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STEM CELL TRANSPLANTATION

What causes aplastic anaemia?

Leukemia volume 37, pages 1191–1193 (2023)Cite this article

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Aplastic anaemia has diverse aetiologies including: (1) direct damage to haematopoietic stem or progenitor cells such as from chemicals, drugs and ionising radiations; (2) an abnormal bone marrow micro-environment, (3) immune-mediated mechanism(s); or (4) combination of these. Aetiologies may differ between persons with similar phenotypes and even genotypes [1] (References in the Supplementary). These aetiologies are not mutually exclusive and can be tested, in part, by analysing results of haematopoietic cell transplants between genetically identical twins, one of whom has aplastic anaemia. Recovery of bone marrow function after transplanting haematopoietic cells from a twin without pretransplant conditioning favours damage to haematopoietic stem or progenitor cells as the aetiology and suggests that a bone marrow micro-environment abnormality is an unlikely aetiology. It also likely excludes a congenital abnormality as aetiology because the donor twin has normal bone marrow function. In contrast, failure to recover after the first unsuccessful transplant without pretransplant conditioning, but recovery after the second transplant with it sometimes combined with posttransplant immune suppression, favours an immune aetiology.

There are several reports of genetically identical twin transplants for aplastic anaemia, mostly of few subjects or with contradictory outcomes [2,3,4,5,6,7,8,9]. A prior Center for International Blood and Marrow Transplant Research (CIBMTR) study analysed data from 40 subjects with aplastic anaemia receiving genetically identical twin transplants from 1964 to 1992 with and without pretransplant conditioning [4]. About one-third of recipients of a twin transplant without pretransplant conditioning recovered normal bone marrow function; the remainder did not.

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Data availability

CIBMTR supports the accessibility of research in accordance with the National Institutes of Health (NIH) Data Sharing Policy and the National Cancer Institute (NCI) Cancer Moonshot Public Access and Data Sharing Policy. The CIBMTR only releases de-identified datasets that comply with all relevant global regulations regarding privacy and confidentiality.

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Acknowledgements

RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. The CIBMTR is supported primarily by Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); HHSH250201700006C from the Health Resources and Services Administration (HRSA); N00014-21-1-2954 and N00014-23-1-2057 from the Office of Naval Research; support is also provided by Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program, and from the following commercial entities: AbbVie; Actinium Pharmaceuticals, Inc.; Adaptimmune; Adaptive Biotechnologies Corporation; ADC Therapeutics; Adienne SA; Allogene; Allovir, Inc.; Amgen, Inc.; Angiocrine; Anthem; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics; BeiGene; bluebird bio, inc.; Bristol Myers Squibb Co.; CareDx Inc.; CRISPR; CSL Behring; CytoSen Therapeutics, Inc.; Eurofins Viracor, DBA Eurofins Transplant Diagnostics; Gamida-Cell, Ltd.; Gilead; GlaxoSmithKline; HistoGenetics; Incyte Corporation; Iovance; Janssen Research & Development, LLC; Janssen/Johnson & Johnson; Jasper Therapeutics; Jazz Pharmaceuticals, Inc.; Kadmon; Karius; Kiadis Pharma; Kite, a Gilead Company; Kyowa Kirin; Legend Biotech; Magenta Therapeutics; Mallinckrodt Pharmaceuticals; Medexus Pharma; Merck & Co.; Mesoblast; Millennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; MorphoSys; Novartis Pharmaceuticals Corporation; Omeros Corporation; OptumHealth; Orca Biosystems, Inc.; Ossium Health, Inc.; Pfizer, Inc.; Pharmacyclics, LLC, An AbbVie Company; Pluristem; PPD Development, LP; Sanofi; Sanofi-Aventis U.S. Inc.; Sobi, Inc.; Stemcyte; Takeda Pharmaceuticals; Talaris Therapeutics; Terumo Blood and Cell Technologies; TG Therapeutics; Vertex Pharmaceuticals; Vor Biopharma Inc.; Xenikos BV. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre and the Ministry of Science and Technology of China (84000-51200002).

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Authors and Affiliations

  1. Centre for Haematology, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK

    Robert Peter Gale

  2. Danube Hospital, Donauspital, Klinik Donaustadt, Vienna, Austria

    Wolfgang Hinterberger

  3. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Neal S. Young

  4. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

    Andrew R. Gennery

  5. Paediatric Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, UK

    Andrew R. Gennery

  6. Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA, USA

    Christopher C. Dvorak

  7. CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Kyle M. Hebert, Michael Heim, Larisa Broglie & Mary Eapen

  8. Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    Larisa Broglie

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Contributions

RPG and ME designed the study. Statistical analyses were done by KMH and MH. RPG and LB prepared the initial typescript with edits from all authors. All authors reviewed and accept responsibility for the final typescript and agree to submit for publication.

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Correspondence to Robert Peter Gale or Larisa Broglie.

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Competing interests

RPG is a consultant to NexImmune Inc. and Nanexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd. CCD reports consulting for Alexion, Inc., Omeros Corp., and Jazz Pharmaceuticals. ARG reports a non-restrictive educational grant from Jazz Pharmaceuticals to conduct a study “Role of endothelial cell damage and activation in idiopathic pneumonia syndrome post stem cell transplantation”. The other authors declare no competing interests.

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Gale, R.P., Hinterberger, W., Young, N.S. et al. What causes aplastic anaemia?. Leukemia 37, 1191–1193 (2023). https://doi.org/10.1038/s41375-023-01892-2

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