Abstract
Background: Patients with relapsed/refractory acute leukemia (R/R AL) and extramedullary disease (EMD) exhibit significantly inferior outcomes following conventional salvage therapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potentially curative strategy; however, EMD remains an independent adverse prognostic factor associated with high relapse rates and mortality. Thiotepa—an alkylating agent with established efficacy in penetrating EMD sites, including the central nervous system—is used to target these reservoirs. Nevertheless, its toxicity profile, particularly severe mucositis, contributes substantially to infection-related mortality. This study evaluated the efficacy and safety of a thiotepa-based conditioning regimen in R/R AL patients with EMD, with a focus on mucositis-associated complications.
Methods: We retrospectively analyzed 101 patients with R/R AL complicated by confirmed or highly suspected EMD, who were refractory to or had relapsed after conventional salvage therapy and subsequently underwent allo-HSCT at our center between January 2020 and January 2025. Exclusion criteria included prior resistance to thiotepa, a history of severe mucositis, severe thrombotic microangiopathy (TMA). The augmented conditioning regimen consisted of thiotepa (10 mg/kg administered over two days) combined with post-transplant cyclophosphamide (PTCy), cladribine, cytarabine, and granulocyte colony-stimulating factor (CLAG), and/or anti-thymocyte globulin (ATG). Primary endpoints included time to engraftment, complications (such as mucositis, infections, and graft-versus-host disease [GVHD]), overall survival (OS), and relapse-free survival (RFS). Secondary endpoints comprised cumulative incidence of relapse (CIR) and non-relapse mortality (NRM).Statistical analyses utilized Kaplan-Meier survival curves and cumulative incidence functions.
Results: The study cohort (median age 31 years, range 15-42; 46.5% male, n=47) comprised 79 patients with AML (78.2%) and 22 with ALL (21.8%). Two patients experienced failure of white blood cell engraftment and three patients had platelet engraftment failure, with median times to white blood cell and platelet engraftment of 15 days (range 11-27) and 17 days (range 8-48), respectively. Post-transplant complications included CMV infection (35.6%, n=36), hemorrhagic cystitis (16.8%, n=17), acute GVHD (22.8%, n=23; grade I: 6.9% [n=7], grade II: 4.0% [n=4], grade III: 5.0% [n=5], grade IV: 6.9% [n=7]; affected sites: skin 6.9%, intestine 14.9%, liver 2.0%), and chronic GVHD (27.7%, n=28). Notably, mucositis occurred in 55.4% (n=56) of patients, with 42.6% (n=43) developing mucositis-associated infections that contributed to death in 12.9% (n=13) of cases. The primary causes of death were relapse (35.6%, n=36), infection (29.7%, n=30), GVHD (23.8%, n=24), and other transplant-related mortality (TRM) (10.9%, n=11).With a median follow-up of 271 days (range 10-1812) , the 1-year, 2-year, and 3-year OS rates were 53.1% (95% CI, 43.7%-64.5%), 50.3% (95% CI, 40.8%-61.9%), and 47.8% (95% CI, 37.9%-60.2%), respectively. The 1-year and 2/3-year RFS rates were 47.9% (95% CI, 38.7%-59.3%) and 44.7% (95% CI, 35.3%-56.5%), respectively, while the 1-year and 2-year CIR was 33.3% (95% CI, 22.1%-42.9%) and 35.9% (95% CI, 23.8%-46.1%), respectively. The 1-year and 2-year NRM rates were 32.4% (95% CI, 21.1%-42.2%) and 34.4% (95% CI, 22.6%-44.4%), respectively.
Conclusion: The thiotepa-containing conditioning regimen demonstrates favorable efficacy in R/R AL patients with EMD, yielding encouraging survival outcomes in this historically poor-prognosis population. Although mucositis and associated infections emerge as significant toxicities contributing to NRM, the implementation of proactive management strategies may help mitigate these risks. This regimen represents a potentially valuable therapeutic option for this challenging patient cohort and merits further investigation to validate its clinical utility.
