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

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.

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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.

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

Blood ◽

10.1182/blood.v122.21.575.575 ◽

2013 ◽

Vol 122 (21) ◽

pp. 575-575 ◽

Cited By ~ 1

Author(s):

Charles T Nakar ◽

Marilyn J. Manco-Johnson ◽

Alice Lail ◽

Sharyne M. Donfield ◽

Jennifer Maahs ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Tolerance Induction ◽

Time Interval ◽

Advisory Committees ◽

Immune Tolerance Induction ◽

Bayer Healthcare ◽

Inhibitor Titer ◽

Partial Success

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.

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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.

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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.

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Benefits of prophylactic emicizumab in enhancing immune tolerance induction in a boy with hemophilia A and very high inhibitor titer

Pediatric Blood & Cancer ◽

10.1002/pbc.29111 ◽

2021 ◽

Author(s):

Nongnuch Sirachainan ◽

Ampaiwan Chuansumrit ◽

Surapan Parapakpenjune ◽

Pakawan Wongwerawattanakoon ◽

Surapong Lertthammakiat ◽

...

Keyword(s):

Immune Tolerance ◽

Hemophilia A ◽

Tolerance Induction ◽

Immune Tolerance Induction ◽

Inhibitor Titer ◽

Very High

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Prevention of Inhibitor Development Using Apoptosis-Induced FVIII Producing ES Cells.

Blood ◽

10.1182/blood.v112.11.3381.3381 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3381-3381

Author(s):

Shogo Kasuda ◽

Yoshihiko Sakurai ◽

Kohei Tatsumi ◽

Tomohiro Takeda ◽

Atsushi Kubo ◽

...

Keyword(s):

Immune Tolerance ◽

Hemophilia A ◽

Es Cells ◽

Tolerance Induction ◽

Target Protein ◽

Apoptotic Cells ◽

Danger Signal ◽

Immune Tolerance Induction ◽

Peptide Epitopes ◽

Inhibitor Titer

Abstract [Background] Hemophilia A is an X-linked bleeding disorder resulting from abnormality in the coagulation factor VIII (FVIII) gene. Development of inhibitors remains a significant problem for a treatment of hemophilia A. Approximately 25–30% of sever type hemophilia A patients develop inhibitor antibodies that reduce or completely negate the benefits of replacement therapy. Furthermore, a major issue that all gene therapy trials for hemophilia are facing is the risk of forming inhibitory antibodies to the transgene product. Although immune tolerance induction (ITI) is the effective method to decrease inhibitor concentration, it costs too expensively and there are some patients who do not show any response to ITI. Thus, it is desired to establish a novel immune tolerance induction method. Recent immunological studies have pointed out that “danger signal” is required to initiate immune reactions and immune tolerance is induced in the absence of danger signal. Apoptotic cell death is considered to be associated with immune tolerance because processing of intracellular antigen occurs without danger signal. Recently, Miyake et al. reported that intravenous injection of apoptotic cells expressing a fragment of myelin oligodendrocyte glycoprotein (MOG) on cell membrane reduced MOG-specific T cell response and prevented the development of experimental autoimmune encephalomyelitis (EAE) [J Clin Invest2007;117:2268–78.]. Based on these principles and findings, we investigated the novel immune tolerance approach with pretreatment of apoptotic embryonic stem (ES) cells secreting FVIII. [Methods] All animal experiments were performed in accordance with institutional and national regulations and approved by the Nara Medical University Animal Care Committee. We have already established mouse ES cells secreting human FVIII by integrating human FVIII gene [Kasuda et al, J Thromb Haemost 2008]. As a pretreatment, hypo-osmotic stress-induced apoptotic ES cells were injected intraperitoneally into the FVIII-KO mouse. After the various periods, administration of hFVIII concentrates (4 IU/body) was repeated every week. Then, titration of inhibitor was measured chronologically with Bethesda methods. [Results] In the non-pretreatment group (n=15), the inhibitor titer was 0.03 ± 0.00 BU/ml at 1 week after first administration of hFVIII concentrates. Then, the inhibitor titer rose to 0.18 ± 0.03 BU/ml and 3.03 ± 0.12 BU/ml with every following hFVIII administration. On the other hand, in the pretreatment group #1 (hFVIII administration was begun 1 week after pretreatment, n=9), inhibitor titer showed the significantly low levels (0.54 ± 0.27 BU/ml) even after thrice administration of hFVIII (p<0.05). Furthermore, in another pretreatment group #2 (hFVIII administration was begun 2 weeks after pretreatment, n=3), inhibitor titer showed much lower levels (0.09 ± 0.03 BU/ml) after thrice administration (p<0.01). [Discussion] We showed the possibility of reduction of inhibitor titer with pretreatment of apoptotic hFVIII secreting ES cells. The efficacy for the reduction of inhibitor titer depended on the period between pretreatment with apoptotic cells and first hFVIII administration, suggesting that a specified period is required to induce immune tolerance. Unlike the method using a peptide fragment of target protein (MOG) in the previous report by Miyake et al., our method features the utilization of a whole target protein (FVIII), by which tolerance to multiple epitopes of the protein would be induced. Identification of the precise peptide epitopes of a target protein would not be necessary since selection and presentation are executed by the host’s own antigen presenting cells. We aspire for the complete suppression of inhibitor formation with an ingenious administration of apoptotic ES cells. We believe that this approach has potential for future clinical therapy.

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Treatment of Haemophilia a (HA) Patients with Inhibitors: Immune Tolerance Induction with a Single Factor VIII/Von Willebrand Factor Concentrate in an Observational Immune Tolerance Induction Study (ObsITI)

Blood ◽

10.1182/blood-2018-99-114408 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2482-2482

Author(s):

C. Escuriola Ettingshausen ◽

Erik Berntorp ◽

Yesim Dargaud ◽

Zeynep Gutowski ◽

Claude Negrier ◽

...

Keyword(s):

Board Of Directors ◽

Von Willebrand Factor ◽

Immune Tolerance ◽

Research Funding ◽

Tolerance Induction ◽

Advisory Committees ◽

Immune Tolerance Induction ◽

Inhibitor Titre ◽

Von Willebrand ◽

Willebrand Factor

Abstract Introduction and objectives: Development of neutralising inhibitors against factor VIII (FVIII) is one of the most serious and costly complications in the treatment of HA. An ongoing international, open-label, uncontrolled, multicentre observational study, ObsITI (ClinicalTrials.gov. NCT 02207894) started in 2005 to assess immune tolerance induction (ITI), the standard of care in patients with inhibitors. The study evaluates patient- and therapy-related variables on ITI course, outcome and morbidity in HA patients with inhibitors. ObsITI satellite studies additionally look at other factors related to tolerisation. Methods and Materials: As of February 2018, 193 patients from 20 countries undergoing ITI have been recruited in ObsITI. 152 patients completed the study and 41 are ongoing. A subgroup of more than 80 prospective patients were treated exclusively during the complete ITI course with a single plasma-derived (pd) FVIII concentrate that contains von Willebrand factor (VWF) in a VWF/FVIII ratio of 0.4 (Octapharma AG). According to the recommended Bonn protocol, low responders at ITI start received 50-100 IU FVIII kg-1 daily, or every other day; high responders received 100 IU FVIII kg-1 every 12 hours. Results: In this ongoing study, the majority of patients treated with the pdFVIII/VWF product achieved a negative inhibitor titre. ITI outcome was significantly correlated with the bleeding rate during ITI, the peak titre during ITI, the inhibitor titre at start of ITI >10 BU, and the number of poor prognosis factors. Conclusion: Treatment with this particular pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in HA patients with inhibitors and corroborates previously published success rates (77.1% complete/partial success in 48 inhibitor patients undergoing ITI with the same product). Disclosures Escuriola Ettingshausen: SOBI: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria; Roche: Honoraria; Grifols: Honoraria; Pfizer: Honoraria; LFB: Honoraria. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: 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; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Research Funding. Pavlova:Novo Nordisk: Honoraria; Octapharma: Honoraria. Oldenburg: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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: 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; 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; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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.

