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Eradication of factor VIII inhibitors in patients with mild and moderate hemophilia A.

ABSTRACT: In hemophilia A, up to 25% of new antifactor VIII (FVIII) inhibitory antibodies (inhibitors) occur in patients with mild or moderate disease. Once the inhibitor develops, options for management include observation, immune modulation, and immune tolerance induction (ITI). Currently, there is little data to guide a clinician's management decisions. In a case series, eight of the 26 subjects with mild or moderate hemophilia complicated by an inhibitor underwent ITI; two were successful, two were unsuccessful, and four were partially successful. In a systematic review of the literature, 12 of the 16 patients with mild or moderate hemophilia responded to rituximab for treatment to eradicate the inhibitor. To increase our understanding of treatment options for inhibitor eradication in patients with mild or moderate hemophilia A complicated by an inhibitor, a secondary analysis of clinical and treatment characteristics in a cohort of 36 patients with mild or moderate hemophilia A and inhibitor was undertaken. In multivariate analyses, rituximab alone (n = 6) and other immune-modulating treatments alone (n = 2) were significantly associated with an increased likelihood of inhibitor clearance [hazard ratio (HR) = 4.4 (95% CI = 1.06–20.03) and 10.21 (95% CI = 1.17–78.28), respectively], whereas ITI alone (n = 9) was not [HR = 1.35 (95% CI = 0.44–4.07)].

SUBMITTER: Kempton CL

PROVIDER: S-EPMC3645919 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Eradication of factor VIII inhibitors in patients with mild and moderate hemophilia A.

Kempton Christine L CL Allen Geoff G Hord Jeffrey J Kruse-Jarres Rebecca R Pruthi Rajiv K RK Walsh Christopher C Young Guy G Soucie J Michael JM

American journal of hematology 20120626 9

In hemophilia A, up to 25% of new antifactor VIII (FVIII) inhibitory antibodies (inhibitors) occur in patients with mild or moderate disease. Once the inhibitor develops, options for management include observation, immune modulation, and immune tolerance induction (ITI). Currently, there is little data to guide a clinician's management decisions. In a case series, eight of the 26 subjects with mild or moderate hemophilia complicated by an inhibitor underwent ITI; two were successful, two were un ...[more]

PMID: 22733686

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Project description:Hemophilia A is a genetic disorder that results in the deficiency of functional factor VIII protein, which plays a key role in blood coagulation. Currently, the majority of hemophilia A patients are treated with repeated infusions of factor VIII protein. Approximately 30% of severe hemophilia A patients develop neutralizing antibodies to factor VIII (known as factor VIII inhibitors) due to treatment, rendering factor VIII protein infusions ineffective. Previously, mice receiving murine IL-2 complexed with α-murine IL-2 mAbs (JES6-1A12) showed a lack of factor VIII inhibitor formation after factor VIII treatment, which was associated with the proliferation and the activation of factor VIII-specific regulatory T cells (Tregs). In this paper, we evaluated if an Fc-fused mutated protein analog of mouse IL-2, named Fc.Mut24, engineered to selectively promote the expansion of Tregs in vivo can modulate factor VIII-specific immune responses. The mice received one intraperitoneal injection of Fc.Mut24. When the regulatory T cell population reached its highest frequency and peak activation, the mice received a hydrodynamic injection of factor VIII plasmid (day 4) followed by a second Fc.Mut24 dose (day 7). Peripheral blood was collected weekly. Flow cytometry was used to characterize the peripheral blood cell populations, while ELISA and Bethesda assays were used to assess the inhibitor concentrations and the functional titers in plasma. The activated partial thromboplastin time assay was used to assess the functional activities of factor VIII in blood. The mice receiving Fc.Mut24 showed a dramatic and transient increase in the population of activated Tregs after Fc.Mut24 injection. Factor VIII gene therapy via hydrodynamic injection resulted in high anti-factor VIII inhibitor concentrations in control PBS-injected mice, whereas the mice treated with Fc.Mut24 produced no inhibitors. Most significantly, there were no inhibitors generated after a second hydrodynamic injection of factor VIII plasmid administered at 19 weeks after the first injection in Fc.Mut24-treated mice. The mice receiving Fc.Mut24 maintained high levels of factor VIII activity throughout the experiment, while the control mice had the factor VIII activity dropped to undetectable levels a few weeks after the first factor VIII plasmid injection. Our data show that human therapies analogous to Fc.Mut24 could potentially provide a method to prevent inhibitor formation and induce long-term immune tolerance to factor VIII in hemophilia patients.

Project description:BackgroundLow-dose pharmacokinetic (PK)-guided extended half-life (EHL) factor VIII (FVIII) prophylaxis can reduce the bleeding risk in hemophilia A (HA) patients. An increase in physical activities for promoting musculoskeletal health may enhance the benefits of prophylactic therapy.ObjectivesTo determine the clinical impact of moderate- to vigorous-intensity physical activities in HA patients during low-dose PK-guided EHL FVIII prophylaxis.Patients/methodsThis prospective study enrolled patients with moderate/severe HA (baseline FVIII levels ≤ 5 IU/dL) who had received low-dose PK-guided EHL FVIII prophylaxis for ≥ 6 months. An individualized exercise protocol was introduced to each participant, targeting a 65% increase in the maximum predicted heart rate for ≥ 150 min/week, while continuing low-dose PK-guided EHL FVIII prophylaxis for 6 months. Before and after implementing the intervention, annualized bleeding rates (ABR), annualized joint bleeding rates (AJBR), Hemophilia Joint Health Scores (HJHS), skeletal muscle mass, hemophilia-specific quality-of-life (QoL) scores and annualized FVIII consumption were compared.ResultsOf 13 participants (mean age ± standard deviation [SD]: 20.1 ± 6.8 years), ABR, AJBR, and HJHS were significantly reduced (mean differences [MD] ± SD: -5.7 ± 2.6 bleeds/year, -4.2 ± 2.6 joint bleeds/year, and -4.3 ± 3.2 marks, respectively; P < 0.05) after applying the 6-month exercise protocol. Skeletal muscle mass and QoL scores had also improved (P = 0.001), while FVIII usage had decreased (MD ± SD: -129.1 ± 208.7 IU/kg/year; P < 0.05).ConclusionsThe combination of moderate- to vigorous-intensity physical activities with low-dose PK-guided EHL FVIII prophylaxis improves bleeding prevention, musculoskeletal status and QoL in patients with moderate/severe HA. By minimizing FVIII consumption, this strategy helps optimize hemophilia care in countries with budget constraints.Clinicaltrialsgov NCT05728528.

Dataset Information

Eradication of factor VIII inhibitors in patients with mild and moderate hemophilia A.

Publications

Eradication of factor VIII inhibitors in patients with mild and moderate hemophilia A.

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