Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes

Abstract

Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T- and B-cell function and, in some types, also of NK cells and function. Mutations in thirteen different genes have been found to cause this condition, which is uniformly fatal in the first 2 years of life unless immune reconstitution can be accomplished. In the 42 years since the first bone marrow transplant was given in 1968, the standard treatment for all forms of SCID has been allogeneic bone marrow transplantation. Both HLA-identical unfractionated and T-cell-depleted HLA-haploidentical bone marrow transplants have been very successful in effecting immune reconstitution, especially if performed in the first 3.5 months of life and without pre-transplant chemotherapy. This paper summarizes the longterm outcome, according to molecular type, of 166 consecutive SCID infants given non-conditioned related donor bone marrow transplants at this institution over the past 28.3 years and reviews published reports of longterm outcomes of transplants in SCID performed at other centers.

Figure 1

Means+\-SEM of absolute lymphocyte counts in 166 SCID infants at presentation, showing the lymphopenia characteristic of all forms of SCID.

Figure 2

a. Means+/−SEM of CD20+ B cells, CD3+ T cells, and CD16+ NK cells in 166 SCID patients before (a) and most recently after transplantation (b) in 122 of the 126 survivors according to genetic type, as compared with ranges for normal controls. Not shown are the data for the SCIDs who had Artemis deficiency, cartilage hair hypoplasia, CD45 deficiency or those male SCIDs of unknown molecular type as there is only 1 survivor of each type.

Figure 2

a. Means+/−SEM of CD20+ B cells, CD3+ T cells, and CD16+ NK cells in 166 SCID patients before (a) and most recently after transplantation (b) in 122 of the 126 survivors according to genetic type, as compared with ranges for normal controls. Not shown are the data for the SCIDs who had Artemis deficiency, cartilage hair hypoplasia, CD45 deficiency or those male SCIDs of unknown molecular type as there is only 1 survivor of each type.

Figure 3

Means+/−SEM cpm [³H] thymidine incorporation by proliferating lymphocytes from the 166 SCIDs before (a) and most recently after transplantation in 122 of the 126 survivors (b) according to genetic type in response to the mitogens, PHA, Con A, and PWM, as compared with means+/−SEM for normal controls. Not shown are the data for the SCIDs who had Artemis deficiency, cartilage hair hypoplasia, CD45 deficiency or those male SCIDs of unknown molecular type as there is only 1 survivor of each type.

Figure 3

Means+/−SEM cpm [³H] thymidine incorporation by proliferating lymphocytes from the 166 SCIDs before (a) and most recently after transplantation in 122 of the 126 survivors (b) according to genetic type in response to the mitogens, PHA, Con A, and PWM, as compared with means+/−SEM for normal controls. Not shown are the data for the SCIDs who had Artemis deficiency, cartilage hair hypoplasia, CD45 deficiency or those male SCIDs of unknown molecular type as there is only 1 survivor of each type.

Figure 4

Survival following bone marrow transplantation of 126 of 166 SCIDs according to genetic type of SCID.

Figure 5

Kaplan Meier survival curve of 166 SCID infants transplanted at Duke University Medical Center from 1982 to 2010 without pre-transplant chemotherapy or post-transplantation GVHD prophylaxis; 149 received rigorously T cell-depleted haploidentical parental marrow and only 17 had HLA-identical donors.

Figure 6

TREC values (N=597) were observed over time in 115 patients for whom samples were available for analysis and the combined results of all 115 patients are shown here. The slope of decline with time is not significantly different from that in normal individuals. Reproduced with permission from: Sarzotti-Kelsoe M, Win CM, Parrott RE, Cooney M, Moser BK, Roberts JL, Sempowski GD, Buckley RH: Blood, 114: 1445−1453, 2009.

Figure 7

A comparison of clinical features reported as percentages of 41 surviving SCID patients who were transplanted prior to 3.5 months of life with the same features reported as percentages of 70 surviving SCID patients who were transplanted after 3.5 months of life and followed longterm for up to 26 years after transplantation. Significant differences are indicated by the asterisks. Reproduced with permission from: Railey MD, Lokhnygina Y, Buckley RH: Journal of Pediatrics, 155:834−840, 2009.