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Immune Tolerance Induction in Severe Hemophilia a Patients Using Wilate®, a Von Willebrand Factor/Factor VIII Concentrate

Blood ◽

10.1182/blood.v124.21.5057.5057 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5057-5057

Author(s):

John K. Wu ◽

Celina Woo ◽

Erica Crilly

Keyword(s):

Risk Factors ◽

High Risk ◽

Board Of Directors ◽

Neutralizing Antibodies ◽

Hemophilia A ◽

Tolerance Induction ◽

Advisory Committees ◽

High Risk Factors ◽

Risk Patients ◽

Inhibitor Titer

Abstract Introduction: To prevent and treat bleeding episodes, hemophilia A patients undergo factor VIII (FVIII) replacement therapy with either recombinant FVIII (r-FVIII) or plasma-derived FVIII (pd-FVIII). Approximately 32% of patients develop neutralizing antibodies to the FVIII protein rendering FVIII therapy ineffective (Gouw et al. N Engl J Med. 2013; 368:231-239). Development of these neutralizing antibodies, or ‘inhibitors’ is the most serious and challenging complication in the treatment of hemophilia A patients and represents the highest economic burden for a chronic disease (Gringeri et al. Blood 2003; 102:2358-2363). The standard approach for eradicating inhibitors is to tolerize the patient to FVIII through prolonged, daily exposure to high-dose FVIII – a process termed immune tolerance induction (ITI). Although costly, ITI can successfully eliminate inhibitors in a large proportion of low-risk patients, however there are several risk factors that reduce the likelihood of ITI success. For high-risk patients, the choice of drug product (r-FVIII versus pd-FVIII) may be particularly important. Several small studies have demonstrated the superiority of pd-FVIII for ITI, as these products contain the FVIII stabilizing protein, von Willebrand Factor (VWF) (Gringeri et al., Haemophilia 2007; 13:373-379). Wilate® (Octapharma) is a high-purity pd-FVIII complex that contains the two proteins (VWF and FVIII) in a 1:1 ratio. In this retrospective study, we present the patient history and outcome for four severe hemophilia A patients that have undergone ITI with Wilate®. Patients and Methods. All patients presented with severe FVIII deficiency (<1%). Only 1/4 patients had undergone and failed a previous ITI attempt using a rFVIII product. The Wilate ITI dosing regimen ranged from 90 U/Kg to 100 U/Kg daily. Three of the four patients presented with high-risk factors for poor ITI outcome: 1 patient had 1, 1 patient had 3 and 1 patient had 5 poor prognostic factors. The definition of ITI success and failure were consistent with the definitions described in the consensus recommendations of the 2006 International ITI workshop (DiMichele et al. Haemophilia 2007;13 Suppl. 1: 1-22). Complete success (CS) was defined as having an undetectable inhibitor titer, FVIII recovery ≥66% and half-life ≥6 hours; partial success (PS) was defined as having a clinical response allowing for commencement of FVIII therapy associated with an inhibitor titer of <5 BU/mL (and with FVIII recovery <66% and/or half-life <6 hours). Results. ITI with Wilate was found to be well tolerated, with no reported drug-related adverse events. Although 75% of the patients presented with high-risk factors for poor ITI outcome, Wilate ITI reduced inhibitor levels below 5 BU/mL for 3 out of 4 patients. The clinical outcome of Wilate ITI correlated with the presence and number of high-risk factors. Patient 1 did not respond to Wilate, and was considered a failure. This patient had 3 high risk factors for poor ITI outcome including FVIII gene mutation type, peak historical titer >50, and inhibitor titer at ITI onset > 10 BU/mL. Of the three patients that responded to Wilate ITI, patient 4 experienced a CS to Wilate ITI in 4 months. For the remaining 2 patients, Wilate ITI is currently ongoing. Despite the presence of high risk factors, these two patients have thus far achieved a PS with inhibitor levels stable for several months at or below 1 BU/mL. One of these patients (patient 2) presented with 5 high-risk factors, including having failed a previous ITI attempt. The frequency of bleeding episodes were significantly reduced upon commencement of Wilate ITI, allowing for the eventual cessation of FEIBA prophylaxis. Conclusion. Despite the presence of high-risk factors, 3 out of 4 patients (75%) experienced a clinical response to Wilate ITI. The patients experienced improved quality of life. Wilate ITI resulted in a significant reduction in bleed episodes in a high-risk patient. The type of FVIII product to use during ITI has been debated, however, some have observed a higher success rate when plasma-derived FVIII products containing VWF are used. From our experience, we conclude that Wilate for ITI in patients with inhibitors is effective and produces high rates of ITI success in high-risk patients. Disclosures Wu: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: 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; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees. Woo:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter: 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. Crilly:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Durability of ITI Utilizing Rfviiifc

