Determinants of successful immune tolerance induction in hemophilia A: systematic review and meta-analysis

Authors: Oomen, I; Camelo, RM; Rezende, SM; Voorberg, J; Mancuso, ME; Oldenburg, J; Carcao, M; Matino, D; Lillicrap, D; Fischer, K; Fijnvandraat, K; Gouw, SC

Affiliations: Amsterdam University Medical Center location University of Amsterdam, Department of Pediatric Hematology, Meibergdreef 9, Amsterdam, The Netherlands. Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands. Department of Internal Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. Res

Publication: Pract Thromb Haemost ; 2023 ; 7. 100020

Abstract: BACKGROUND: Immune tolerance induction (ITI) aims to eradicate anti-factor VIII (FVIII) antibodies (inhibitors) in persons with hemophilia A. However, this burdensome treatment fails in 10% to 40%. To estimate the chance of ITI success in clinical decision making, it is important to identify the predictors of ITI success. OBJECTIVES: We performed a systematic review and meta-analysis to summarize the current evidence on determinants of ITI outcome in persons with hemophilia A. METHODS: A literature search was conducted to identify randomized controlled trials, cohort, or case-control studies reporting on the predictors for ITI outcome in persons with hemophilia A. The main outcome was ITI success. Methodological quality was assessed using an adapted Joanna Briggs Institute checklist, rating as high if ≥11 of 13 criteria were met. Pooled odds ratios (ORs) for ITI success were calculated for each determinant. ITI success was defined as negative inhibitor titer (<0.6 BU/mL), FVIII recovery ≥66% of expected, and FVIII half-life ≥6 hours in 16 (59.3%) studies. RESULTS: We included 27 studies, involving 1,734 participants. Methodological quality of 6 (22.2%) studies (418 participants) was rated as high. Twenty different determinants were assessed. Historical peak titer ≤100 BU/mL (compared with >100 BU/mL, OR, 1.7; 95% CI, 1.4-2.1), pre-ITI titer ≤10 BU/mL (compared with >10 BU/mL, OR, 1.8; 95% CI, 1.4-2.3), and peak titer during ITI ≤100 BU/mL (compared with >100 BU/mL, OR, 2.7; 95% CI, 1.9-3.8) were associated with a higher chance of ITI success. CONCLUSION: Our results suggest that determinants related to the inhibitor titer are associated with ITI success.