Outcome of Hematopoietic Cell Transplantation for DNA-Double Strand Breakage Repair Disorders.
Abstract
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.
Type
Journal articleSubject
Ataxia-TelangiectasiaCernunnos-XLF deficiency
DNA Ligase 4 deficiency
DNA repair disorders
Hematopoietic stem cell transplantation
Nijmegen Breakage syndrome
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https://hdl.handle.net/10161/14232Published Version (Please cite this version)
10.1016/j.jaci.2017.02.036Publication Info
Slack, 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Rebecca Hatcher Buckley
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
Suhag H. Parikh
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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