[en] Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.
Disciplines :
Hematology
Author, co-author :
Albert, Michael H ; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
Sirait, Tiarlan; Statistical Unit and Data Office, European Society for Blood and Marrow Transplantation (EBMT), Leiden, The Netherlands
Eikema, Dirk-Jan; Statistical Unit and Data Office, European Society for Blood and Marrow Transplantation (EBMT), Leiden, The Netherlands
Bakunina, Katerina; Statistical Unit and Data Office, European Society for Blood and Marrow Transplantation (EBMT), Leiden, The Netherlands
Wehr, Claudia; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany ; Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Suarez, Felipe; Department of Adult Hematology, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
Fox, Maria Laura ; Department of Hematology, Hospital Universitari Vall d'Hebron, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital Campus, Barcelona, Spain
Mahlaoui, Nizar ; Pediatric Immuno-Hematology and Rheumatology Unit, Necker-Enfants University Hospital and French National Reference Center for Primary Immunodeficiencies (CEREDIH), AP-HP, Paris, France
Gennery, Andrew R; Department of Pediatric Immunology & Haematopoietic Stem Cell Transplantation (HSCT), Great North Children's Hospital, Newcastle upon Tyne, United Kingdom ; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
Lankester, Arjan C; Department of Pediatrics, Pediatric Stem Cell Transplantation Program, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands
Beier, Rita; Department of Pediatric Hematology and Oncology, Medizinische Hochschule Hannover (MHH), Hannover, Germany
Bernardo, Maria Ester; Department of Pediatric Immunohematology, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
Bigley, Venetia ; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom ; Northern Center for Cancer Care, Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust, Newcastle upon Tyne, United Kingdom
Lindemans, Caroline A; Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands ; Department of Pediatric Blood and Bone Marrow Transplantation, Princess Maxima Center, Utrecht, The Netherlands
Burns, Siobhan O; Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, United Kingdom ; Institute of Immunity and Transplantation, University College London (UCL), London, United Kingdom
Carpenter, Ben ; Department of Clinical Hematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
Dybko, Jaroslaw; Department of Hematology and Cellular Transplantation, Lower Silesian Center of Oncology, Wroclaw, Poland
Güngör, Tayfun ; Department of Hematology/Oncology/Immunology, Gene-Therapy, and Stem Cell Transplantation, University Children's Hospital Zurich - Eleonore Foundation & Children's Research Center (CRC), Zürich, Switzerland
Hauck, Fabian ; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
Lum, Su Han; Department of Pediatric Immunology & Haematopoietic Stem Cell Transplantation (HSCT), Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
Balashov, Dmitry; Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russian Federation
Meisel, Roland ; Division of Pediatric Stem Cell Therapy, Department of Paediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Moshous, Despina; Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades University Hospital, AP-HP, Paris, France
Schulz, Ansgar; Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
Speckmann, Carsten; Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany ; Department of Pediatric Hematology and Oncology, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Slatter, Mary A; Department of Pediatric Immunology & Haematopoietic Stem Cell Transplantation (HSCT), Great North Children's Hospital, Newcastle upon Tyne, United Kingdom ; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
Strahm, Brigitte ; Department of Pediatric Hematology and Oncology, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Uckan-Cetinkaya, Duygu; Department of Pediatrics, Bone Marrow Transplantation (BMT) Unit, Hacettepe University, Faculty of Medicine, Ankara, Turkey
