Abstract
Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P<.001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P< .001). Genetic subgroups did not differ in 2-year OS (P= .1) and EFS (P=.073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor-deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5×10e3/μL at+1 year were identified as independent predictors of favorable clinical and immunologic outcome. Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.
Highlights
Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome
The 2-year overall survival (OS) of the pooled IL-2 receptor gamma chain (IL2Rg)-JAK3IL7R–deficient SCID patients (83.6%; 95% confidence interval [Confidence interval event-free survival (EFS) (CI)], 78.0-89.7), RAG1/2- and DCLRE1C-deficient (T2/B2) SCID patients (79.8%; 95% CI, 72.5-87.7), adenosine deaminase (ADA)-deficient patients (85.7%; 95% CI, 75.8-97.0), and the minor ‘‘other’’ subgroup (64.3%; 95% CI, 48.7-84.7) showed no significant differences (Fig 1, A; P 5 .1)
The 2-year EFS was similar in ADA-deficient (78.4%; 95% CI, 66.8-91.9), IL2Rg-Janus kinase 3 (JAK3)-IL-7 receptor (IL7R)–deficient (77.7%; 95% CI, 71.3-84.6), RAG1/2-DCLRE1C–deficient (71.4%; 95% CI, 63.4-80.5), and the group of ‘‘other’’ SCID (57.1%; 95% CI, 41.4-78.7) patients (Fig 1, B; P 5 .073)
Summary
We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. EDIH) and European Registry for Stem Cell Transplantation for Primary Immunodeficiencies (SCETIDE), H^opital Universitaire Necker-Enfants malades, Assistance Publique-H^opitaux de Paris (AP-HP), Paris; fDr von Haunersches University Children’s Hospital, Munich; gthe Hospital Clınic, Sant Creu i Sant Pau Hospital, Bone Marrow Transplantation Unit, Barcelona; hthe Department for Children and Adolescents Medicine, Division for Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt; ithe Department for Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology, Moscow; jthe Klinik f€ur P€adiatrische H€amatologie und Onkologie, Hannover Medical School, Hannover; kthe Institut d’Hematologie et d’Oncologie Pediatrique, Hospices Civils de Lyon and Universite Claude Bernard Lyon 1, Lyon; lthe Department of Pediatric Hemato-oncology and Stem Cell Transplant, Ghent University Hospital, Ghent; mthe Translational and Clinical Research Institute, Newcastle.
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