Roseline d'Oiron

Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A.

Six recombinant factor VIII (rFVIII) products have been marketed worldwide. In 2013, the Research of Determinants of Inhibitor Development (RODIN) study group reported an unexpectedly high risk of inhibitor development with a second-generation full-length rFVIII (Product D) in previously untreated patients (PUPs) with severe hemophilia A (HA). In 1994, French public health authorities established a prospective cohort to monitor hemophilia treatment safety. A PUP subgroup was designed to investigate inhibitor risk factors. We analyzed this subcohort in view of the RODIN findings. After excluding 50 patients who participated in the RODIN study, the primary analysis focused on 303 boys with severe HA first treated with a rFVIII product. A clinically significant inhibitor was detected in 114 boys (37.6%). The inhibitor incidence was higher with Product D vs the most widely used rFVIII product (adjusted hazard ratio [aHR], 1.55; 95% confidence interval [CI], 0.97-2.49). Similar results were found for high-titer inhibitors and in 10 sensitivity analyses. No heterogeneity was observed between RODIN and our results. Combined aHRs were 1.58 (95% CI, 1.17-2.14) for all inhibitors and 1.70 (95% CI, 1.15-2.52) for high-titer inhibitors. Our results confirm the higher immunogenicity of Product D vs other rFVIII products in PUPs with severe HA.

Protein A Sepharose immunoadsorption can restore the efficacy of platelet concentrates in patients with Glanzmann's thrombasthenia and anti-glycoprotein IIb-IIIa antibodies

Summary. Type I Glanzmanns thrombasthenia is a rare congenital platelet function disorder, characterized by undetectable platelet membrane glycoprotein IIb–IIIa (GPIIb–IIIa). Severe bleeding is controlled by transfusion of normal platelets, leading in some cases to the occurrence of anti‐GPIIb–IIIa isoantibodies, which induces a loss of transfused platelet efficacy. We used immunoadsorption on protein A Sepharose (IA‐PA), which has been shown to be efficient in decreasing the titre of antibodies in several immune diseases, in three patients with Glanzmanns thrombasthenia and anti‐GPIIb–IIIa isoantibodies on five different occasions. IA‐PA was well tolerated with no deleterious side‐effects reported. It induced a dramatic decrease of total immunoglobulin (Ig)G, including anti‐GPIIb–IIIa isoantibody levels, as assessed by the monoclonal antibody‐specific immobilization of platelet antigens test and the ex vivo inhibition of normal platelet aggregation induced by the patients platelet‐rich or platelet‐poor plasma. Elimination of the antibody was associated with a correction of the bleeding time following platelet transfusion. IA‐PA combined with platelet transfusion made it possible to control two life‐threatening haemorrhages, and allowed two surgical procedures and one bone marrow transplantation to be performed safely. Our experience suggests that IA‐PA, which restores the haemostatic efficacy of platelet transfusion, is a valuable therapeutic strategy in patients with Glanzmanns thrombasthenia and anti‐GPIIb–IIIa isoantibodies.

Protein A sepharose immunoadsorption: immunological and haemostatic effects in two cases of acquired haemophilia

Acquired haemophilia is a life‐threatening disorder caused by circulating auto‐antibodies that inhibit factor VIII coagulant activity (FBIII:C). Immunoadsorption on protein A sepharose (IA‐PA) was performed in two bleeding patients with acquired haemophilia: we observed a dramatic and quick decrease in the anti‐FVIII:C inhibitor titre leading to a normal, albeit transient, haemostatic status. In one case, IA‐PA was the only procedure which succeeded in stopping massive haemorrhage. In the second case, IA‐PA reinforced the haemostatic effect of recombinant activated factor VII by increasing the endogenous plasma factor VIII level. The efficacy of IA‐PA was sustained with immunosuppressive treatment introduced, respectively, 10 and 15u2003d before the IA‐PA procedures. Our experience with IA‐PA suggests that this extracorporeal anti‐FVIII:C removal procedure is a valuable therapeutic tool for acquired haemophilia and can alleviate life‐threatening haemorrhages.

Reappraisal of in utero Stem Cell Transplantation Based on Long-Term Results

The therapeutic field of in utero transplantation of stem cells, into human fetuses, has developed since 1988 with the hope of improved probability of engraftment and tolerance, due to immune immaturity of the host. Fifteen years later, it is possible to evaluate the results that we and others have obtained in the treatment of several fetal diseases. Seven fetal patients have been treated in Lyon: In 2 cases, pregnancy termination was induced by the in utero injection; in the 5 other cases, engraftment was obtained and repeatedly documented with presence of donor HLA antigens and/or Y chromosome in recipients. In the 2 patients with combined immunodeficiency disease, a sustained reconstitution of immunity was obtained as a result of the transplant but other complications occurred thereafter. In patients with thalassemia major, Niemann-Pick disease or hemophilia, a very partial and very transitory benefit was only obtained. Approximately 33 other patients with immunodeficiencies, hemoglobinopathies or inborn errors of metabolism have been treated worldwide, over the last 13 years, with a comparable method, using parental or fetal stem cells transplanted in utero. Successful treatment has usually been recorded in immunodeficiencies, and insufficient results have been obtained in the other cases. This form of treatment can therefore be recommended after prenatal diagnosis of combined immunodeficiency but additional research is required to improve the degree of engraftment, the lack of resistance of the host and the ‘space’ available for hematopoiesis in the other conditions.

