Hematopoietic stem cell transplantation for CTLA-4 insufficiency across Europe: A European Society for Blood and Marrow Transplantation Inborn Errors Working Party study - 24/09/24

Doi : 10.1016/j.jaci.2024.08.020

Christo Tsilifis, MBBS, PhD ^a,^b,^⁎ , Carsten Speckmann, MD ^c,^d, Su Han Lum, MD, PhD ^a,^b, Thomas A. Fox, MBChB, PhD ^e,^f, Adriana Margarit Soler, MD ^g, Yasmina Mozo, MD ^h, Dolores Corral, MD ^h, Anna-Maria Ewins, MD ⁱ, Rosie Hague, MD ^j, Christina Oikonomopoulou, MD, PhD ^k, Krzysztof Kałwak, MD, PhD ^l, Katarzyna Drabko, MD, PhD ^m, Robert Wynn, MB, MD ⁿ, Emma C. Morris, MB, BChir, PhD ^e,^f, Suzanne Elcombe, MBBS, PhD ^o, Venetia Bigley, MB, BChir, PhD ^b,^p, Vassilios Lougaris, MD ^q, Michele Malagola, MD ^q, Fabian Hauck, MD, PhD ^r, Petr Sedlacek, MD, PhD ^s, Alexandra Laberko, MD, PhD ^t, Jennifer M.L. Tjon, MD, PhD ^u, Emilie P. Buddingh, MD, PhD ^v, Claudia Wehr, MD ^w, Bodo Grimbacher, MD ^c,^x,^y,^z, Andrew R. Gennery, MD, PhD ^a,^b, Arjan C. Lankester, MD, PhD ^v, Michael H. Albert, MD ^r, Bénédicte Neven, MD ^aa, Mary A. Slatter, MD, PhD ^a,^b
^a Paediatric Haematopoietic Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
^b Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
^c Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^d Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^e UCL Institute of Immunity and Transplantation, UCL, London, The Netherlands
^f Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
^g Bone Marrow Transplant Unit, Oncology Service, Hospital Sant Joan de Déu, Barcelona, Spain
^h Paediatric Haematopoietic Stem Cell Transplant Unit, University Hospital La Paz, Madrid, Spain
ⁱ Paediatric Stem Cell Transplantation, Royal Hospital for Children, Glasgow, United Kingdom
^j Paediatric Immunology, Royal Hospital for Children, Glasgow, United Kingdom
^k Stem Cell Transplant Unit, Aghia Sophia Children’s Hospital, Athens, Greece
^l Department of Pediatric Hematology, Oncology and BMT, Wroclaw Medical University, Wroclaw, Poland
^m Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, Lublin, Poland
ⁿ Department of Blood and Marrow Transplantation, Royal Manchester Children’s Hospital, Manchester, United Kingdom
^o Department of Immunology, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
^p Northern Centre for Bone Marrow Transplantation, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
^q Adult Bone Marrow Transplant Unit, ASST Spedali Civili, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
^r Department of Pediatrics, Dr von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
^s Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University Motol, Prague, Czech Republic
^t Department of Haematopoietic Stem Cell Transplantation, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
^u Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands
^v Department of Pediatrics, Willem-Alexander Children’s Hospital, Pediatric Stem Cell Transplantation Program, Leiden University Medical Center, Leiden, The Netherlands
^w Department of Haematology and Oncology, University Hospital Freiburg, Freiburg, Germany
^x Department of Medicine I/Hematology, Oncology, and Stem Cell Transplantation, Medical Center–University of Freiburg, Faculty of Medicine, Freiburg, Germany
^y CCI, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^z Department of Rheumatology and Clinical Immunology, CCI, University Hospital Freiburg, Freiburg, Germany
^aa Pediatric Immunology, Hematology, and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France

^∗Corresponding author: Christo Tsilifis, MBBS, PhD, Paediatric Haematopoietic Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom.Paediatric Haematopoietic Stem Cell Transplant UnitGreat North Children’s HospitalNewcastle upon TyneUnited Kingdom

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Tuesday 24 September 2024

Abstract

Background

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterized by lymphoproliferation, dysgammaglobulinemia, and multiorgan autoimmunity including cytopenias and colitis.

Objective

We examined the outcome of hematopoietic stem cell transplantation (HSCT) for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4 fusion protein (CTLA-4–Ig) therapy and pre-HSCT immune dysregulation on survival and immunologic outcome.

Methods

This was a retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Primary end points were overall survival (OS) and disease- and chronic graft-versus-host disease–free survival (DFS). Secondary end point was immunologic outcome assessed by immune dysregulation disease activity (IDDA) score.

Results

Forty patients were included over a 25-year period. Before HSCT, 60% received CTLA-4–Ig, and median (range) IDDA score was 23.3 (3.9-84.0). Median (range) age at HSCT was 14.2 (1.3-56.0) years. Patients received peripheral blood stem cell (58%) or marrow (43%) from a matched unrelated donor (75%), mismatched unrelated donor (12.5%), or matched family donor (12.5%). Median (range) follow-up was 3 (0.6-15) years, and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, disease of 28 of 30 surviving patients was in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity before HSCT (IDDA < 23, P = .002 and P = .006, respectively). CTLA-4–Ig receipt did not influence OS or DFS. Cause of death was transplant related in 7 of 8 patients.

Conclusion

HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity.

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Key words : Allogeneic HSCT, abatacept, belatacept, primary immune regulatory disorder, CTLA-4

Abbreviations used : aGvHD, ATG, cGvHD, CTLA-4, CTLA-4–Ig, DFS, EBMT, EBV, GvHD, HSCT, IDDA, LRBA, MUD, OS, Treg