Comparative analysis of efficacy and safety between high-dose TMLI and TBI combined with myeloablative chemotherapy in allogeneic hematopoietic stem cell transplantation for acute leukemia with extramedullary lesions

Abstract Background and Significance Total Body Irradiation (TBI) is a key component of conditioning regimens for allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in acute leukemia patients with extramedullary infiltration. However, its clinical application is limited by acute and long-term toxicities caused by whole-body radiation. Total marrow and lymphoid irradiation (TMLI), with its advantages of high target conformity and superior organ-at-risk sparing, has emerged as a potential alternative. Nevertheless, its efficacy and recurrence risk in high-risk patients with extramedullary lesions remain unclear. This study compares the efficacy and safety of TMLI versus TBI in this population to inform clinical conditioning regimen selection. Key Findings In acute leukemia patients with extramedullary lesions, TMLI and TBI showed comparable hematopoietic reconstitution and incidence of acute graft-versus-host disease (aGVHD). However, the TMLI group had a lower incidence and later onset of cytomegalovirus (CMV) infection. There was no statistically significant difference in overall survival outcomes between the two groups, but TMLI demonstrated an advantage in overall survival (OS) in the acute lymphoblastic leukemia (ALL) subgroup, especially in ALL patients with pre-transplant bone marrow remission. Age ≥30 years and pre-transplant bone marrow non-remission were identified as independent risk factors for poor prognosis in the TMLI group. Methods and Results This was a single-center retrospective cohort study, enrolling 91 patients with acute leukemia who underwent allo-HSCT between January 2019 and December 2023 and had extramedullary lesions before transplantation or during the disease course. Patients were divided into the TMLI group (32 cases) and TBI group (59 cases) based on conditioning radiotherapy modality. The TMLI group received 12Gy in 3 fractions, while the TBI group received 12Gy in 6 fractions; both groups were combined with myeloablative chemotherapy. The primary endpoint was 3-year OS, and secondary endpoints included engraftment, CMV infection, aGVHD, disease-free survival (DFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). Patient Baseline: The two groups were balanced in terms of age, gender and pre-transplant bone marrow status, with a significant difference only in disease distribution (TMLI: 53.1% ALL vs. TBI: 61.0% Acute Myeloid Leukemia (AML); p=0.009). Engraftment & aGVHD: There was no significant difference in neutrophil engraftment (median time: 13.5 vs 13.0 days, p=0.405) or platelet engraftment (14.0 vs 15.0 days, p=0.665) between the two groups. The 100-day cumulative incidence of aGVHD (47.5% vs 41.1%, p=0.512) and grade Ⅱ-Ⅳ aGVHD (31.0% vs 17.3%, p=0.181) also showed no statistical differences. CMV Infection: The TBI group had a higher 100-day cumulative incidence of CMV infection (71.9% vs 57.7%, p=0.046) and an earlier onset of infection (median: 39.0 vs 57.0 days, p=0.030). Survival Analysis: With a median follow-up of 341 days, there were no statistically significant differences between the TMLI and TBI groups in 3-year OS (64.4% vs 45.7%, p=0.183), DFS (48.3% vs 39.7%, p=0.547), CIR (32.4% vs 26.1%, p=0.734), or NRM (19.2% vs 29.9%, p=0.245). Subgroup Analysis: In the ALL subgroup, the TMLI group showed a trend toward improved 3-year OS (88.2% vs 57.1%, p=0.062) and DFS (76.5% vs 50.6%, p=0.093). Notably, in ALL patients with pre-transplant bone marrow remission, the TMLI group had significantly higher 3-year OS (100% vs 64.2%, p=0.034). No differences in survival outcomes were observed in the AML subgroup. Risk Factors: Multivariate analysis in the TMLI group revealed that age ≥30 years (OS: HR=7.42, p=0.031; DFS: HR=4.65, p=0.012; CIR: HR=7.68, p=0.007) and pre-transplant bone marrow non-remission (CIR: HR=5.28, p=0.040) were independent risk factors for adverse prognosis. Conclusion TMLI demonstrates a favorable safety profile with a lower risk of CMV infection in allo-HSCT for acute leukemia with extramedullary lesions and shows potential survival benefits in the ALL subgroup, particularly among those with pre-transplant bone marrow remission. TMLI efficacy in AML requires validation through dose optimization (e.g., increasing TMLI dose). Age and pre-transplant bone marrow status are critical for TMLI patient prognosis assessment.