Tailoring Intensity: A Perspective on Thiotepa, Busulfan, and Fludarabine (TBF) Conditioning for Acute Leukemias and Myeloproliferative Neoplasms.

Optimal conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains of paramount importance for outcomes in hematologic malignancies. Thiotepa-busulfan-fludarabine (TBF) is a chemotherapy-only conditioning regimen combining 2 alkylating agents and a purine analog. It was introduced to enhance antileukemic efficacy, lower the risk of relapse, and serve as an alternative to total body irradiation (TBI) or other chemotherapy-based regimens in transplants using different donor types. This review looks into the pharmacologic rationale of TBF and critically evaluates clinical results in acute leukemias, myelodysplastic syndrome and myelofibrosis, including comparisons with TBI-based and other busulfan-based regimens. A literature search was conducted in PubMed and EMBASE, focusing on studies evaluating TBF conditioning in allo-HSCT. Analyses were included for context. Outcomes of interest were engraftment, survival, relapse, nonrelapse mortality (NRM), graft-versus-host disease (GVHD), and regimen-related toxicities. Over 40 primary and secondary sources were reviewed. Data were synthesized in a narrative format, and key comparative outcomes were tabulated. Evidence suggests that TBF may improve disease control and lower relapse rates in several high-risk scenarios, particularly in AML and MF. However, these benefits may be offset by an increased incidence of NRM and regimen-related toxicities. Strategies such as risk-adapted dose modulation and pharmacokinetic monitoring of busulfan are highlighted as critical measures to mitigate toxicity and optimize the therapeutic index. TBF constitutes a powerful, yet complex conditioning regimen in the HSCT armamentarium. Its optimal application requires a personalized approach that carefully balances its ability to control disease against the substantial toxicity risks. With careful patient selection, refinement, dose adjustment and prospective validation, TBF may evolve into a preferred conditioning regimen for myeloid malignancies.