Hematopoietic stem cell transplantation as treatment for patients with DOCK8 deficiency
J Allergy Clin Immunol Pract.
Aydin SE1, Freeman AF2, Al-Herz W3, Al-Mousa HA4, Arnaout RK5, Aydin RC1, Barlogis V6, Belohradsky BH7, Bonfim C8, Bredius RG9, Chu JI10, Ciocarlie OC11, Doğu F12, Gaspar HB13, Geha RS14, Gennery AR15, Hauck F1, Hawwari A16, Hickstein DD17, Hoenig M18, Ikinciogullari A12, Klein C1, Kumar A19, Ifversen MRS20, Matthes S21, Metin A22, Neven B23, Pai SY24, Parikh SH25, Picard C26, Renner ED27, Sanal Ö28, Schulz AS18, Schuster F29, Shah NN30, Shereck EB31, Slatter MA32, Su HC33, van Montfrans J34, Woessmann W35, Ziegler JB36, Albert MH37; Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation and the European Society for Primary Immunodeficiencies.
1 Dr von Hauner University Children’s Hospital, Ludwig Maximilians Universität, Munich, Germany.
2 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
3 Department of Pediatrics, Al-Sabah Hospital, Kuwait, Kuwait.
4 Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
5 Department of Medicine, Allergy & Immunology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
6 Pediatric Hematology, Assistance publique des Hopitaux de Marseille, Marseille, France.
7 Deutsche Selbsthilfe Angeborene Immundefekte, Schnaitsee, Germany.
8 Pediatric Blood and Marrow Transplantation Program, Hospital de Clinicas, Federal University of Parana, Curitiba, Brazil.
9 Pediatric Immunology, LUMC, Leiden, The Netherlands.
10 Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
11 Department of Bone Marrow Transplantation, Great Ormond Street Hospital NHS Trust, London, United Kingdom.
12 Department of Pediatric Immunology & Allergy, Ankara University School of Medicine, Ankara, Turkey.
13 Molecular Immunology Unit, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
14 Department of Immunology, Boston Children’s Hospital, Boston, Mass.
15 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
16 King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
17 ETI/CCR/NCI, National Institutes of Health, Bethesda, Md.
18 Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.
19 BMT/Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.
20 Department for Children and Adolescents, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
21 Stem Cell Transplantation, St Anna Children’s Hospital, Vienna, Austria.
22 Pediatric Immunology, Ankara Children’s Hematology Oncology Training and Research Hospital, Ankara, Turkey.
23 Department for Pediatric Immuno-Hematology and Rheumatology, Necker Hospital, Paris, France.
24 Boston Children’s Hospital, Dana-Farber Cancer Institute, Boston, Mass.
25 Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, NC.
26 Study Center of Primary Immunodeficiency, Necker Children’s Hospital, Paris, France.
27 Environmental Medicine, TU Munich, Neuherberg, Germany.
28 Department of Pediatrics, Hacettepe University, Ankara, Turkey.
29 Department of Pediatrics, Düsseldorf University Hospital, Düsseldorf, Germany.
30 Pediatric Oncology Branch, National Cancer Institute, Bethesda, Md.
31 Pediatric Hematology/Oncology, Oregon & Health Science University, Portland, Ore.
32 Paediatric BMT, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom.
33 Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, Bethesda, Md.
34 Pediatric Immunology and Infectious Diseases, UMC Utrecht, Utrecht, The Netherlands.
35 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
36 Immunology & Infectious Diseases, Sydney Children’s Hospital, Randwick, NSW, Australia.
37 Dr von Hauner University Children’s Hospital, Ludwig Maximilians Universität, Munich, Germany. Electronic address: firstname.lastname@example.org.
Year of Publication:
Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease.
To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables.
We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients.
We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive.
HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.