Outcomes of HLA-mismatched HSCT with TCRαβ/CD19 depletion or post-transplant cyclophosphamide in patients with inborn errors of immunity – an EBMT inborn errors working party analysis

Abstract

HLA-mismatched donor HSCT is an increasingly utilized approach for patients with inborn errors of immunity (IEI) lacking a matched donor, thanks to the development of in-vivo T-cell depletion with post-transplant cyclophosphamide (PTCY) or in-vitro TCRαβ/CD19 depletion (TCRab). Our study analyzed the outcome with these approaches in patients with IEI. Pediatric patients who received a first HSCT between 2011 and 2019 from haploidentical related or ≤9/10 HLA-mismatched unrelated (MMUD) donors were included in this retrospective study.We included 296 patients, 139 with PTCY and 157 with TCRab, who received HSCT at a median age of 1.4 years (0.1–19.6) from haploidentical donors (n = 282) or MMUD (n = 14). There were significant differences in patient characteristics: PTCY recipients had a higher rate of pre-HSCT infections (p = 0.002), and organ damage (p < 0.001), had lower performance scores (0.008), and were transplanted more recently (p = 0.001). Owing to the approach, there was a higher proportion with busulfan-based conditioning and multi-drug GVHD prophylaxis, and a lower proportion with serotherapy in the PTCY group; and lower CD34+ but higher CD3+ numbers were infused to PTCY recipients (all p < 0.001). Neutrophil and platelet engraftment occurred significantly earlier after TCRab depletion (p < 0.001). Acute GVHD°III-IV occurred in 10.3% of patients, more frequently after PTCY (p = 0.022), while 14.3% of patients required secondary cellular therapy (boost, DLI, 2nd HSCT), more frequently after TCRab (p = 0.026). Adenoviremia was more frequent (p = 0.012) and veno-occlusive disease (p = 0.015), acute kidney injury (p = 0.028), autoimmune cytopenia (p = 0.032), and pulmonary complications (p = 0.011) less frequent after TCRab. Overall survival at 3 years was 81% (95%CI: 75–88%) and 70% (63–78%; p = 0.001) after TCRab and PTCY, respectively, while event free survival (graft failure, extensive chronic GVHD) was 69% (62–77%) and 63% (55–71%), respectively. In univariate analysis, use of PTCY, conditioning other than busulfan or treosulfan, pre HSCT organ damage, preHSCT infections and number of preHSCT morbidities correlated negatively with overall survival.This study of HLA-mismatched HSCT in IEI demonstrated better overall but not event-free survival after TCRab, but patients with PTCY had significantly higher rates of preHSCT risk factors. We conclude that both approaches are feasible and efficacious in patients with IEI lacking an HLA-matched donor.