Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B

Abstract

A B S T R A C T BackgroundThe occurrence of factor inhibitory antibodies, or inhibitors, is a significant complication in the care of individuals with congenital haemophilia A or B. Currently, immune tolerance induction is the only known intervention to successfully eradicate inhibitors. However, ideal dosing regimens, and the comparative safety and efficacy of different immune tolerance induction regimens have not yet been established. ObjectivesThe objective of this review was to assess the effects of immune tolerance induction (different protocols of this therapy versus each other, or versus only bypassing agents) for treating inhibitors in people with congenital haemophilia A or B. Search methodsWe searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched: MEDLINE (from 1946 to 15 July 2013); Embase (from 1980 to 15 July 2013) via the OVID platform; CINAHL (from conception to 15 July 2013); and ClinicalTrials.gov (most recent search: 15 July 2013). We also searched the reference lists of relevant articles and reviews. Selection criteriaRandomised controlled trials comparing either different immune tolerance induction regimens or immune tolerance induction versus only bypassing therapy for the eradication of factor inhibitory antibodies in patients with congenital haemophilia A or B. Data collection and analysisTwo review authors independently completed data collection, extraction and assessment of the risk of bias of trials. Main resultsOne methodologically sound randomised controlled trial met the inclusion criteria and was included in the review. One further randomised controlled trial has been recently stopped, but it has not yet been reported. Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B (Review)We found one randomised trial that compared high-and low-dose immune tolerance induction, which included 115 males with haemophilia A and inhibitors. Key results and conclusionsThe single included trial was too small to be certain that both doses of immune tolerance induction were equally successful at removing inhibitors. However, the high-dose treatment destroyed all inhibitors faster and with less bleeding events than the low-dose treatment.Since there was only one available trial, further trials are needed to establish the best immune tolerance induction regimen with respect to starting time, dosing intensity and frequency. 2 Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B (Review) ]. Haemophilia 2006; 12 Suppl 2:57-69. DiMichele DM, Hay CRM. The international immune tolerance study: a multicenter prospective randomized trial in progress. Journal of Thrombosis and Haemostasis 2006;4 (10):2271-3. Hay CRM, DIMichele DM. The principal results of the international immune tolerance study: Morbidity [abstract]. Journal of Thrombosis and Haemostasis 2011;9:845...

Management of haemophilia A with inhibitors: A regional cross‐talk

“…Several regimens for ITI have been described, with different dosing schedules and combined therapies [50][51][52][53][54][55][56] ; the selection of an ITI regimen is usually considered on a case-by-case basis. 57 The International ITI study is the only randomised controlled trial to date to evaluate the efficacy of ITI in patients with severe HA and good risk features (historical inhibitor titres <200 BU and immediate pre-ITI titres <10 BU), comparing a low-dose daily FVIII regimen of 50 IU/kg three times weekly with a high-dose regimen of 200 IU/kg. 55 The study demonstrated an almost 70% overall success rate in achieving tolerance, with no statistically significant difference between the two arms.…”

“…After successful ITI, patients are able to resume factor replacement therapies for prophylaxis and acute bleeding. Several regimens for ITI have been described, with different dosing schedules and combined therapies 50–56 ; the selection of an ITI regimen is usually considered on a case‐by‐case basis 57 …”

Profilaxis con CCPa en pacientes con hemofilia A con inhibidores de alta respuesta

“…Con el advenimiento de mejores técnicas en la producción de factores, los métodos de inactivación viral y el uso de biotecnología en su producción, las complicaciones infecciosas han disminuido y prácticamente desaparecido, si bien continúa existiendo un riesgo potencial por nuevos agentes infecciosos. Los pacientes con inhibidores de alta respuesta requieren de estrategias de tratamiento como la inducción de tolerancia inmune para intentar la erradicación del inhibidor, sin embargo, hasta en 10-15% de los casos no se consigue su erradicación (9,10). En los pacientes con inhibidores de alta respuesta, hay mayor dificultad para el control de los sangrados con agentes de puente, la tasa de control de los sangrados varía entre 70 y 90%.…”

Assessing options for treating haemophilia with inhibitors

“…Several reviews [18], [19] have supported this assertion, but we note that Earnshaw et al's protocol for secondary ("rescue") ITI includes the option of using concentrates containing Factor VIII complexed to von-Willebrand factor (VWF). A recent systematic review and meta-analysis [20] assessed the effect of VWF on inhibitor eradication in patients with severe haemophilia A but failed to demonstrate an association between product type and ITI outcome, although the heterogeneity observed by the authors among different studies might reflect differences in the response to different products. Thus, considering this background and also that the final results of the randomized controlled RESIST study [21], which could contribute to clarify this controversial issue, are still awaited, we concur with the most recent Cochrane Review on ITI [20] that "The choice of immune tolerance induction regimen should be considered individually for each case, until further research provides additional evidence".…”