scholarly journals Combined anti‐CD20 and mTOR inhibition with factor VIII for immune tolerance induction in hemophilia A patients with refractory inhibitors

2020 ◽  
Vol 18 (4) ◽  
pp. 848-852 ◽  
Author(s):  
Bhavya S. Doshi ◽  
Leslie J. Raffini ◽  
Lindsey A. George
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Mtor Inhibition ◽  
Immune Tolerance Induction ◽  
Anti Cd20

Successful Treatment of Inhibitor Formation in Adult Congenital Hemophilia A with Rituximab.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4074-4074 ◽  
Author(s):  
Chirag J. Amin ◽  
Alice D. Ma
Keyword(s):  
Factor Viii ◽  
Knee Replacement ◽  
Immune Tolerance ◽  
Bolus Dose ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
Recombinant Factor Viii ◽  
Promising Alternative ◽  
Immune Tolerance Induction

Abstract Inhibitor development in congenital hemophiliacs can be clinically catastrophic. Immune tolerance induction therapy has previously been the standard of care in eradicating inhibitors; however due to a multitude of factors, this may not be applicable in certain patients. The role of Rituximab is receiving more attention in this subset of patients. In this abstract, we report that treatment with Rituximab led to successful eradication of high-titer inhibitors in 3 patients with mild to moderate hemophilia A who developed inhibitors after receiving intensive treatment with recombinant Factor VIII (FVIII). Patient Characteristics: Three patients, aged 50–70, with baseline FVIII levels of 2–9%, developed inhibitors after recombinant Factor VIII infusion. Patient A was treated with continuous infusion FVIII for a post-surgical hemarthrosis for approximately 7 days. Patient B received bolus dose FVIII for a GI bleed for at least 10 days, and Patient C received bolus dose FVIII for knee replacement for 10 days. Factor VIII inhibitors were detected in these patients after one month. None of these patients had been treated with immune tolerance previously or had known inhibitors. Each patient received Rituximab 375mg/m2 every week for 4 weeks total. During and after treatment, FVIII levels and Bethesda inhibitor titers (BU) were monitored. Results: All three patients had eradication of their inhibitors (Figure 1) and return of their FVIII levels to baseline by six months post-treatment. Notably, patient C’s inhibitor peak was 117 BUs, 7 months prior to Rituximab treatment. Patient C’s initial response to Rituximab has been previously reported at ASH in abstract form. We now report that 4 years later, this patient has had a recurrence of his inhibitor after monoclonal FVIII for a contralateral knee replacement but with a peak titer of only 2 (Table 1). Inhibitor Trends after Rituximab Treatment Inhibitor Trends after Rituximab Treatment Bethesda Inhibitor Titer (BU) per Month (*) after Receiving Rituximab 0* 1 3 6 36 48 51 NA=Not applicable as data has not matured yet Patient A (BU) 5 0.7 0 0 NA NA NA Patient B (BU) 17 7 2 0 NA NA NA Patient C (BU) 40 4 0 0 0 2 0.5 Conclusion: Inhibitors in patients with mild-moderate hemophilia differ from those with severe FVIII deficiency, behaving more like the autoantibodies seen in patients with spontaneous FVIII inhibitors. In support of this idea, we successfully treated high titer inhibitors which developed in 3 patients with baseline FVIII levels of 2–9%. All three patients had prompt resolution of their inhibitor titers during the course of therapy, with return of their baseline FVIII levels. Historically, patients with mild-moderate hemophilia treated at the Harold R. Roberts Comprehensive Hemophilia Center at the University of North Carolina were treated either with immune tolerance induction or by bypass agents alone, with inhibitor eradication taking months to years (data not shown). While performance of larger prospective trials would be ideal, the small number of patients with this condition limits the ability to perform these trials. Our findings, in combination with other case series from other institutions, reveal a promising alternative for prompt and reliable treatment in mild-moderate hemophiliacs with inhibitors.

