Haploidentical hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) is a practical, accessible treatment for ALL patients without matched donors. In Latin America, data are limited, but this approach provides a low-cost, feasible option in resource-constrained settings. Evaluating regional outcomes is essential to improve success rates across transplant centers.

To analyze the impact of various clinical and treatment-related factors on OS, DFS, CIR and NMR, and to assess changes in outcomes over time to identify areas for further improvement in resource-limited settings.

This retrospective, registry-based study includes data from 18 centers across Brazil, Mexico, Argentina, and Chile. Patients aged ≥ 15 years with ALL or ambiguous lineage leukemia who underwent a first allogeneic HCT between January 2007 and December 2024 were included. Endpoints were overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). Multivariate Cox regression analyses included variables with p < 0.1 in univariate analysis.

During the study, 302 haploidentical transplants were performed. The median age was 27 years (range 20–43), with males representing 47%. B-cell ALL was predominant (86.4%). Transplants were mainly in Mexico (39.1%), Brazil (32.8%), Chile (20.5%), and Argentina (7.6%). Philadelphia chromosome positivity (Ph+) was in 26.8%, CNS involvement at diagnosis in 18.8%. Nearly half (48.8%) underwent HCT during first complete remission (CR1), 46.5% in CR2 or beyond, and 4.7% with refractory disease. Prior to HCT, 21% had measurable residual disease (MRD). Peripheral blood stem cells were used in 89%. Myeloablative conditioning (MAC) was administered in 81.1%, with total body irradiation (TBI) in 68.4%. All cases used post-cyclophosphamide GVHD prophylaxis. The median donor age was 33.61 years, with 55.7% male. The 1-year cumulative incidence of acute and chronic GVHD was 41.54% (95% CI, 37.9–45.1%). With a median follow-up of 47.7 months, the 4-year OS and DFS were 44.5% (95% CI, 38.1–52.1%) and 35% (95% CI, 19.3–63.6%), respectively. The 4-year CIR and NRM were 29.4% (95% CI, 23.5–35.5%) and 29.3% (95% CI, 25.6–35.3%). Multivariate analysis showed refractory disease as the only independent predictor of OS (HR 2.30; 95% CI, 1.16–4.59; p = 0.02). Although other variables did not reach significance, univariate analysis indicated that MRD positivity significantly correlated with worse OS (HR 1.72; 95% CI 1.13–2.62; p = 0.01). Use of TBI showed a trend towards improved OS (HR 0.71; 95% CI 0.50–1.01; p = 0.06). Similarly, univariate analysis for DFS revealed a positive trend with TBI (p = 0.06), while MRD positivity (p = 0.011) and CR2 or later remission (p = 0.001) were negatively associated. Analysis of NRM over different periods (2007–2012, 2013– 2016, 2017–2020, 2021–2024) showed a significant reduction in risk over time. Compared to 2007– 2012, hazard ratios were 0.46 (p = 0.082) for 2013–2016, 0.47 (p = 0.066) for 2017–2020, and 0.32 (p = 0.0057) for 2021–2024, reflecting a progressive decrease likely due to improvements in supportive care and protocols. This Latin American multicenter study shows promising results with haploidentical transplantation using PTCy in ALL, with improving survival and manageable relapse and NRM rates. Refractory disease predicts poorer outcomes, and declining NRM reflects advances in care. Future data on toxicities are essential for further progress.