title: Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders.
abstract: 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).
  
  
  
  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/m2fludarabine or less and 40 mg/kg cyclophosphamide or less were used.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
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authors.affiliation: Dr. von Hauner University Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Michael H
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authors.affiliation: Immunology and Hematopoietic Stem Cell Transplantation Department, Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
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authors.affiliation: Dr. von Hauner University Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
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authors.affiliation: Stem Cell Transplant Unit, Department of Hematology and Oncology, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
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authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: a.r.gennery@ncl.ac.uk.
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mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D049914:DNA Repair-Deficiency Disorders / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000209:etiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D011379:Prognosis; D016896:Treatment Outcome; D014777:Virus Diseases; D055815:Young Adult
keywords: Ataxia-telangiectasia; Cernunnos-XLF deficiency; DNA ligase IV deficiency; DNA repair disorders; Nijmegen breakage syndrome; hematopoietic stem cell transplantation