Prediction of the chance of successful immune tolerance induction in persons with severe hemophilia A and inhibitors: a clinical prediction model

Ilja Oomen; Amal Abdi; Ricardo M Camelo; Fábia M R A Callado; Luany E M Carvalho; Ilenia L Calcaterra; Manuel Carcao; Giancarlo Castaman; Jeroen C J Eikenboom; Kathelijn Fischer; Vivian K B Franco; Martijn W Heymans; Frank W G Leebeek; David Lillicrap; Cláudia S Lorenzato; Maria Elisa Mancuso; Davide Matino; Matteo N D Di Minno; Alex B Mohseny; Johannes Oldenburg; Suely Meireles Rezende; Georges-Etienne Rivard; Natalia Rydz; Saskia E M Schols; Jan Voorberg; Karin Fijnvandraat; Samantha C Gouw; International Genetic and clinical determinants for the outcome of immune tolerance induction study group

doi:10.1016/j.rpth.2024.102580

Prediction of the chance of successful immune tolerance induction in persons with severe hemophilia A and inhibitors: a clinical prediction model

Res Pract Thromb Haemost. 2024 Oct 3;8(7):102580. doi: 10.1016/j.rpth.2024.102580. eCollection 2024 Oct.

Authors

Ilja Oomen^{1

2}, Amal Abdi¹, Ricardo M Camelo³, Fábia M R A Callado⁴, Luany E M Carvalho⁵, Ilenia L Calcaterra⁶, Manuel Carcao⁷, Giancarlo Castaman⁸, Jeroen C J Eikenboom⁹, Kathelijn Fischer¹⁰, Vivian K B Franco¹¹, Martijn W Heymans^{12

13}, Frank W G Leebeek¹⁴, David Lillicrap¹⁵, Cláudia S Lorenzato¹⁶, Maria Elisa Mancuso¹⁷, Davide Matino¹⁸, Matteo N D Di Minno⁶, Alex B Mohseny¹⁹, Johannes Oldenburg²⁰, Suely Meireles Rezende³, Georges-Etienne Rivard^{21

22}, Natalia Rydz²³, Saskia E M Schols^{24

25}, Jan Voorberg², Karin Fijnvandraat^{1

2}, Samantha C Gouw¹; International Genetic and clinical determinants for the outcome of immune tolerance induction study group

Affiliations

¹ Department of Pediatric Hematology, Amsterdam University Medical Centers location University of Amsterdam, Amsterdam, the Netherlands.
² Department of Molecular Hematology, Sanquin Research, Amsterdam, the Netherlands.
³ Department of Internal Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
⁴ Fundação de Hematologia e Hemoterapia de Pernambuco, Recife, Brazil.
⁵ Centro de Hematologia e Hemoterapia do Ceará, Fortaleza, Brazil.
⁶ Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
⁷ Department of Pediatrics, Division of Hematology and Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.
⁸ Department of Oncology, Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Florence, Italy.
⁹ Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
¹⁰ Department of Hematology, Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht, the Netherlands.
¹¹ Centro de Hematologia e Hemoterapia de Santa Catarina, Florianópolis, Brazil.
¹² Department of Epidemiology and Biostatistics, Amsterdam University Medical Centers, Vrije Universiteit University, Amsterdam, the Netherlands.
¹³ Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands.
¹⁴ Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁵ Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
¹⁶ Coagulopathy Clinic, Hemocentro do Paraná, Curitiba, Brazil.
¹⁷ Department of Hematology, Center for Thrombosis and Hemorrhagic Diseases, Instituto di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital, Rozzano, Milan, Italy.
¹⁸ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
¹⁹ Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands.
²⁰ Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany.
²¹ Molecular Diagnostic Laboratory, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec, Canada.
²² Department of Pediatrics, Division of Hematology-Oncology, Montréal University, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec, Canada.
²³ Department of Hematology and Hematologic Malignancies, Foothills Medical Center, Calgary, Alberta, Canada.
²⁴ Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
²⁵ Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands.

Abstract

Background: Inhibitor eradication to restore factor (F)VIII efficacy is the treatment goal for persons with severe hemophilia A (HA) and inhibitors. Immune tolerance induction (ITI) is demanding and successful in about 70% of people. Until now, it has remained difficult to quantify the probability of ITI success or failure, complicating the decision to initiate or not initiate ITI. Estimating the individual chance of ITI success allows clinicians, patients, and their families to support shared decision-making.

Objectives: We aimed to identify clinical predictors of ITI success and to develop a clinical prediction model to estimate the chance of successful ITI in persons with severe HA.

Methods: This multicenter study included persons with severe HA who received ITI. Clinical data were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. A multivariable logistic regression model was developed. Model performance and internal validation were performed.

Results: Of 206 participants with a median age of 19.8 months (IQR, 12.1-38.8) at ITI start, 148 (71.8%) achieved ITI success. Our clinical prediction model included 4 predictors of ITI success: cumulative number of FVIII exposure days at inhibitor development, peak inhibitor titer, ethnicity, and F8 mutation type. The C statistic was 0.801 (95% CI, 0.70-0.87).

Conclusion: In our study, including 206 people with severe HA and inhibitors, we developed a clinical prediction model to estimate the chance of successful ITI. After future external validation, this clinical prediction model may be useful for informing clinicians and families.

Keywords: factor VIII; hemophilia A; immune tolerance; probability; treatment outcome.