A Case Series Evaluating the Use of a Von Willebrand Factor/Factor VIII Concentrate (Wilate®) for Immune Tolerance Induction (ITI) in Children with Severe Factor VIII Deficiency

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5050-5050
Author(s):  
Mark J. Belletrutti ◽  
Roxanne Seiferman-Nelson ◽  
Bonny Granfield
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Bleeding Episodes ◽  
Recombinant Fviii ◽  
Von Willebrand

Abstract Introduction: Development of circulating anti-factor VIII antibodies (inhbitors) is the most serious and challenging complication in the treatment of hemophilia A. Up to 38% of hemophilia patients develop inhibitors with recombinant FVIII (rFVIII) products (Gouw et al. N Engl J Med. 2013; 368:231-239). The presence of inhibitors leads to an increased risk of bleeding, poor physical functioning and quality of life (Benson et al., Eur. J. Haematol. 2012; 88:371-379). Immune tolerance induction (ITI) is the most common method for eliminating inhibitors, historically performed with high dose, and prolonged treatment with plasma-derived (pd), or recombinant FVIII (rFVIII) concentrates. Although ITI for the eradication of inhibitors has become standard of care for hemophilia patients the therapeutic superiority of a particular product type (rFVIII vs. pd-FVIII) has not yet been conclusively demonstrated. In accordance with its role in stabilizing FVIII, the presence of von Willebrand factor (VWF) in pd-FVIII concentrates has been shown to improve the outcome of ITI. Wilate® (Octapharma) is a high-purity human plasma derived complex containing two proteins (VWF and FVIII) in a 1:1 ratio. The aim of this study was to determine the effectiveness of Wilate for primary ITI therapy for six patients with severe hemophilia A. Patients and Methods: The case history for six pediatric hemophilia A patients prior to and during primary Wilate ITI was reviewed. For 5/6 patients, inhibitors developed during rFVIII factor replacement therapy. For the sixth patient, inhibitors were detected at the time of hemophilia diagnosis. ITI began once patients achieved an inhibitor titer of less than 10 BU/mL. The ITI dosing regimen ranged from 50-60 IU/Kg of Wilate three times per week to 200 IU/Kg once daily. Inhibitor titers were measured regularly, prior to and during ITI using the Nijmegen-Bethesda assay. The number of port-a-cath infections and bleeding episodes were also monitored. ITI success was defined as: an undetectable inhibitor level (<0.6 BU/mL), FVIII plasma recovery ≥ 66% of predicted, and FVIII half-life ≥6 hours. Results: Wilate ITI was well tolerated in all patients, with no product-related adverse events. All patients had a port-a-cath device inserted for Wilate injections. Two port-a-cath infections occurred during ITI. Five of six patients had poor prognostic factors for ITI outcome. These poor prognostic factors included a high-risk FVIII gene mutation, historical peak inhibitor titer greater than 50 BU/mL, age of ITI onset greater than 6 years, and ITI onset more than 12 months from inhibitor development. The frequency of these poor prognostic factors varied amongst the patients: 1 patient had 4, 1 patient had 2, and 3 patients presented with 1 poor prognostic factor. Despite the presence of these high-risk factors, Wilate was successful at reducing the inhibitor titers to undetectable levels in all patients. Furthermore, inhibitor titers have remained low or undetectable without significant spikes for the duration of treatment. Patient plasma recovery and FVIII half-life results have also indicated that patients are progressing towards successful ITI. Importantly, for 6/6 patients (including 3 patients who had previously been treated with Anti-Inhibitor Coagulant Complex (FEIBA) prophylaxis therapy) - Wilate therapy was successful at reducing the number of bleeding episodes allowing for the cessation of FEIBA prophylaxis. Since commencing Wilate ITI, 6/6 patients have not reported any major bleeding episodes. The improved clinical outcome was perceived by the patients as an improved well-being, and quality of life. Conclusion: Wilate ITI was found to be well tolerated, safe, and successful at reducing inhibitor levels to below the detectable range for six severe hemophilia A patients. Patients experienced no treatment related adverse events, had a low rate of port-a-cath infections, and did not present with any major bleeding episodes while on Wilate ITI. In light of the 3-5 fold increase in overall treatment costs of immune tolerance induction, careful consideration should be given to choice of product (rFVIII versus pd-FVIII) – especially for patients at high-risk of failure. (Dimichele et al. Haemophilia 2004: 10 Suppl 4;140-145). The present data suggest that Wilate, a pd-FVIII product, is effective in managing patients with inhibitors. Disclosures Belletrutti: Baxter Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring Canada: Honoraria.

