually tailored prophylaxis regimen using dose, product class, and timing with activities, in order to achieve more effective prophylaxis. Table 1 Bleeding Rates on Continuous Prophylaxis. No intracranial or gastrointestinal hemorrhages were recorded in this population. Table 1. Bleeding Rates on Continuous Prophylaxis. No intracranial or gastrointestinal hemorrhages were recorded in this population. Figure 1 Relationship between Bleeding Rates, Hemophilia Severity and Adherence Figure 1. Relationship between Bleeding Rates, Hemophilia Severity and Adherence Figure 2 No correlation was found between bleeding rates and factor VIII utilization as measured in units per kg per week. Figure 2. No correlation was found between bleeding rates and factor VIII utilization as measured in units per kg per week. Disclosures Warren: HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program: Research Funding. Wang:Biogen: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Baxalta: Honoraria; NovoNordisk: Honoraria; BiogenIdec: Honoraria; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria.

Download Full-text

Prognostic Parameters For Remission Of and Survival In Acquired Hemophilia A: Results Of The GTH-AH 01/2010 Multicenter Study

Blood ◽

10.1182/blood.v122.21.205.205 ◽

2013 ◽

Vol 122 (21) ◽

pp. 205-205 ◽

Cited By ~ 1

Author(s):

Andreas Tiede ◽

Jan-Malte Blumtritt ◽

Robert Klamroth ◽

Saskia Gottstein ◽

Katharina Holstein ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Performance Status ◽

Immunosuppressive Treatment ◽

Treatment Protocol ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Advisory Committees ◽

Inhibitor Titer

Abstract Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII:C). Immunosuppressive treatment may result in remission of disease over a period of days to months. Until remission, patients are at high risk of bleeding and complications from immunosuppression. Prognostic parameters to predict remission and the time needed to achieve remission could be helpful to guide treatment intensity, but have not been established so far. GTH-AH01/2010 was a prospective multicenter cohort study using a standardized immunosuppressive treatment protocol. The primary study endpoint was time to achieve partial remission (PR, defined as FVIII:C activity >50 IU/dl after cessation of any hemotherapy for >24h, and no active bleeding). Secondary endpoints were time to achieve complete remission (CR, defined as PR plus negative FVIII:C inhibitor, steroid tapered to <15 mg/d prednisolone, and cessation of any other immunosuppressive treatment), and overall survival (OS). Enrolment was strictly prospective and only allowed within 7 days of starting immunosuppression. Outcome data were recorded in all patients enrolled. The treatment protocol consisted of prednisolone (100 mg/d from day 1 to the day of PR, then tapered down to <15 mg/d over 5 weeks), oral cyclophosphamide (150 mg/d, from day 21-42, unless PR was achieved), and rituximab (375 mg/m2 weekly for 4 weeks starting on day 43, unless PR was achieved). If AHA was first diagnosed in patients previously on prednisolone >15 mg/d, or equivalent, they received prednisolone (100 mg/d) and rituximab from day 1. If cyclophosphamide was contraindicated, patients received prednisolone (100 mg/d) and rituximab from day 21. One hundred twenty-four patients from 21 treatment centers in Germany and Austria were enrolled between April 2010 and April 2013 (36 months). The patients from two centers not compliant with the treatment protocol were excluded (N=18), as were patients in whom AHA was not confirmed (N=2) or follow-up was too short at the time of this analysis (N=7). The remaining 97 patients from 17 centers were followed for a median of 256 days (interquartile range [IQR] 84-561). Median age was 74 years (IQR 64-82). AHA was associated with other autoimmune disorders (19%), malignancy (12%), pregnancy or puerperium (5%), but was most often idiopathic (66%). The median FVIII:C activity at baseline was 1 IU/dl (IQR <1-3), and the median inhibitor titer was 20 BU/ml (IQR 7.7-78). PR and CR were achieved after a median time of 35 and 102 days, respectively. Patients achieving PR prior to day 21 (N=22) compared with patients not achieving PR within 21 days (N=75) had a higher baseline FVIII:C activity (median 3 vs. <1 IU/dl, p<0.01) and a lower FVIII:C inhibitor (median 12 vs. 29 BU/ml, p<0.05). Multivariate analysis with adjustment for age, sex, underlying disorder, and WHO performance status on admission demonstrated that baseline FVIII:C activity (<1 IU/dl vs. >=1 IU/dl) had a strong impact on the time to achieve PR (HR 2.76 [95% confidence interval 1.73-4.42], p<0.001) and CR (HR 2.36 [1.34-4.14], p<0.01). Baseline FVIII:C activity was also a predictor of PR and CR when other cutoffs were used (2 or 3 IU/dl instead of 1 IU/dl), or when it was analyzed as a continuous variable in Cox regression analysis. In contrast, FVIII:C inhibitor titer assessed by the local laboratory did not affect time to PR or CR significantly. OS after 300 days, estimated by the Kaplan Meier method, was 69%. Age, WHO performance status, and FVIII:C activity at baseline were independent predictors of OS. In summary, GTH-AH 01/2010 is the largest prospective study of patients with AHA treated according to a standardized protocol. The study demonstrated a robust effect of baseline FVIII:C activity on the time needed to achieve PR and CR. Baseline FVIII:C activity, together with age and performance status, also affected OS. Therefore, baseline FVIII:C activity may be considered to guide individually tailored immunosuppression in future studies. Disclosures: Tiede: Baxter: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding. Off Label Use: Prednisolone, cyclophosphamid, and rituximab for immunosuppression in acquired hemophilia. Klamroth:Bayer: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding. Gottstein:Novo Nordisk: Honoraria; Baxter: Honoraria. Holstein:Baxter: Honoraria, Speakers Bureau. Scharf:CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria, Research Funding. Huth-Kühne:SRH Kurpfalz Hospital and Hemophilia Center: Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Greil:Roche: Consultancy, Honoraria, Research Funding. Miesbach:Novo Nordisk: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding. Trappe:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Other; AMGEN: Research Funding, Travel, Travel Other; CSL Behring: Honoraria, Research Funding, Speakers Bureau, Travel, Travel Other; Mundipharma: Research Funding, Travel, Travel Other; Takeda: Consultancy, Research Funding, Travel Other; Novartis: Consultancy, Research Funding, Travel, Travel Other; Novartis: Research Funding, Travel Other; Cellgen: Travel, Travel Other. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria.