Analyses of the FranceCoag cohort support immunogenicity differences among one plasma-derived and two recombinant factor VIII brands in boys with severe hemophilia A

Around one third of boys with severe hemophilia A develop inhibitors (neutralizing antibodies) against their therapeutic factor VIII product. This adverse effect may result in more life-threatening bleeding, disability, impaired quality of life, and costly care. We compared the incidence of inhibitors in boys treated with the three factor VIII products most used in France: one plasma-derived (Factane) and two recombinant products (Advate and Kogenate Bayer). A previously untreated cohort of patients was created in 1994 to investigate risk factors for inhibitor development. We selected boys with severe hemophilia A (factor VIII <1 IU/dL) first treated with one of the three factor VIII products studied. Details of product infusions, inhibitor assays and main fixed and time-varying inhibitor risk factors were recorded for the first 75 exposure days. Three outcomes (all inhibitors, high-titer inhibitors and subsequently treated inhibitors) were analyzed by univariate and multivariate Cox models. We studied 395 boys first treated between 2001 and 2016 (131, 137, and 127 with Factane, Advate, and Kogenate Bayer, respectively). Clinically significant inhibitors were diagnosed in 121 patients (70 high-titer). The incidence of high-titer inhibitors was significantly associated with the factor VIII product received (P=0.005): the cumulative incidence at 75 exposure days was 12.7% (95% CI: 7.7–20.6) with Factane, 20.4% (95% CI: 14.0–29.1) with Advate, and 31.6% (95% CI: 23.5–41.7) with Kogenate Bayer. The low inhibitor incidence observed with Factane is concordant with recent findings from the SIPPET randomized trial. These consistent results from observational and experimental studies should lead to improved care for previously untreated patients and cost savings for healthcare systems worldwide.

Anti-αIIbβ3 immunization in Glanzmann thrombasthenia: review of literature and treatment recommendations

Glanzmann thrombasthenia (GT) is caused by inherited defects of the αIIbβ3 platelet glycoprotein. This bleeding disorder can be treated with platelet transfusion therapy, but some patients will be immunized and begin to form anti‐human leucocyte antigen (HLA) and/or anti‐αIIbβ3 antibodies. These antibodies can bind and interfere with the function of the transfused platelets, rendering treatment ineffective. However, platelet transfusion refractoriness attributable to HLA antibodies may be managed by the selection of compatible donors, although they are not always readily available, particularly in an emergency. Thus, anti‐αIIbβ3 antibodies represent one of the most severe complications in GT. Both genetic and environmental factors may contribute to the risk of anti‐αIIbβ3 development, but the underlying pathogenic mechanisms are still unknown. This review will summarize the current knowledge of the risk factors for development of anti‐αIIbβ3 antibodies in patients with GT and discuss how these findings may influence the clinical management of patients.

Choice of factor VIII/IX regimen in adolescents and young adults with severe or moderately severe haemophilia. A French national observational study (ORTHem 15-25).

INTRODUCTIONnThe value and challenges of long-term prophylaxis (LTP) in adolescents and young adults need further characterisation.nnnAIMnTo determine the proportions of adolescents and young adults with severe or moderately severe haemophilia in France under LTP and treatment on demand (OD).nnnMETHODSnPatients 15 to 25years old with haemophilia A or B, factor VIII/IX ≤2% and no current inhibitor could be included if they had been under factor VIII/IX treatment at least 12months and kept a treatment and bleeding diary.nnnRESULTSnLTP was administered to 169/212 patients (79.7%) and OD treatment to 40/212 patients (18.9%). The most frequent reasons for initiating LTP were joint bleeding, target joints and frequent bleeds; whereas OD treatment was most often selected on the basis of mild bleeding phenotype or because of constraints on LTP. The mean annual bleed rate (ABR) in the OD group (6.33) was higher than in the LTP group (3.07, p<0.001). Mean ABR did not differ significantly between age strata (15-18, >18-21 and >21-25years), but was significantly higher for patients with severe haemophilia (4.02) as compared to those with moderate haemophilia (1.97, p=0.002). No significant difference was observed in mean ABR for joint bleeds between the LTP and OD groups. Physician reported LTP compliance was good or excellent in 97.0% of patients.nnnCONCLUSIONnLTP is the predominant factor VIII/IX treatment among adolescents and young adults with severe or moderately severe haemophilia in France. LTP was associated with low ABR and high compliance.