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

Ilja Oomen; Ricardo M Camelo; Suely Meireles Rezende; Jan Voorberg; Maria Elisa Mancuso; Johannes Oldenburg; Manuel Carcao; Davide Matino; David Lillicrap; Kathelijn Fischer; Karin Fijnvandraat; Samantha C Gouw; International Genetic and clinical determinants of the Outcome of Immune Tolerance Induction (GO-ITI) study group

doi:10.1016/j.rpth.2022.100020

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

Res Pract Thromb Haemost. 2022 Dec 20;7(1):100020. doi: 10.1016/j.rpth.2022.100020. eCollection 2023 Jan.

Authors

Ilja Oomen^{1

2}, Ricardo M Camelo^{3

4}, Suely Meireles Rezende³, Jan Voorberg², Maria Elisa Mancuso⁵, Johannes Oldenburg⁶, Manuel Carcao⁷, Davide Matino⁸, David Lillicrap⁹, Kathelijn Fischer¹⁰, Karin Fijnvandraat^{1

2}, Samantha C Gouw^{1

4}; International Genetic and clinical determinants of the Outcome of Immune Tolerance Induction (GO-ITI) study group

Affiliations

¹ Amsterdam University Medical Center location University of Amsterdam, Department of Pediatric Hematology, Meibergdreef 9, Amsterdam, The Netherlands.
² Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.
³ Department of Internal Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
⁴ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Center for Thrombosis and Hemorrhagic Diseases, Instituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Rozzano, Milan, Italy.
⁶ Department of Internal Medicine, University Clinic Bonn, University of Bonn, Bonn, Germany.
⁷ Division of Hematology/Oncology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada.
⁸ Department of Medicine, McMaster University, University of Hamilton, Hamilton, Canada.
⁹ Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada.
¹⁰ Department of Hematology, Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands.

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.

Keywords: antibodies; factor VIII; hemophilia A; immune tolerance; systematic review.