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J Allergy Clin Immunol. 2018 Jan;141(1):322-328.e10. doi: 10.1016/j.jaci.2017.02.036. Epub 2017 Apr 7.

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

Author information

1
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
2
Dr. von Hauner University Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
3
Immunology and Hematopoietic Stem Cell Transplantation Department, Federal Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
4
Stem Cell Transplant Unit, Department of Hematology and Oncology, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
5
Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
6
Infection, Immunity, Inflammation, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
7
Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway.
8
Duke University School of Medicine, Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, NC.
9
Paediatric BMT Unit, Robert Debre Hospital, Paris, France.
10
Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland.
11
Center for International Blood and Marrow Transplant Research, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wis.
12
Department of Haematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
13
Department of Systems Medicine, University of Rome "Tor Vergata", Unit of Immune and Infectious Diseases, Children's Hospital Bambino Gesù, Rome, Itlay.
14
Infection, Immunity, Inflammation, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Düsseldorf, Germany.
15
Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, NJ.
16
Immunodeficiencies, Hematology & Oncology Unit, Pediatrics, Hospital 12 Octubre, and Universidad Complutense, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
17
Division of Immunology and Allergy, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
18
Division of Stem Cell Transplantation, University Children's Hospital Zürich, Zürich, Switzerland.
19
BørneUngeKlinikken, Copenhagen, Denmark.
20
Paediatric Research Center, University Hospital of Tampere, Tampere, Finland.
21
Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
22
Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
23
Department of Pediatric Hematology, Oncology and BMT, Wroclaw Medical University, Wroclaw, Poland.
24
Department of Dermatology, Wakayama Medical University, Wakayama, Japan.
25
Bahcesehir University Faculty of Medicine, Göztepe Medicalpark Hospital Pediatric Stem Cell Transplantation Unit, Istanbul, Turkey.
26
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences / Lower Silesian Center for Cellular Transplantation, Wrocław, Poland.
27
French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Immuno-Hematology Unit, Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
28
Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Düsseldorf, Germany.
29
Immuno-Hematology Unit, Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
30
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
31
Duke University School of Medicine, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, NC.
32
Mother and Child Health Institute, Medical Faculty, University of Belgrade, Belgrade, Serbia.
33
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
34
Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital and Child and Family Research Institute, Vancouver, British Columbia, Canada.
35
Department of Oncology, Children's Hospital at Westmead, Westmead, Australia.
36
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.
37
Department of Pediatric Hematology Oncology, Hannover Medical, Hannover, Germany.
38
Department of Hematology and Oncology, Wakayama Medical University, Wakayama, Japan.
39
Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Helsinki University Hospital, Helsinki, Finland.
40
Paediatric Haematology & Oncology, Kinderklinik der Technische Universität München, Krankenhaus München-Schwabing, Munich, Germany.
41
Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland.
42
Allergy Immunology and Blood and Marrow Transplant Division, University of California San Francisco Benioff Children's Hospital, San Francisco, Calif.
43
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.

Abstract

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.

KEYWORDS:

Ataxia-telangiectasia; Cernunnos-XLF deficiency; DNA ligase IV deficiency; DNA repair disorders; Nijmegen breakage syndrome; hematopoietic stem cell transplantation

PMID:
28392333
PMCID:
PMC5632132
[Available on 2019-01-01]
DOI:
10.1016/j.jaci.2017.02.036

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