Impact of TBI, donor age, and transplant era on outcomes of allogeneic transplantation in acute lymphoblastic leukemia: Evidence from 748 patients in Latin America

Abstract

Abstract Introduction: Allogeneic hematopoietic stem-cell transplantation (HCT) remains a key component of consolidation therapy for many adults with acute lymphoblastic leukemia (ALL). The role of HCT is especially critical in settings where pediatric-inspired protocols may be excessively toxic or difficult to implement, and novel agents for B-cell ALL are not readily available. In recent years, the use of haploidentical donors and reduced-intensity conditioning (RIC) regimens expanded treatment options for selected patients. However, there are currently no comprehensive data describing HCT outcomes for ALL in Latin America (LA). In this study, we aimed to assess survival and response outcomes in a large, multicenter cohort, with an additional focus on less-studied subgroups of the disease. Methods: This is a retrospective registry-based study that included HCT data from 18 centers in LA. We included patients aged ≥15 years with ALL or ambiguous lineage leukemia who underwent a first HCT between January 2007 and December 2024. Primary endpoints were overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). Multivariate Cox regression analyses (MVA) were performed. Country was incorporated as a frailty term in the models. Results: A total of 748 patients were included. The median age was 29 years (range, 15–69), mostly with B-cell ALL (84%). Most transplants were performed in Brazil (49.9%), followed by Mexico (22.7%), Argentina (15.4%), and Chile (12%). Ph+ ALL was observed in 28.5% of patients, and CNS disease at diagnosis or relapse occurred in 16.9%. Most patients underwent HCT in CR1 (57.2%), while 37.4% received it in CR2+ and 5.4% in refractory disease. Pre-HCT MRD was positive in 22.8%. The most common donor type was haploidentical (40.6%), followed by matched sibling donor (MSD, 39.3%), matched unrelated donor (MUD, 11.6%), mismatched unrelated donor (MMUD, 5.5%), and umbilical cord blood (2.7%). Peripheral blood was the graft source in 78.1%. Myeloablative conditioning (MAC) was predominant (84.3%), and total body irradiation (TBI) was used in 69.6%. With a median follow-up of 47.7 months, the 4-year OS and DFS were 46.8% (95% CI, 42.9-51) and 42.5% (95% CI, 38.8-46.6), respectively. Excluding refractory cases, the 4-year DFS was 45.4%. The 4-year CIR and NRM were 29.9% (95% CI, 25.5-32.5) and 28.5% (95% CI, 25.1-32), respectively. No significant differences in survival were observed according to donor type, although MUD was associated with a lower relapse incidence (HR 0.551, p=0.027). In multivariable analysis for OS, independent predictors included age (HR 1.014, p=0.005), CR2+ status (HR 1.398, p=0.01), TBI use (HR 0.749, p=0.02), donor age (HR 1.01, p=0.035), and HCT period from 2019 onwards (HR 0.759, p=0.038). TBI was associated with improved DFS (p=0.0003) and reduced relapse risk (p=0.003) without increasing NRM (p=0.25). This benefit persisted in the MAC setting (p=0.044) but not in RIC conditioning (p=0.25). Donor age also predicted DFS (p=0.036) and NRM (p=0.03) but not relapse (p=0.54). For HCT performed from 2019, adjusted analyses showed protection against relapse (HR 0.546, p=0.0005) without effect on NRM (p=0.68). MRD positivity affected OS, DFS, relapse, and NRM (all, p<0.05). In Ph+ ALL (n=196), donor age strongly impacted OS (HR 1.02, p=0.004) due to increased NRM (p=0.004) but not relapse (p=0.5), while TBI (p=0.786) and age (p=0.946) showed no influence. Among pts ≥50 years (n=116), neither age nor donor age influenced OS. However, RIC was associated with reduced NRM (HR 0.49, p=0.032) without affecting relapse (p=0.27). TBI incorporation in older pts reduced relapse risk (HR 0.413, 95% CI, 0.174-0.983; p=0.046) without increasing NRM (p=0.36). Country of transplantation was not significant in any model (p>0.05). Conclusions: These findings demonstrate that allogeneic HCT for ALL in LA yields survival outcomes comparable to international benchmarks despite marked heterogeneity in practice. TBI-based conditioning and more recent transplant periods were associated with improved disease control without increasing NRM, while donor age remains an important predictor of adverse outcomes. RIC regimens reduced toxicity in older patients without apparently compromising relapse risk. These results highlight the importance of optimizing conditioning strategies, careful donor selection, and regional collaboration to improve HCT outcomes in LA.