Comparison of outcomes in pediatric patients with acute leukemia undergoing allogeneic HLA-haploidentical hematopoietic stem cell transplantation (HSCT) after in vitro a/b T- and CD19-cell depletion or In Vivo administration of post-transplant cyclop

Abstract Background HLA-haploidentical relatives are increasingly used to transplant children with acute leukemia (AL) requiring an allograft. The 2 most widely employed platforms to overcome the bidirectional alloreactivity are in vitro a/b T- and CD19-cell depletion (a/b-TCD) and in vivo administration of post-transplant cyclophosphamide (PTCY). While a recent study compared the outcomes of children with inborn errors of immunity transplanted using either of the 2 platforms (Lum et al. Blood 2024), no large comparative analysis in children with AL has been conducted so far. This study includes pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) transplanted from 2010 to 2022 and reported to the EBMT registry with either of the 2 approaches. Patients and methods The whole population included 1071 children with either AML (n=375) or ALL (n=696); among them, 541 received an in vitro a/b T- and CD19-cell depleted transplant, while 530 were treated with the PTCY approach. In order to evaluate the impact between the two groups, a 1:1 pair-match analysis was performed. Disease (AML or ALL) and disease status (complete remission, CR, or non-CR) were considered as exact matching, disease risk index (DRI), patient age, patient sex, donor sex, Lansky score and use of total body irradiation as part of the conditioning regimen were used for propensity score matching with a caliper set at 0.2. The different impact of the two groups were estimated using a Cox model including a cluster effect on matching subgroups. Results The pair-match cohort included 506 patients, 253 transplanted from each of the 2 HLA-haplo platform [median year of HSCT 2019 (interquartile range, IQR, 2016-2020)]. Median age at HSCT was 8.4 years (IQR 4.7-13); 278 children had ALL and 228 AML. As expected by the differences in the platform approaches, a/b-TCD patients received a significantly higher number of CD34+ positive cells/kg (but not different total nucleated cells), more serotherapy before transplant, less CD3+ cells/kg and the source of stem cells was more frequently peripheral blood, as compared to PTCY patients. Additionally, donor age was slightly higher for a/b-TCD patients (median 38.2 versus 36 for PTCY patients, p<0.001); all other transplant variables did not differ between the 2 groups. With a median follow-up of 4.4 years (95% CI 4.1-4.8), the 4-yr non-relapse mortality (NRM) and relapse incidence of the pair-match cohort were 13.4% and 37.1%, respectively, while cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) and extensive chronic GVHD were 10.1% and 14.6%, respectively. In the PTCY group, the 100-day cumulative incidence of grade III-IV acute GVHD and extensive chronic GVHD were 13.1% and 19.5%, respectively, while in the a/b-TCD group they were 7.2% and 10%, respectively. More patients in the PTCY group died of GVHD and infections (9 and 19, respectively) as compared to those given an a/b-TCD HSCT (3 and 10, respectively). The 4-yr overall survival (OS), leukemia-free survival (LFS) and GVHD/relapse-free survival (GRFS) of the whole cohort were 55.7%, 49.6% and 38.8%, respectively. In the a/b-TCD group, the 4-yr OS and LFS were 58.5% and 54.4%, respectively, while in the PTCY group they were 52.8% and 44.8%, respectively. The GRFS in the 2 groups were 46.7% for a/b-TCD and 30.8% for PTCY, respectively. According to the Cox model, in comparison to a/b T- and CD19-cell depleted recipients (reference), patients of the PTCY group had worse LFS (hazard ratio, HR, 1.31, 95% CI 1.02-1.67, p=0.03) and GRFS (HR 1.53, 95% CI 1.23-1.89, p<0.001) and higher NRM (HR 1.87, 95% CI 1.15-3.05, p=0.02), grade III-IV acute GVHD (HR 1.81, 95% CI 1.09-3.02, p=0.02), chronic GVHD (HR 2.35, 95% CI 1.41-3.94, p=0.001) and extensive chronic GVHD (HR 2.18, 95% CI 1.30-3.67, p=0.003). Conclusions These data indicate that both HLA-haploidentical transplant platforms are a suitable option for children with AL needing HSCT and lacking a suitable HLA-matched donor or with an urgent transplant indication. However, the a/b-TCD platform is associated with less severe acute and chronic GVHD, lower risk of NRM and better LFS and GRFS as compared to PTCY. The latter strategy for preventing bidirectional alloreactivity is easier to be performed and potentially more accessible, as compared to the a/b-TCD platform that requires a dedicated team with significant expertise in graft manipulation.