Outcomes Following Matched Sibling Donor Transplant for Severe Combined Immunodeficiency: A Report from the Pidtc

Hematopoietic cell transplant (HCT) for SCID using an HLA-matched sibling donor (MSD) is associated with excellent survival and low risk of morbidity and GVHD. In the largest cohort of MSD outcomes in SCID patients to date, we examined the impact on survival and immune recovery of 1) use of a conditioning regimen and 2) GVHD prophylaxis approach. 133 patients were included, including 91 (68.4%) with typical SCID, 36 (27.1%) with leaky SCID and 6 (4.5%) with Omenn syndrome who underwent MSD HCT at 30 PIDTC centers between 1980-2023 and enrolled on PIDTC Protocol 6901 (prospective) or 6902 (retrospective and cross-sectional). 8/91 (8.8%), 13/37 (36.1%), and 5/6 (83.3%) of patients with typical SCID, leaky SCID and Omenn syndrome received conditioning. All conditioned patients received pharmacologic or serotherapy based GVHD prophylaxis vs. 56% of those who did not receive conditioning. 5-year overall survival (OS) was 96.2%. Patients without an active infection at the time of HCT had survival superior to those with infection (100% vs. 93.3%, p<0.01; Fig. 1). Similarly, those without failure to thrive (FTT) did better than those with FTT (98.7% vs 92.4%, p=0.04; Fig. 1). 5-year event free survival (EFS; alive without 2nd transplant) was 91.4%, with 3.1% requiring a 2nd transplant in year 1. 6-month cumulative incidence (CI) of grade II-IV and grade III-IV aGVHD and 2-year CI of cGVHD were 19.7%, 6.25% and 6.4% respectively. These outcomes were independent of GVHD prophylaxis, conditioning regimen, SCID type, or presence of maternal engraftment. Chronic GVHD free EFS (CGF-EFS) was 85.3% for the entire cohort. Patients without active infection at the time of HCT had superior CGF-EFS vs. those with infection (91.7% vs. 73.7%, p=0.02; Fig.2). T cell reconstitution (≥2 of: CD3+ >1000/ul, CD4+ >500/ul, CD4+CD45RA+ >200/ul, PHA >30% of lower limit control) at 6m was less likely achieved with use of GVHD prophylaxis or serotherapy (p=0.02), leaky or Omenn phenotype (p=0.03), and at 6m, 1yr and 2-5 years less likely with ADA, DCLRE1C or RAG genotype (p<0.001, 0.002, 0.001). B cell reconstitution (freedom of IVIG) at 1 year and 2-5 years was negatively impacted by development of grade II and III-IV acute GVHD (p=0.049, p=0.002). Conditioning did not impact T or B cell reconstitution. Outcomes after MSD HCT for SCID were excellent. OS and CGF-EFS were better for patients without active infection therefore it is crucial to proceed with MSD HCT as early as possible. Omitting conditioning or GVHD prophylaxis in patients with typical SCID did not appear to negatively impact OS, EFS or rates of GVHD. Our previous studies showed conditioning improved immune reconstitution in non-MSD HCT. Few patients with typical and leaky SCID in our study received conditioning; more data will be needed to understand whether conditioning improves long-term T and B cell immune reconstitution in MSD HCT.

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