The Evolving Landscape of Reduced-Intensity Conditioning: Balancing Efficacy and Toxicity Across Hematologic Malignancies

Abstract Purpose Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has evolved from traditional myeloablative conditioning toward reduced-intensity conditioning (RIC) and strategies using donor-derived immune effector cells. This review summarizes trends in RIC, proposes a practical classification of regimens, and underscores personalized risk stratification and disease-specific conditioning. Recent Findings Fludarabine-based backbones combined with alkylating agents—melphalan (Flu-Mel), busulfan (Flu-Bu), or cyclophosphamide (Flu-Cy)—remain widely adopted due to favorable tolerability and antitumor activity. Large CIBMTR analyses indicate melphalan-based RIC confers superior long-term survival in older patients with myeloid malignancies, primarily through reduced relapse rates. The emergence of integrated prognostic tools such as the Hematopoietic Cell Transplant–Composite Risk (HCT-CR) score and the HCT Frailty Scale enhances pretransplant risk assessment and patient selection. Incorporation of measurable residual disease (MRD) testing and next-generation sequencing (NGS) chimerism refines conditioning intensity decisions and enables earlier relapse detection and intervention. While most prospective trials have focused on AML and MDS, accumulating evidence supports RIC efficacy in selected patients with ALL and various lymphomas. Collectively, data emphasize that optimal conditioning is disease-, risk-, and patient-specific, requiring tailored approaches. Summary RIC has extended allo-HSCT to older, frailer patients, achieving outcomes comparable to myeloablative regimens despite relapse risk. Future work should prioritize prospective disease-specific trials comparing RIC regimens; integration of dynamic biomarkers (MRD, immune profiling, NGS chimerism) into adaptive conditioning; development of frailty-adjusted protocols; and evaluation of post-transplant cellular therapies and targeted maintenance to prevent relapse. These advances aim to personalize conditioning and post-transplant management to maximize survival and minimize toxicity.