Meyts, Isabelle ; Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium ; Department of Microbiology, Immunology, and Transplantation, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
Vallée, Tanja C; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany
Wynn, Robert; Blood and Marrow Transplant Program, Royal Manchester Children's Hospital, Manchester, United Kingdom
Neven, Bénédicte; Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades University Hospital, AP-HP, Paris, France
Morris, Emma C; Department of Immunology, Royal Free London Hospitals NHS Foundation Trust, London, United Kingdom ; Institute of Immunity and Transplantation, University College London (UCL), London, United Kingdom ; Department of Clinical Hematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
Aiuti, Alessandro
Maschan, Alexei
Aljurf, Mahmoud
Gedde-Dahl, Tobias
Gurman, Gunhan
Bordon, Victoria
Kriván, Gergely
Locatelli, Franco
Porta, Fulvio
Valcárcel, David
Beguin, Yves ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
The authors thank Alessandro Aiuti, Alexei Maschan, Mahmoud Aljurf, Tobias Gedde-Dahl, Gunhan Gurman, Victoria Bordon, Gergely Kriván, Franco Locatelli, Fulvio Porta, David Valcárcel, Yves Beguin, Maura Faraci, Nicolaus Kröger, Aleksandr Kulagin, Peter J. Shaw, Joan Hendrik Veelken, Cristina Diaz de Heredia, Franca Fagioli, Matthias Felber, Bernd Gruhn, Wolfgang Holter, Claudia Rössig, Petr Sedlacek, Jane Apperley, Mouhab Ayas, Ivana Bodova, Goda Choi, J.J. Cornelissen, Anne Sirvent, Anjum Khan, Alphan Kupesiz, Stig Lenhoff, Hakan Ozdogu, Nicolas von der Weid, Montserrat Rovira, Rik Schots, and Donald C. Vinh for providing patient data. Contribution: E.C.M. M.H.A. A.C.L. N.M. F.S. M.L.F. and A.R.G. conceived and designed the study; T.S. managed the data; D.-J.E. and K.B. performed the statistical analysis; M.H.A. and E.C.M. analyzed the data and wrote the manuscript; all authors except D.-J.E. T.S. and K.B. contributed clinical data; all authors reviewed and edited the manuscript; and T.S. and D.-J.E. directly accessed and verified the underlying data.
Tangye, SG, Al-Herz, W, Bousfiha, A, et al. The ever-increasing array of novel inborn errors of immunity: an interim update by the IUIS Committee. J Clin Immunol 41:3 (2021), 666–679.
Lankester, AC, Neven, B, Mahlaoui, N, et al. Hematopoietic cell transplantation in severe combined immunodeficiency: the SCETIDE 2006-2014 European cohort. J Allergy Clin Immunol 149:5 (2022), 1744–1754.e8.
Ferrua, F, Galimberti, S, Courteille, V, et al., SCETIDE, PIDTC, EBMT & ESID IEWP. Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study. J Allergy Clin Immunol 143:6 (2019), 2238–2253.
Chiesa, R, Wang, J, Blok, HJ, et al. Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults. Blood 136:10 (2020), 1201–1211.
Burroughs, LM, Petrovic, A, Brazauskas, R, et al. Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report. Blood 135:23 (2020), 2094–2105.
Passweg, JR, Baldomero, H, Chabannon, C, et al., European Society for Blood and Marrow Transplantation (EBMT). The EBMT activity survey on hematopoietic-cell transplantation and cellular therapy 2018: CAR-T's come into focus. Bone Marrow Transplant 55:8 (2020), 1604–1613.
Morris, EC, Allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency. Hematol Am Soc Hematol Educ Program 2020 (2020), 649–660.
Marsh, RA, Leiding, JW, Logan, BR, et al., submitted on behalf of the Primary Immune Deficiency Treatment Consortium. Chronic Granulomatous disease-associated IBD resolves and does not adversely impact survival following allogeneic HCT. [published correction appears in J Clin Immunol. 2020;40(8):1211–1213] J Clin Immunol 39:7 (2019), 653–667.
Burns, SO, Morris, EC, How I use allogeneic HSCT for adults with inborn errors of immunity. Blood 138:18 (2021), 1666–1676.
Wehr, C, Gennery, AR, Lindemans, C, et al., Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiency. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. J Allergy Clin Immunol 135:4 (2015), 988–997 e6.
Albert, MH, Hauck, F, Wiebking, V, et al. Allogeneic stem cell transplantation in adolescents and young adults with primary immunodeficiencies. J Allergy Clin Immunol Pract 6:1 (2018), 298–301.e2.