Blood ◽

10.1182/blood.v128.22.3793.3793 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3793-3793

Author(s):

Margaret V. Ragni ◽

Lynn M. Malec ◽

Janna M. Journeycake

Keyword(s):

Immune Tolerance ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Tolerance Induction ◽

Severe Hemophilia ◽

Immune Tolerance Induction ◽

Viii Inhibitor ◽

Inhibitor Titer

Introduction: The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy in patients with severe hemophilia A who develop inhibitors. The long-acting recombinant factor VIII Fc fusion protein, rFVIIIFc (Eloctate™), which is safe and effective in the prevention and treatment of bleeding events, may promote tolerance to FVIII as shown in preclinical animal models and an inhibitor prone child, as Fc suppresses immunoregulatory Tcells to proteins to which Fc is attached. We therefore previously hypothesized rFVIIIFc would provide effective ITI, specifically shortening and simplifying ITI, and have previously described successful inhibitor eradication in three patients. Long-term follow-up data after successful ITI in patients with severe hemophilia remains limited. In the International Immune Tolerance Induction study, at 1-year follow-up, 6 of 66 subjects who had achieved tolerance demonstrated evidence of relapse at a median of 9.5 months. Of these 6 subjects, 1 had a measurable inhibitor titer and 5 had reduced FVIII recovery. We aim to provide follow-up data on our cohort of patients who had successful inhibitor eradication utilizing rFVIIIFc for ITI. Methods: Immune tolerance induction was initiated in three patients with severe hemophilia A and anti-VIII >5 B.U., in two as initial ITI (Pt. 1, 3), and one as salvage (Pt. 2) after failing to achieve ITI with standard rFVIII due to poor compliance. 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., FVIII recovery of at least 60%, and half-life (t½) >6 hours. Once a t½ >6 hours was documented, incremental reduction to rFVIIIFc occurred. Patients continued to be followed by their local HTC as per standard of care. Results: ITI was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc every other day or three times weekly per MD discretion. The time to initial anti-FVIII <0.6 B.U. was 4-12 weeks. Patient 1 and 2 were able to achieve tolerance, with a FVIII recovery of at least 60%, and half-life (t½) >6 hours, at weeks 18 and 17, respectively, after initiation of ITI. Patient 3 has improved but is not yet fully tolerized, as evidenced by 57% recovery and a t½ of approximately 7 hours. Anti-VIII inhibitor titers remain negative at 15, 16 and 15 months, from the initiation of ITI in patients 1, 2, and 3 respectively. Patients 1 and 2 have been able to decrease their post ITI prophylaxis dosing regimen to 80 IU/kg and 65 IU/kg three times a week while maintaining a FVIII trough of >1%. No patients were maintained on bypassing prophylaxis during ITI and no patients have experienced hemarthroses or other major bleeding event since the initiation of ITI. 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. At a mean duration of follow up of 15.3 months, all patients achieved an anti-VIII inhibitor titer of 0 B.U. Repeat pharmacokinetics studies will be available at planned subsequent follow-up visit. To date, these data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in three children with inhibitors, and has provided durable and continuing immune tolerance to FVIII. Whether rFVIIIFc ITI will be successful and durable in a larger cohort of children with severe hemophilia A 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 Hemophilia Inhibitor Response to Eloctate (HIRE) Study, has begun recruitment. Disclosures Ragni: SPARK: Research Funding; Shire: Consultancy; Novo Nordisk: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding. Malec:Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding; Biogen: Consultancy. Journeycake:CSL: Consultancy; Biogen: Consultancy; Baxalta/Shire: Consultancy.

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