Viral infection prior to transplantation, n (%) Median age in mo at transplantation (range in mo) Patients contributed by each center, n (%)
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Statistical analyses used Stata/IC 12.0 for Mac software (StataCorp). For all modeling (Cox, logistic regression, and Poisson) patients were clustered using a group variable in the model to take into account between-center variability. The same variables were used as in Cox analysis, and the final model was built by a stepwise procedure. Risk factors associated with late complications occurrence (all complications mixed, and then analyzed separately: autoimmunity and infection, damage, and teething problems) in the cohort with >2 years of follow-up were studied using Poisson modeling. Early and late immune reconstitution (CD4 + T-cell count at 1, 2, and 5 years post-HCT, and requirement for intravenous immunoglobulins (IVIG) at last follow-up) were studied by logistic regression models, including a continuous time variable. Proportionality assumption of the Cox proportional hazard model was tested using Schoenfeld and scaled Schoenfeld residuals tests. All variables were entered into the multivariate Cox model, and we used a backward stepwise selection technique, with a significance limit of P >. Factors included in the model were (1) pre-engraftment data such as molecular diagnosis, Omenn syndrome, viral infection, ulcers, (2) characteristics of type of conditioning regimen and HCT, and (3) early features of HCT data (early complications, myeloid chimerism, additional post-HCT procedures). Survival analysis was then performed using Cox modeling to identify risk factors of death. Population characteristics of the overall cohort and of the late cohort were presented and compared at baseline using the Fisher exact test and a nonparametric Kruskal-Wallis test. Clinical follow-up post-HCT focused on acute organ toxicity, acute and chronic GVHD, secondary malignancies, and persistent medical problems following HCT. Data collection included clinical data upon presentation, genetic mutations, HCT characteristics, engraftment, chimerism studies, immunologic reconstitution, and late clinical outcome.
Retrospective data collection was in accordance with the ethical committees of the 3 centers. Informed consent from the parents for data collection and analysis had been obtained upon hospital admission in accordance with the Declaration of Helsinki. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.ĭata from the medical records of all patients with genetically confirmed ARTEMIS and RAG deficiencies who received transplants between 19 at the University of California, San Francisco Benioff Children’s Hospital, Hôpital Necker–Enfants Malades, France (Paris), and at the Department of Pediatric and Adolescent Medicine, University Medical Center Ulm, Germany (Ulm) were collected by each center, combined, and analyzed retrospectively in a multicenter study. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. Secondary malignancies were not observed. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T −B −NK +SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T −B −NK +SCID due to DCLRE1C/ARTEMIS defects.
A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement.