Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients
Hashem, Hasan; Bucciol, Giorgia; Ozen, Seza; Unal, Sule; Bozkaya, Ikbal Ok; Akarsu, Nurten; Taskinen, Mervi; Koskenvuo, Minna; Saarela, Janna; Dimitrova, Dimana; Hickstein, Dennis D.; Hsu, Amy P.; Holland, Steven M.; Krance, Robert; Sasa, Ghadir; Kumar, Ashish R.; Müller, Ingo; de Sousa, Monica Abreu; Delafontaine, Selket; Moens, Leen; Babor, Florian; Barzaghi, Federica; Cicalese, Maria Pia; Bredius, Robbert; van Montfrans, Joris; Baretta, Valentina; Cesaro, Simone; Stepensky, Polina; Benedicte, Neven; Moshous, Despina; Le Guenno, Guillaume; Boutboul, David; Dalal, Jignesh; Brooks, Joel P.; Dokmeci, Elif; Dara, Jasmeen; Lucas, Carrie L.; Hambleton, Sophie; Wilson, Keith; Jolles, Stephen; Koc, Yener; Güngör, Tayfun; Schnider, Caroline; Candotti, Fabio; Steinmann, Sandra; Schulz, Ansgar; Chambers, Chip; Hershfield, Michael; Ombrello, Amanda; Kanakry, Jennifer A.
(2021) Journal of Clinical Immunology, volume 41, issue 7, pp. 1633 - 1647
(Article)
Abstract
Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for
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the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2. Methods: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS). Results: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT. Conclusion: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency. Clinical Implications: HCT is a definitive cure for DADA2 with > 95% survival.
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Keywords: Autoinflammation, Bone marrow failure, DADA2, Deficiency of adenosine deaminase 2, Hematopoietic cell transplantation, Immunodeficiency, Inborn error of immunity, Immunology and Allergy, Immunology, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Intramural, Journal Article, Research Support, N.I.H., Extramural
ISSN: 0271-9142
Publisher: Springer New York
Note: Funding Information: We thank the affected children and their parents for their participation and their confidence. We thank the DADA2 Foundation ( www.dada2.org ) for organizing the Inaugural International Conference on the Deficiency of ADA2, with special thanks to Chip Chambers, MD for forming the foundation. We thank Ms. Jo Vencken for technical assistance and all colleagues who contributed to the care for these patients. We thank Nancy J. Ganson, PhD and Susan J. Kelly, PhD at Duke University Center, Durham, for performing numerous ADA2 enzyme activity measurements. We also thank Amy Cruickshank, DO at the University of New Mexico, for her contributions. This study was made possible by collaboration with the European Society of Blood and Bone Marrow Transplantation (EBMT), Inborn Errors Working Party (IEWP), and the DADA2 Foundation and European Society for Immunodeficiencies. SU and NA would like to thank ERARE for supporting DBA molecular work-up as a part of the EuroDBA Project. This work is supported by ERN-RITA. Funding Information: We thank the affected children and their parents for their participation and their confidence. We thank the DADA2 Foundation (www.dada2.org ) for organizing the Inaugural International Conference on the Deficiency of ADA2, with special thanks to Chip Chambers, MD for forming the foundation. We thank Ms. Jo Vencken for technical assistance and all colleagues who contributed to the care for these patients. We thank Nancy J. Ganson, PhD and Susan J. Kelly, PhD at Duke University Center, Durham, for performing numerous ADA2 enzyme activity measurements. We also thank Amy Cruickshank, DO at the University of New Mexico, for her contributions. This study was made possible by collaboration with the European Society of Blood and Bone Marrow Transplantation (EBMT), Inborn Errors Working Party (IEWP), and the DADA2 Foundation and European Society for Immunodeficiencies. SU and NA would like to thank ERARE for supporting DBA molecular work-up as a part of the EuroDBA Project. This work is supported by ERN-RITA. Funding Information: This project was funded in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and (in part) by the National Institute of Allergy and Infectious Diseases, the Sir Jules Thorn Charitable Trust (12/JTA), and the Wellcome Trust (207556_Z_17_Z). Specific ERARE grant funding was attributed to the EuroDBA researchers of Turkey by the Scientific and Technological Research Council of Turkey (TÜBITAK, 315S192).SD is supported by the Personal Research Foundation – Flanders grant 11F4421N. CLL received support from the Immune Deficiency Foundation and Yale University School of Medicine. IM is a Senior Clinical Investigator at the Research Foundation – Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies paid to KU Leuven; by the KU Leuven C1 Grant C16/18/007; by a VIB GC PID Grant, by the FWO Grants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 948959, MORE2ADA2). Publisher Copyright: © 2021, The Author(s).
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