SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery

Abstract

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with ,, or defects and was significantly better compared with patients with or mutations. Patients with or mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4 and CD4CD45RA cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4 cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.

RAG gene defects at the verge of immunodeficiency and immune dysregulation

“…Immune reconstitution was more frequently achieved when chemotherapy was used as part of the conditioning regimen for haploidentical transplantation; however, survival in this group of patients was significantly lower (~60%) . Data from the PIDTC give a different picture, with an overall survival of ~80% after transplantation from donors other than matched siblings; however, also this study confirmed that in the absence of myeloablative or reduced intensity conditioning, RAG‐deficient patients experienced a high rate of graft failure and poor T‐ and B‐cell immune reconstitution . Natural killer (NK) cells may contribute to the increased rate of graft rejection following unconditioned haploidentical HCT for RAG deficiency.…”

“…Besides donor type, other factors that are associated with superior outcome after HCT include young age (<3.5 months of life) and lack of infections at the time of transplantation . These data emphasize the importance of newborn screening in order to achieve early detection and prompt referral to transplant for RAG‐deficient patients.…”

“…In any case, the increased cytotoxic activity of NK cells from RAG-mutated patients may contribute to the higher rate of graft rejection. For this reason, inclusion of serotherapy-depleting NK cells in the conditioning regimen of HCT for RAG deficiency may be beneficial.Besides donor type, other factors that are associated with superior outcome after HCT include young age (<3.5 months of life) and lack of infections at the time of transplantation 130,136. These data emphasize the importance of newborn screening in order to achieve early detection and prompt referral to transplant for RAGdeficient patients.…”

Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

“…[4][5][6][7][8] Hematopoietic stemcell transplants from a matched sibling donor are effective but available for less than 20% of patients, and transplants from alternative donors are associated with an increased risk of graft-versus-host disease and incomplete immune reconstitution. [9][10][11][12][13][14] Gene therapy is an experimental treatment that inserts a normal copy of the coding region of IL2RG into the genome of a patient's own hematopoietic stem cells. Previous studies of gene therapy showed that first-generation γ-retroviral vectors restored T-cell immunity but resulted in vector-induced leukemia.…”

Haematopoietic stem cell transplantation for inborn errors of immunity: 25‐year experience from University of Malaya Medical Centre, Malaysia

“…However, patients who received conditioning demonstrate more durable thymopoiesis, improved T and B cell reconstitution, and are more likely to be immunoglobulin‐free than unconditioned patients . Nevertheless, the use of chemotherapy should be weighed against a higher risk of GvHD and potential long‐term side effects . In our eight patients with SCID; four received MAC, three received RIC and one had no conditioning.…”