Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study

Abstract

The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/μL, CD8 < 50 cells/μL, CD45RA < 10%, or a restricted Vβ T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.

Conflict of interest statement

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

Figures

Figure 1.

An increasing percentage of SCID patients in North America are being diagnosed due to NBS. Percentage of SCID patients diagnosed via NBS increased dramatically during the study period, while SCID diagnosis triggered by infection decreased. Rates of diagnosis due to family history or other/known factors were stable for the duration of the study period.

Figure 2.

Survival by stratum, donor type, and infection at the time of transplant. (A) OS was significantly better in patients transplanted without infection (OS, 95%) compared with those with active infection at the time of transplant (OS, 81%; P = .009). (B) OS was similar in those presenting with typical SCID and assigned to stratum A (OS, 89%) compared with those presenting with leaky SCID or Omenn syndrome and assigned to stratum B (OS, 90%; P = .66). (C) OS was similar in those diagnosed via NBS/FH (OS, 90%) compared with those diagnosed by other means (OS, 90%; P = .67). (D) OS was not significantly different by donor type: 100% for MRD; 96% for MMRD; 90% for URD; and 81% for UCB (P = .17).

Figure 3.

Immune reconstitution by genotype. Patients with IL2RG, JAK3, and IL7R SCID mutations had significantly higher mean T-cell counts and percentages of naive T cells at 1 year post-HCT compared with RAG1/RAG2/Artemis or other mutations. (A) CD3, 2291 cells/μL vs 1646 cells/μL vs 982 cells/μL (P = .013). (B) CD4: 1366 cells/μL vs 826 cells/μL vs 754 cells/μL (P = .047). (C) CD8: 814 cells/μL vs 434 cells/μL vs 339 cells/μL (P = .007). (D) CD45RA: 30% vs 16% vs 12% (P = .031)

Figure 4.

Immune reconstitution by conditioning regimen. (A) Patients who received conditioning (RIC or MAC) attained higher levels of T-cell chimerism at all time points measured (P ≤ .001 at 100 days, P < .001 at 180 days, and P < .001 at 365 days, respectively). (B) Patients who received conditioning (RIC or MAC) attained higher levels of B-cell chimerism at all time points measured (P ≤ .001 at 100 days, P < .001 at 180 days, P < .001 at 365 days, respectively). (C) Patients who received conditioning (RIC or MAC) attained higher levels of myeloid cell chimerism at all time points measured (P ≤ .001 at 100 days, P < .001 at 180 days, P < .001 at 365 days, respectively). (D) At 1 year post-HCT, conditioned vs nonconditioned patients had higher median CD4 cell counts (1352 cells/μL vs 855 cells/μL; P = .02).