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 RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C 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 CD4+CD45RA+ 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.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Probability of survival. Probability of survival according to donor type (P < .0001, log-rank test; pairwise comparisons: MSD vs MORD, P = .042; MSD vs MMRD, P < .001; and MSD vs URD, P < .001) (A), stratum (P = .627) (B), and decade (P = .970) (C).

Figure 2.

Survival in non-MSD patients. Survival in non-MSD patients according to genotype (P < .001) (A) and age and infection status at transplantation (P < .001) (B). (C) Cumulative probability of graft failure in non-MSD HCT, according to conditioning regimen (P = .025).

Figure 3.

Landmark analysis of survival after 6 months and 1 year post-HCT according to CD4+cell counts and ROC curves of predictive value of CD4+counts at 6 months and 1 year for long-term T-cell reconstitution. Kaplan-Meier plots estimating survival for all patients who were alive at 6 months (A) or at 1 year (B) and did not receive second treatment according to CD4+ cell count, with log-rank test applied to evaluate the association. Estimates and 95% CIs were provided at each time point. ROC curve showing the predictive value of CD4+ cell counts at 6 months (C) or at 1 year (D) posttransplant for long-term T-cell reconstitution at 2-5 years (red) or 6-10 years (blue). Area under the ROC curve is 0.807 for 2-5 year outcome and 0.678 for 6-10 year outcome (C) and 0.890 for 2-5 year outcome and 0.755 for 6-10 year outcome (D).