Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC-busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC-treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8-99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8-25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7-100.0%) and 79% (55-91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT: two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.

Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαβ/CD19-depleted haploidentical family donor transplant (TCRαβ-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαβ-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8-16.6). Donors were TCRαβ-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52-99%) for TCRαβ-HaploSCT, 80% (41-98%) for MFD, 87% (36-98%) for MUD, and 89% (43-98%) for CB (p = 0.89). Cumulative incidence of grade II-IV acute graft-versus-host disease was 11% (2-79%) after TCRαβ-HaploSCT, 0 after MFD, 29% (7-100%) after MUD, and 11% (2-79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0-100%) versus unconditioned transplant (median 3%, 0-9%) (p < 0.001), as was the proportion of immunoglobulin-free long-term survivors (n = 29/36, 81% vs n = 4/9, 54%) (p < 0.001). TCRαβ-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors.