Transplantation outcomes for severe combined immunodeficiency, 2000-2009

Abstract

Background: The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth.

Methods: We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009).

Results: Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival.

Conclusions: Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Figure 1. Cumulative Incidence of a Second Transplantation, Cumulative Incidence of Graft-versus-Host Disease (GVHD), and Survival in 240 Infants with Severe Combined Immunodeficiency

The cumulative incidence of a second transplantation at 5 years in recipients of grafts from HLA-matched sibling donors (MSD), recipients of umbilical-cord blood (UCB), recipients of bone marrow or peripheral blood from other matched related or unrelated donors (OD), and recipients of grafts from mismatched related donors (MMRD) was 3%, 14%, 15%, and 24%, respectively (Panel A). The cumulative incidence of acute GVHD of grade 2 to 4 at 100 days, acute GVHD of grade 3 or 4 at 100 days, and chronic GVHD at 2 years was 20%, 8%, and 15%, respectively (Panels B and C). For acute GVHD, there were no significant differences according to donor type (Table S5 in the Supplementary Appendix). For chronic GVHD, a four-group comparison of donor types (Panel C) and a comparison including only transplants with rigorous T-cell depletion (Table S5 in the Supplementary Appendix) showed no significant differences. Factors that significantly affected survival in multivariate analyses include age at the time of transplantation and infection status, donor type, and conditioning regimen (Panels D through H). The survival rate at 5 years was higher among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) than among older infants with resolved infection (82%) or with active infection (50%) at the time of transplantation (Panel D). Survival among children receiving transplants from alternative donors (MMRD, OD, or UCB) was inferior to that among children receiving MSD transplants; in addition, survival was reduced among recipients of MMRD transplants who underwent a conditioning regimen of immunosuppression, reduced-intensity conditioning, or myeloablative conditioning (Panel E). Infants 3.5 months of age or younger at the time of transplantation had high survival rates regardless of donor type or conditioning (Panel F). The effect of donor type and conditioning on the survival rate was not significant among infants of any age who did not have active infection at the time of transplantation (MSD, 100% among 17 infants; OD, 93% among 14 infants; MMRD with no conditioning, 91% among 48 infants; MMRD with conditioning, 81% among 33 infants; UCB, 77% among 22 infants; P = 0.16) (Panel G) but was significant among infants with active infection at the time of transplantation (MSD, 93% among 15 infants; MMRD with no conditioning, 65% among 39 infants; OD, 53% among 13 infants; UCB, 40% among 21 infants; MMRD with conditioning, 39% among 18 infants; P = 0.006) (Panel H).