Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 1; pp. 322 - 328.e10
• Main Authors: Slack, James, MD, Albert, Michael H., MD, Balashov, Dmitry, PhD, Belohradsky, Bernd H., MD, Bertaina, Alice, PhD, Bleesing, Jack, PhD, Booth, Claire, PhD, Buechner, Jochen, PhD, Buckley, Rebecca H., MD, Ouachée-Chardin, Marie, MD, Deripapa, Elena, MD, Drabko, Katarzyna, MD, Eapen, Mary, MD, Feuchtinger, Tobias, MD, Finocchi, Andrea, PhD, Gaspar, H. Bobby, PhD, Ghosh, Sujal, MD, Gillio, Alfred, MD, Gonzalez-Granado, Luis I., MD, Grunebaum, Eyal, MD, Güngör, Tayfun, MD, Heilmann, Carsten, MD, Helminen, Merja, PhD, Higuchi, Kohei, MD, Imai, Kohsuke, PhD, Kalwak, Krzysztof, MD, Kanazawa, Nubuo, PhD, Karasu, Gülsün, MD, Kucuk, Zeynep Y., MD, Laberko, Alexandra, MD, Lange, Andrzej, MD, Mahlaoui, Nizar, MD, Meisel, Roland, MD, Moshous, D., PhD, Muramatsu, Hideki, PhD, Parikh, Suhag, MD, Pasic, Srdjan, PhD, Schmid, Irene, MD, Schuetz, Catharina, PhD, Schulz, Ansgar, MD, Schultz, Kirk R., MD, Shaw, Peter J., MD, Slatter, Mary A., MD, Sykora, Karl-Walter, PhD, Tamura, Shinobu, PhD, Taskinen, Mervi, MD, Wawer, Angela, MD, Wolska-Kuśnierz, Beata, PhD, Cowan, Morton J., MD, Fischer, Alain, PhD, Gennery, Andrew R., MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2018; Elsevier Limited
• Subjects: Alkylation; Allergy and Immunology; Anemia; Antigens; Ataxia; Ataxia telangiectasia; Bone marrow; Bone marrow transplantation; Cell cycle; Cernunnos-XLF deficiency; Chemotherapy; Complications; Conditioning; Consortia; Cyclophosphamide; Deoxyribonucleic acid; DNA; DNA damage; DNA ligase (ATP); DNA ligase IV deficiency; DNA repair; DNA repair disorders; Double-strand break repair; Graft-versus-host reaction; hematopoietic stem cell transplantation; Immunodeficiency; Immunological tolerance; Immunology; Infections; Kinases; Lymphocytes; Malignancy; Mortality; Mutation; Nijmegen breakage syndrome; Patients; Proteins; Radiation therapy; Radiosensitivity; Stem cell transplantation; Stem cells; Transplantation; Transplants & implants; Severe combined immunodeficiency; Nijmegen breakage syndrome; Nonhomologous end-joining factor 1; DNA repair disorders; SCID; Anti-thymocyte globulin; Chronic graft-versus-host disease; Hematopoietic cell transplantation; aGvHD; hematopoietic stem cell transplantation; PTLD; Recombination-activating gene; Reduced-intensity conditioning; Myeloablative conditioning; NBS; NHEJ1; Graft-versus-host disease; GvHD; LIG4; Nonhomologous end-joining; DNA double-strand break; RIC; DNA ligase IV deficiency; MAC; Cernunnos-XLF deficiency; Cernunnos-XLF; Cernunnos–XRCC4-like factor; Ataxia-telangiectasia; AT; ATG; Ataxia-telangiectasia mutated; Natural killer; DNA-dsb; Acute graft-versus-host disease; HCT; Posttransplantation lymphoproliferative disorder; RAG; ATM; cGvHD; NHEJ; NK
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2017.02.036

Background Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos–XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). Methods Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. Results Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC ( P  = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P  = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. Conclusion RIC HCT resolves DNA repair disorder–associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.