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

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/m(2) 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.Peer reviewe

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

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

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor kappa B essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftmentwas documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlyingmutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.St. Giles FoundationRockefeller UniversityINSERMParis Descartes UniversityCentre de Reference des Deficits Immunitaires Hereditaires (CEREDIH)German Ministry for Education and ResearchNational Institute for Health Research and GOSH Biomedical Research CentreRobert A. Good/Jeffrey Modell FellowshipNecker Hosp Sick Children, AP HP, Study Ctr Immunodeficiencies, Paris, FranceTokyo Med & Dent Univ, Dept Pediat & Dev Biol, Tokyo, JapanNiigata Univ, Grad Sch Med & Dent Sci, Dept Pediat, Niigata, JapanAnn & Robert H Lurie Childrens Hosp Chicago, Div Pediat Dermatol, Chicago, IL 60611 USANorthwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USACincinnati Childrens Hosp, Med Ctr, Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH USAKyoto Univ, Grad Sch Med, Dept Pediat, Kyoto, JapanHirosaki Univ, Grad Sch Med, Dept Pediat, Hirosaki, Aomori, JapanUniv Hosp, Pediat Oncohematoimmunol Unit, Angers, FranceUniv Lyon 1, Sch Med, Genet Unit, Hosp Civils Lyon, Bron, FranceEmory Univ, Dept Pediat, Div Bone Marrow Transplant, Aflac Canc & Blood Disorders Ctr Childrens Hlth, Atlanta, GA 30322 USAUniv Zurich, Univ Childrens Hosp Zurich, Div Stem Cell Transplantat, Zurich, SwitzerlandUniv Hosp, Dept Biochem & Genet, Angers, FranceNatl Inst Pediat, Clin Immunol Dept, Mexico City, DF, MexicoNatl Inst Pediat, Program Hematopoiet Stem Cell Transplantat, Mexico City, DF, MexicoUCL, Great Ormond St Inst Child Hlth, London, EnglandNatl Jewish Hlth, Dept Pediat, Immunodeficiency Diag & Treatment Program, Denver, CO USAOregon Hlth & Sci Univ, Dept Pediat Dermatol, Portland, OR 97201 USAStarship Hosp, Starship Blood & Canc Ctr, Paediat Haematol, Auckland, New ZealandUniv Wales Hosp, Immunodeficiency Ctr Wales, Cardiff, S Glam, WalesUniv Freiburg, Ctr Chron Immunodeficiency, Freiburg, GermanyNewcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne, Tyne & Wear, EnglandNewcastle Tyne Hosp NHS Fdn Trust, Great North Childrens Hosp, Paediat Immunol Dept, Newcastle Upon Tyne, Tyne & Wear, EnglandUniv Fed Sao Paulo, Inst Biomed Sci, Dept Pediat, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, BrazilGreat Ormond St Hosp Children NHS Fdn Trust, Blood & Marrow Transplant Unit, London, EnglandNIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USANIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USAParis Descartes Univ, Imagine Inst, Paris, FranceNecker Hosp Sick Children, AP HP, Pediat Hematol Immunol & Rheumatol Unit, Paris, FranceCambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, EnglandOxford Univ Hosp NHS Fdn Trust, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford, EnglandNecker Hosp Sick Children, INSERM, UMR1163, Lab Human Genet Infect Dis,Necker Branch, Paris, FranceRockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USAHoward Hughes Med Inst, New York, NY USATexas Childrens Hosp, Baylor Coll Med, Sect Immunol Allergy & Rheumatol, Ctr Human Immunobiol, Houston, TX 77030 USAUniv Fed Sao Paulo, Inst Biomed Sci, Dept Pediat, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, BrazilWeb of Scienc