Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients

Authors

Hasan Hashem, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Bone Marrow Transplant Unit, King Hussein Cancer Center (KHCC), P.O Box 1269, Amman, 11941, Jordan
Giorgia Bucciol, Department of Pediatrics, ERN RITA Core Center, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium; Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium
Seza Ozen, Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey; Hacettepe University Vasculitis Research Center, Ankara, Turkey
Sule Unal, Department of Pediatric Hematology, Research Center for Fanconi Anemia and Other Inherited Bone Marrow Failure Syndromes, Hacettepe University, Ankara, Turkey
Ikbal Ok Bozkaya, Division of Pediatric Hematology and Oncology, Bone Marrow Transplant Unit, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
Nurten Akarsu, Department of Medical Genetics, Hacettepe University, Sihhiye, 06100, Ankara, Turkey
Mervi Taskinen, Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Helsinki University Hospital, Helsinki, Finland
Minna Koskenvuo, Pediatric Hematology, Oncology and Stem Cell Transplantation, Children and Adolescents, Helsinki University Hospital, Helsinki, Finland
Janna Saarela, Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland; Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway
Dimana Dimitrova, Experimental Transplantation and Immunotherapy Branch, National Cancer Institute of the National Institutes of Health, Bethesda, MD, USA
Dennis D. Hickstein, Immune Deficiency Cellular Therapy Program, CCR, NCI, MD, Bethesda, USA
Amy P. Hsu, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
Steven M. Holland, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
Robert Krance, Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
Ghadir Sasa, Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
Ashish R. Kumar, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; University of Cincinnati College of Medicine, Cincinnati, OH, USA
Ingo Müller, Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Monica Abreu de Sousa, Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Selket Delafontaine, Department of Pediatrics, ERN RITA Core Center, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium; Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium
Leen Moens, Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium
Florian Babor, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
Federica Barzaghi, San Raffaele Telethon Institute for Gene Therapy (TIGET), Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute Milan, Milan, Italy
Maria Pia Cicalese, Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Robbert Bredius, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands
Joris van Montfrans, Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, Netherlands
Valentina Baretta, Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
Simone Cesaro, Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
Polina Stepensky, Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Medical Center, Jerusalem, Israel
Neven Benedicte, Pediatric Immunology, Hematology and Rheumatology Unit, Hôpital Necker-Enfants Malades, APHP, Paris, France
Despina Moshous, Pediatric Immunology, Hematology and Rheumatology Unit, Hôpital Necker-Enfants Malades, APHP, Paris, France
Guillaume Le Guenno, Department of Internal Medicine, University Hospital Estaing, CHU Clermont-Ferrand, Clermont-Ferrand, France
David Boutboul, Clinical Immunology Department, Hospital Saint Louis, Université de Paris, Paris, France
Jignesh Dalal, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH, USA
Joel P. Brooks, Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
Elif Dokmeci, Department of Pediatrics, University of New Mexico, Albuquerque, NM, USA
Jasmeen Dara, Department of Pediatrics, Division of Allergy, Immunology, Blood and Marrow Transplantation, University of California San Francisco, San Francisco, CA, USA
Carrie L. Lucas, Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
Sophie Hambleton, Newcastle University Translational and Clinical Research Institute and Great North Children's Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, , Newcastle Upon Tyne, UK
Keith Wilson, Department of Hematology, University Hospital of Wales, Cardiff, UK
Stephen Jolles, Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, UK
Yener Koc, Stem Cell Transplant Unit, Medicana International, Istanbul, Turkey
Tayfun Güngör, Division of Hematology/Oncology/Immunology, Gene Therapy, and Stem Cell Transplantation, University Children's Hospital Zurich - Eleonore Foundation & Children's Research Center (CRC), Steinwiesstrasse 75, CH-8032, Zurich, Switzerland
Caroline Schnider, Pediatric Immuno-Rheumatology of Western Switzerland, Department Women-Mother-Child, Lausanne University Hospital, Lausanne, Switzerland
Fabio Candotti, Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Sandra Steinmann, Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
Ansgar Schulz, Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
Chip Chambers, Vanderbilt University Medical Center, Nashville, TN, USA
Michael Hershfield, Department of Medicine and Biochemistry, Duke University Medical Center, Durham, NC, USA
Amanda Ombrello, Metabolic, Cardiovascular, and Inflammatory Disease Genomics Branch, National Human Genome Research Institute (NHGRI), Bethesda, MD, USA
Jennifer A. Kanakry, Department of Pediatrics, ERN RITA Core Center, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium
Isabelle Meyts, Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

Document Type

Article

Publication Date

10-1-2021

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 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.

Publisher

Kluwer Academic/Plenum Publishers

Publication Title

Journal of clinical immunology

ISSN

1573-2592

Volume

41

Issue

7

First Page

1633

Last Page

1647

DOI

10.1007/s10875-021-01098-0

Recommended Citation

Hashem H, Bucciol G, Ozen S, Unal S, Bozkaya IO, Akarsu N, Taskinen M, Koskenvuo M, Saarela J, Dimitrova D, Hickstein DD, Hsu AP, Holland SM, Krance R, Sasa G, Kumar AR, Müller I, de Sousa MA, Delafontaine S, Moens L, Babor F, Barzaghi F, Cicalese MP, Bredius R, van Montfrans J, Baretta V, Cesaro S, Stepensky P, Benedicte N, Moshous D, Le Guenno G, Boutboul D, Dalal J, Brooks JP, Dokmeci E, Dara J, Lucas CL, Hambleton S, Wilson K, Jolles S, Koc Y, Güngör T, Schnider C, Candotti F, Steinmann S, Schulz A, Chambers C, Hershfield M, Ombrello A, Kanakry JA, Meyts I. Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients. J Clin Immunol. 2021 Oct;41(7):1633-1647. doi: 10.1007/s10875-021-01098-0. Epub 2021 Jul 29. Erratum in: J Clin Immunol. 2022 Apr 30;: PMID: 34324127; PMCID: PMC8452581.