Low-dose immune tolerance induction in hemophilia A patients with inhibitors

Blood ◽  
1995 ◽  
Vol 86 (3) ◽  
pp. 983-988 ◽  
Author(s):  
EP Mauser-Bunschoten ◽  
HK Nieuwenhuis ◽  
G Roosendaal ◽  
HM van den Berg
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Low Dose ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
Two Factors ◽  
Inhibitor Level ◽  
Dose Factor

Abstract In patients with hemophilia A and inhibitory alloantibodies against factor VIII, various dosage schedules are used to obtain immune tolerance. In this study, we have evaluated the results of 13 years of low-dose immune tolerance induction and factors that are predictive of a positive result. The effect of immune tolerance induction in relation to age at inhibitor development, number of exposure days, age at start of therapy, maximum inhibitor titer, factor VIII products involved, and virologic status were determined. We evaluated 24 patients with severe hemophilia A and inhibitors who were treated with regular infusions with low-dose (25 U/kg every other day) factor VIII to obtain immune tolerance. In 21 of 24 patients (87%), immune tolerance induction was successful. The response time was determined by two factors: the highest inhibitor level and the age at inhibitor development. In patients with maximum inhibitor levels of less than 40 Bethesda units (BU)/mL, immune tolerance was obtained sooner than in patients with inhibitor levels exceeding 40 BU/mL (P = .005). Patients in whom an inhibitor developed before the age of 2.5 years also tended to have a quick immune response (P = .014). Immune tolerance with low-dose factor VIII is often successful in hemophilia A patients with inhibitors. Young children and patients with maximum inhibitors of less than 40 BU/mL show a relatively rapid response.

scholarly journals Economic Impact of Immune Tolerance Induction (ITI) with Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) Compared to Conventional Recombinant Factor VIII (rFVIII)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3520-3520
Author(s):  
Nanxin Li ◽  
Koo Wilson ◽  
Marc Botteman ◽  
Daniel Nicoloso ◽  
Sangeeta Krishnan ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Research Funding ◽  
Impact Analysis ◽  
Budget Impact ◽  
Hemophilia A ◽  
Case Reports ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Clinical Profiles

