Impact of the rest period between sequential chemotherapy and conditioning regimen prior to allogeneic hematopoietic stem cell transplantation for high-risk myeloid malignancies

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment for relapsed/refractory acute myeloid leukemia (r/rAML), high-risk myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN). Sequential conditioning, combining cytoreductive chemotherapy with reduced-intensity conditioning, was designed to reduce toxicity while preserving efficacy in frail patients. While numerous studies have evaluated different sequential regimens, the impact of rest period duration between the two phases remains unexplored. This bicentric retrospective study analyzed 82 allo-HSCT between 2013 and 2021, in patients with high-risk myeloid malignancies (median age 58 years). Short-bridge-to-transplant regimens (SBTT, n=44) with rest periods of 7 days or less, including the well-known FLAMSA-RIC, were compared to long-bridge-to-transplant regimens (LBTT, n=38) with rest periods longer than 7 days. After a median follow-up of 33 months, rest period duration did not significantly affect progression-free survival (PFS), overall survival, relapse incidence or non-relapse mortality (NRM). Two-year PFS was 35.1% for SBTT versus 57.2% for LBTT (aHR 1.62; P=0.13). However, measurable residual disease-free survival (MRD-FS) was significantly improved with LBTT (aHR 2.15; P=0.02). Despite longer median aplasia, LBTT showed comparable complications and enabled more intensive chemotherapy without increased NRM. LBTT appears feasible and not inferior to SBTT, with a signal of improved MRD control that may reflect better temporal separation and management of treatment-related toxicities, safe delivery of higher-dose or more intensive chemotherapy, and potential leukemic cell-cycle synchronization effects. While center-specific practices and regimen heterogeneity limit definitive conclusions, these hypothesis-generating findings highlight an underexplored dimension of sequential conditioning and warrant further investigation in larger prospective studies.