Fox, TA, Chakraverty, R, Burns, S, et al. Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency. Blood 131:8 (2018), 917–931.
Dimitrova, D, Gea-Banacloche, J, Steinberg, SM, et al. Prospective study of a novel, radiation-free, reduced-intensity bone marrow transplantation platform for primary immunodeficiency diseases. Biol Blood Marrow Transplant 26:1 (2020), 94–106.
Duarte, RF, Labopin, M, Bader, P, et al., European Society for Blood and Marrow Transplantation (EBMT). Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant 54:10 (2019), 1525–1552.
Kanate, AS, Majhail, NS, Savani, BN, et al. Indications for hematopoietic cell transplantation and immune effector cell therapy: guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant 26:7 (2020), 1247–1256.
Lankester, AC, Albert, MH, Booth, C, et al., Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immune Deficiencies, and European Reference Network on Rare Primary Immunodeficiency Autoinflammatory Autoimmune diseases (RITA). EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity. Bone Marrow Transplant 56:9 (2021), 2052–2062.
Filipovich, AH, Weisdorf, D, Pavletic, S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11:12 (2005), 945–956.
Rosenberg, E, Dent, PB, Denburg, JA, Primary immune deficiencies in the adult: a previously underrecognized common condition. J Allergy Clin Immunol Pract 4:6 (2016), 1101–1107.
Morris, EC, Albert, MH, Allogeneic HSCT in adolescents and young adults with primary immunodeficiencies. Front Pediatr, 7, 2019, 437.
Thakar, MS, Broglie, L, Logan, B, et al. The Hematopoietic Cell Transplant Comorbidity Index predicts survival after allogeneic transplant for nonmalignant diseases. Blood 133:7 (2019), 754–762.
Sorror, M, Storer, B, Sandmaier, BM, et al. Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer 112:9 (2008), 1992–2001.
Valcárcel, D, Sureda, A, Graft failure. Carreras, E, Dufour, C, Mohty, M, Kröger, N, (eds.) The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies, 7th ed., 2018, Springer, Cham, Switzerland, 307–315.
Güngör, T, Teira, P, Slatter, M, et al., Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study. Lancet 383:9915 (2014), 436–448.
Albert, MH, Bittner, TC, Nonoyama, S, et al. X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options. Blood 115:16 (2010), 3231–3238.
Acevedo, MJ, Wilder, JS, Adams, S, et al. Outcomes of related and unrelated donor searches among patients with primary immunodeficiency diseases referred for allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 25:8 (2019), 1666–1673.
Luu, S, Spelman, D, Woolley, IJ, Post-splenectomy sepsis: preventative strategies, challenges, and solutions. Infect Drug Resist 12 (2019), 2839–2851.
Resnick, ES, Moshier, EL, Godbold, JH, Cunningham-Rundles, C, Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 119:7 (2012), 1650–1657.
Gathmann, B, Mahlaoui, N, Gérard, L, et al., European Society for Immunodeficiencies Registry Working Party. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol 134:1 (2014), 116–126.
Edwards, ESJ, Bosco, JJ, Aui, PM, et al. Predominantly antibody-deficient patients with non-infectious complications have reduced naive B, Treg, Th17, and Tfh17 Cells. Front Immunol, 10, 2019, 2593.
Shah, AJ, Sokolic, R, Logan, B, et al. Quality of life of patients with Wiskott Aldrich syndrome and X-linked thrombocytopenia: a Study of the Primary Immune Deficiency Consortium (PIDTC), Immune Deficiency Foundation, and the Wiskott-Aldrich Foundation. J Clin Immunol 39:8 (2019), 786–794.
Pulvirenti, F, Sangerardi, M, Plebani, A, et al. Health-related quality of life and emotional difficulties in chronic granulomatous disease: Data on adult and pediatric patients from Italian Network for Primary Immunodeficiency (IPINet). J Clin Immunol 40:2 (2020), 289–298.