Download Full-text

Outcome of the Japanese Immune Tolerance Induction (ITI) Registry and Predictors of Successful ITI

Blood ◽

10.1182/blood.v126.23.3526.3526 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3526-3526 ◽

Cited By ~ 1

Author(s):

Keiji Nogami ◽

Masashi Taki ◽

Tadashi Matsushita ◽

Shouichi Ohga ◽

Hideji Hanabusa ◽

...

Keyword(s):

Success Rate ◽

Board Of Directors ◽

Research Funding ◽

Retrospective Cohort ◽

Tolerance Induction ◽

Successful Outcome ◽

Advisory Committees ◽

Immune Tolerance Induction ◽

Chugai Pharmaceutical ◽

Severe Type

Abstract [Background] Immune tolerance induction (ITI) therapy is the only therapeutic approach that can eradicate factor (F)VIII and FIX inhibitors in patients with hemophilia A (HA) and B (HB), respectively. Although results of several retrospective cohort studies have been published, predictors of successful outcome are still debated. Nonetheless, little information is so far available in terms of large ITI cohort in non-Caucasian countries. [Aim] In this study, we performed a retrospective cohort study on ITI therapy carried out for Japanese hemophilia patients with inhibitors to understand the status of practice on this therapy in Japan and to study the predictors of successful outcome. [Methods] As of March 31, 2015, the registry of ITI therapy in Japanese hemophilia patients had received reports on 155 HA patients (140 severe type, high responder 69.1%) and 7 HB patients (7 severe type, high responder 42.5%) who have undergone this therapy from 45 hospitals including Hemophilia Treatment Centers since 2000. The ITI outcome was centrally reviewed. The success of ITI was defined as an undetectable inhibitor for 2 successive measurements, and the salvage ITI was defined as any rescue ITI regimen by using von Willebrand factor-containing FVIII concentrates. [Results] Among the completed ITI courses, the overall success rate of ITI therapy was 71.2% (94/132) and 83.3% (5/6) for HA and HB patients, respectively. Cumulated ITI success rates of 50% and 80% for HA patients were achieved at 1.6 and 4.3 years after the inhibitor diagnosis, and 0.6 and 2.3 years after the initiation of ITI, respectively. Significant predictors for success of ITI in HA were (i) low responding inhibitors (success 35/37 (94.5%)) compared to high responding inhibitors (59/93 (63.4%); p <0.0001), (ii) shorter intervals from inhibitor diagnosis to the initiation of ITI (success (S): 1.85±3.52 vs failure (F): 3.38±3.77 years; p =0.02), (iii) lower historical peak titers on pre-ITI (S: 24.9±55.2 vs F: 132±295 BU/ml; p =0.04), and (iv) lower peak inhibitor titers on-ITI (S: 72.4±231 vs F: 916±1,307 BU/ml; p <0.01). However, outcome was not significantly different (p =0.77) between high dose regimens (>90 IU/kg, 7 days/wk) and low dose regimens (<75 IU/kg, 3 days/wk). Also, either FVIII products (plasma-derived or recombinant) at the initiation or the insertion of central venous access devise (CVAD) did not affect the outcome (p =0.32 and 0.85). Although the outcome prediction was difficult for HB because of low number of the cases registered, success rate was much higher than those of previous reports. The success rate of salvage ITI was 50% (6/12) for HA. The significant predictive parameter for outcome was only the age at the initiation of salvage ITI (p =0.03). The inhibitor relapsed in 6 cases, and all cases were HA patients (4.5% 6/140). In 86 cases with insertion of CVAD, the catheter-related infection was complicated in 21 cases (12.9%). [Conclusion] This study underscores the importance of initiating the ITI as early as possible after the diagnosis of inhibitor and the low response of inhibitor titer before and during the ITI to maximize the success of the treatment for Japanese hemophilia patients. Disclosures Nogami: Chugai: Membership on an entity's Board of Directors or advisory committees; Bayer, NovoNordisk, Baxalta, Chugai, Kaketsuken, Pfizer, Biogen: Honoraria; Bayer, Novo Nordisk, Baxalta. Biogen: Research Funding. Taki:Biogen, Baxalta, Bayer, Novo, Pfizer: Honoraria; Biogen, Baxalta, NovoNordisk, CSL-Behring, Kaketsuken, Chugai: Research Funding. Matsushita:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CLS-Behling: Research Funding; Japan Blood Products Organization: Honoraria, Research Funding; Kyowa-Kirin: Honoraria, Research Funding; Octapharma AG: Honoraria; Sysmex: Speakers Bureau; Seamens: Speakers Bureau; Nihon Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Kaketsuken: Honoraria, Research Funding, Speakers Bureau; Asahi Kasei Pharma: Honoraria, Research Funding, Speakers Bureau; Eisai: Research Funding; Novartis Pharma: Honoraria, Speakers Bureau; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Shima:Pfizer: Honoraria, Research Funding; Kaketsuken: Honoraria; Biogen: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding.

Download Full-text