Abstract Introduction: Hemophilia A results from a clotting protein factor VIII (FVIII) deficiency, which leads to the need for the use of exogenous FVIII. Such therapy is effective unless alloantibodies (inhibitors) develop and render FVIII replacement ineffective. Patients with high-titer inhibitors may try to eradicate the presence of these inhibitors by undergoing ITI, an often costly process that requires the prolonged use of frequent doses of FVIII to induce FVIII antigen-specific tolerance. There is no consensus on the best approach to achieve tolerance and no product has been approved by any regulatory agency for ITI treatment in hemophilia A patients with inhibitors. The Fc portion of rFVIIIFc has shown immunomodulatory properties in mice, and chart reviews and case reports suggest that tolerization with rFVIIIFc in first-attempt ITI patients can potentially be achieved rapidly (i.e., ≤18 months) and therefore may possibly offer cost savings compared to conventional rFVIII. This analysis assessed the economic consequences and budget impact of using rFVIIIFc vs. conventional rFVIII for first-attempt immune tolerance induction (ITI) in hemophilia A patients with inhibitors. Methods: A literature-based model was developed to estimate the effect of rFVIIIFc vs conventional rFVIII on drug cost of first-attempt ITI, based on modelled ITI duration and outcome (rates and time to ITI success or failure) for US patients with varying clinical profiles (e.g., historical peak titer, FVIII dose) over a 3-year period. In the model, at any given time after ITI initiation (on either rFVIIIFc or rFVIII), a patient was categorized as ongoing ITI, post-ITI as success, or post-ITI as failure. The duration and outcomes for patients treated with rFVIIIFc ITI were based on observed data for first-attempt ITI patients with varied clinical profiles and ITI regimens from in chart reviews and case reports (n = 9). In the absence of direct head-to-head observations, the duration and outcome of ITI for the exact same patients in a scenario in which they received rFVIII (instead of rFVIIIFc) at the same doses were estimated indirectly using a previously published regression model (Bojke et al. 2009, Value in Health, 12(7), A378-A379) based on data for 113 patients from international and national registries that adjusts for historical and pre-ITI titer levels, time from inhibitor diagnosis to ITI start, and ITI factor dose. To place the cost comparison results in the perspective of a third-party US payer, a budget impact analysis was undertaken on a population of typical hemophilia A patients (after adjusting for patient characteristics) who are embarking on first-attempt ITI in a plan of 10 million insured members. In this analysis, the number of patients starting ITI each year was assumed constant, and patients who successfully eradicated inhibitors with ITI would transition back to FVIII prophylaxis. Results: The model predicted that, compared to rFVIII, rFVIIIFc would result in a reduction in estimated time to ITI success (rFVIIIFc: 9.43 months, rFVIII: 16.80 months), increased success probability at 20 months (rFVIIIFc: 67%, rFVIII: 25%), and lower 3-year per-patient costs (rFVIIIFc: $1,709,000, rFVIII: $3,630,000), respectively. In the budget impact analysis for a US health plan of 10 million insured members, 11.2 patients were expected to be newly diagnosed hemophilia A patients, among whom 1.17 patients were expected to develop inhibitors to FVIII and initiate ITI each year. By year 3, the predicted number of successful ITI patients increased by 23% and the budget savings for the plan were $103,738 per patient per year (for the ~1 patient who started ITI each year) after the inclusion of rFVIIIFc for ITI and subsequent prophylaxis when patients successfully eradicated inhibitors. Conclusions: Based on this mathematical economic model of first-attempt ITI patients, the modeled faster time to tolerization with rFVIIIFc vs. rFVIII, resulted in estimated per-patient and overall budget savings in ITI from a US payer perspective. Current prospective studies (e.g. verITI-8) will provide additional evidence on the efficacy of rFVIIIFc for ITI in Hemophilia A patients with inhibitors. Disclosures Li: Bioverativ: Employment. Wilson:SOBI: Employment. Botteman:Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding; Pharmerit International: Employment, Equity Ownership, Research Funding; Celgene: Research Funding; Bioverativ: Consultancy, Other: Provided consulting to Bioverativ, Research Funding. Nicoloso:Bioverativ: Other: an employee of Pharmerit, which provided consulting to Bioverativ. Krishnan:Bioverativ: Employment. Su:Bioverativ: Employment.

Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Jenny Goudemand ◽  
Chantal Rothschild ◽  
Virginie Demiguel ◽  
Christine Vinciguerrat ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Adjusted Relative Risk ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
End Point ◽  
History Of

Abstract Inhibitor development is the major treatment complication in children with severe hemophilia A. It is not clear whether the risk of inhibitors is higher with recombinant factor VIII or with plasma-derived factor VIII. We used multivariate analysis to compare 2 cohorts of previously untreated patients (PUPs) with severe hemophilia A: 62 patients treated with the same brand of high-purity plasma-derived FVIII (pFVIII) containing von Willebrand factor (VWF) and 86 patients treated with full-length recombinant FVIII (rFVIII). In addition to the usual end points (all inhibitors, high inhibitors), we also examined a third end point (high inhibitors and/or immune tolerance induction). The risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; nonwhite origin; history of inhibitors in patients with a family history of hemophilia; age at first FVIII infusion). The adjusted relative risk (RRa) for inhibitor development with rFVIII versus pFVIII was 2.4 (all inhibitors), 2.6 (high inhibitors), and 3.2 (high inhibitors and/or immune tolerance induction), respectively, depending on the end point (above). The pathophysiology of this large effect must be understood in order to improve the characteristics of recombinant products and to reduce the incidence of inhibitors to FVIII.

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