Pre-transplant minimal residual disease (MRD) negativity predicts superior GVHD-free/relapse-free survival after allogeneic HCT in pediatric acute lymphoblastic leukemia

Abstract

Abstract Introduction: Allogeneic HCT is the only curative option for children with high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL), but relapse and transplant complications remain common. Pre-transplant MRD negativity is strongly associated with better outcomes. A composite endpoint such as GVHD-free/relapse-free survival (GRFS) better captures transplant success than OS or EFS. Methods: We retrospectively analyzed outcomes in 210 pediatric ALL patients who underwent allogeneic HCT at our center (2003–2025). The primary endpoint was GVHD-free/relapse-free survival (GRFS), defined as survival without grade 3–4 acute GVHD, moderate-to-severe chronic GVHD, relapse, or death. Conditioning regimens, donor type, graft source, and pre-transplant MRD status were recorded. One-year and five-year overall survival (OS), event-free survival (EFS), and GRFS were estimated by Kaplan–Meier analysis. Cox regression was used for univariable and multivariable analyses of predictors, including age, donor type, conditioning, and MRD status. Results: Among 210 pediatric ALL transplant recipients (median age 10, range 2–19 years), median follow-up was 28 months (range 3–247). Most patients (97%) received myeloablative conditioning and 81% received peripheral blood stem cell grafts. Donor sources were matched related donors (138 patients, 66%), unrelated cord blood (13, 6%), and haploidentical donors with post-transplant cyclophosphamide (59, 28%). Remission status at HCT was CR1 in 77 patients (37%) and second or later CR in 133 (63%). Median neutrophil and platelet engraftment were day 16 and 21, respectively. One-year OS, EFS, and GRFS were 83%, 76%, and 50%, respectively. At five years, OS, EFS, and GRFS were 65%, 63%, and 43%, respectively. On univariable analysis, pre-transplant MRD negativity (HR 2.80, p<0.001), age <12 years (HR 1.57, p=0.019), and a matched related donor (HR 1.51, p=0.036) were associated with superior GRFS. In multivariable analysis, MRD negativity independently predicted improved OS (HR 8.53, p<0.001), EFS (HR 7.21, p<0.001), and GRFS (HR 2.77, p<0.001). Younger age showed a trend toward better GRFS (HR 1.40, p=0.091), and total body irradiation (TBI)-based conditioning was associated with better OS (HR 0.19, p=0.002). Conclusion: Pre-transplant MRD negativity strongly predicts better OS, EFS, and GRFS after allogeneic HCT in pediatric ALL. GRFS provides a meaningful composite endpoint capturing both relapse and transplant-related morbidity. These findings support incorporating MRD status and GRFS into transplant decision-making and outcome evaluation for high-risk pediatric leukemia.