Outcome of Hematopoietic Cell Transplantation for DNA-Double Strand Breakage Repair Disorders.
Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for ImmunodeficienciesShow More
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BACKGROUND: Rare DNA breakage-repair disorders predispose to infection and lympho-reticular malignancies. Hematopoietic cell transplantation (HCT) is curative but co-administered chemo- or radio-therapy is damaging due to systemic radio-sensitivity. We collected HCT outcome data for Nijmegen Breakage syndrome (NBS), DNA ligase IV deficiency (LIG4), Cernunnos-XLF deficiency and ataxia-telangiectasia. METHODS: Data from 38 centres worldwide, including indication, donor, conditioning regimen, graft-versus-host disease (GvHD) and outcome were analyzed. Conditioning was classified as myeloablative (MAC) if it contained radiotherapy or alkylators and reduced intensity (RIC) if no alkylators and/or fludarabine ≤150 mg/m(2) and cyclophosphamide ≤ 40 mg/kg were used. RESULTS: 55 new, 14 updated and 18 previously published patients were analyzed. Median age at HCT was 48 (range 1.5 - 552) months. 29 were transplanted for infection, 21 malignancy, 13 bone marrow failure, 13 pre-emptively, 5 had multiple indications, and 6 had no information. 22 received MAC, 59 RIC, 4 were infused;- information unavailable for 2. 73/77 patients with LIG4, Cernunnos-XLF deficiency or NBS received conditioning. Survival was 53/77 (69%), worse for MAC than RIC (p=0.006). Most deaths occurred early post-transplant suggesting poor tolerance of conditioning. Survival in ataxia-telangiectasia patients was 25%. 41/83 patients experienced aGvHD (49%): less in RIC compared to MAC, 26/56 (46%) vs 12/21 (57%) (p=0.45). Median follow-up was 35 (range 2-168) months. No secondary malignancies were reported during 15 years follow-up. Growth and developmental delay remained post-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 ataxia-telangiectasia is not recommended.
DNA Ligase 4 deficiency
DNA repair disorders
Hematopoietic stem cell transplantation
Nijmegen Breakage syndrome
Published Version (Please cite this version)10.1016/j.jaci.2017.02.036
Publication InfoSlack, James; Albert, Michael H; Balashov, Dmitry; Belohradsky, Bernd H; Bertaina, Alice; Bleesing, Jack; ... Primary Immunodeficiency Treatment Consortium (2017). Outcome of Hematopoietic Cell Transplantation for DNA-Double Strand Breakage Repair Disorders. J Allergy Clin Immunol. 10.1016/j.jaci.2017.02.036. Retrieved from https://hdl.handle.net/10161/14232.
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James Buren Sidbury Distinguished Professor of Pediatrics, in the School of Medicine
The overall emphasis of Dr. Buckley's research is in human T,B and NK cell development and in aberrations in their development and regulation. The work involves three particular areas of investigation: 1) the cellular and molecular bases of genetically-determined human immunodeficiency diseases, 2) the use of bone marrow stem cells to cure genetically-determined immunodeficiency diseases, and 3) the use of human SCID bone marrow stem cell chimeras to study human thymic education, T and B cell on
Associate Professor of Pediatrics
Stem cell transplantation for a variety of disorders - ranging from malignant diseases such as leukemia, lymphoma and myelodysplastic syndrome to nonmalignant diseases such as sickle cell disease, thalassemias, aplastic anemia, histiocytosis and leukodystrophies. My clinical research interest is stem cell transplantation for children with primary immune deficiency disorders and hemoglobinopathies such as sickle cell anemia,thalassemia and other non-malignant disorders. In addition,I am intereste
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