ALLOGENEIC STEM CELL TRANSPLANTATION IN REFRACTORY ACUTE MYELOID LEUKEMIA

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a only potentially curative option for patients with refractory acute myeloid leukemia (AML), although outcomes are heterogeneous and depend on multiple prognostic factors. According to the 2022 ELN recommendations, AML is considered refractory if complete remission is not achieved after two cycles of intensive induction chemotherapy, or by a defined response landmark (e.g., 180 days after starting less-intensive therapy). The main determinants of transplant failure are high disease burden, adverse genetics (complex karyotype, TP53 mutations, MECOM rearrangements), and poor clinical status. Key clinical risk factors include older age (≥50 years), poor performance status (ECOG ≥2), presence of extramedullary disease at diagnosis, high peripheral blood blast count at transplant (≥10%). Because disease control strongly influences outcome, many centers attempt pre-transplant cytoreduction. Salvage chemotherapy may induce short responses, while venetoclax plus hypomethylating agents often lower blasts enough to proceed to HSCT. In FLT3-mutated AML, gilteritinib is preferred as bridge to transplant and may also be used post-HSCT to reduce relapse risk. Relapse remains the main cause of transplant failure, making maintenance strategies essential. FLT3 inhibitors (sorafenib, midostaurin, gilteritinib) improve relapse-free survival, while IDH inhibitors are under study in IDH1/2-mutated disease. To enhance graft-versus-leukemia, strategies include donor lymphocyte infusions (prophylactic or pre-emptive), rapid tapering of immunosuppression, and novel immunotherapies (CAR-T, CAR-NK). Conditioning intensity should be tailored to age, fitness, and genetic risk. Myeloablative regimens may reduce relapse in younger, fit patients, whereas reduced-intensity or sequential conditioning (e.g., melphalan-based regimens) approaches are preferred in older or frail patients. Although fully HLA-matched donors remain the preferred option, time to transplant is the most critical factor. With the use of high-dose post-transplant cyclophosphamide, mismatched unrelated and haploidentical family donors have also become valid and effective options. In summary, prognosis of refractory AML undergoing allo-HSCT depends on disease burden, biology, and patient fitness. Pre-transplant cytoreduction, including targeted FLT3 inhibition, can facilitate transplant, while post-HSCT maintenance improves durability of remission. References Bono R, et al. Allogeneic stem cell transplantation in refractory acute myeloid leukemia. Cancers (Basel). 2024;16(4):1105. Ciurea SO, Kongtim P, Varma A, Rondon G, Chen J, Srour S, et al. Is there an optimal conditioning for older patients with AML receiving allogeneic hematopoietic cell transplantation? Blood. 2020;135(6):449-52. Craddock C, et al. Preventing relapse after allogeneic transplantation in AML: the role of targeted maintenance therapy. Blood Rev. 2021;45:100692. Daver N, et al. Venetoclax plus gilteritinib for FLT3-mutated relapsed/refractory AML: results of a phase Ib/II study. J Clin Oncol. 2022;40(35):4048-59. Döhner H, et al. Diagnosis and management of AML in adults: 2022 ELN recommendations from an international expert panel. Blood. 2022;140(12):1345-77. Konuma T, Shimomura Y, Mizuno S, Yamasaki S, Yui S, Uchida N, et al. Prognostic factors for allogeneic haematopoietic cell transplantation outcomes in primary refractory acute myeloid leukaemia (2013–2022): A retrospective study by the adult acute myeloid leukaemia working group of the Japanese Society for Transplantation and Cellular Therapy. Br J Haematol. 2025. Nagler A, et al. Longitudinal outcome over two decades of unrelated allogeneic stem cell transplantation for relapsed or refractory AML: an EBMT registry analysis. Clin Cancer Res. 2022;28(19):4258-67. Ofran Y, et al. Allogeneic stem cell transplantation soon after first relapse or with active disease in AML: lessons from the ETAL-3-ASAP trial. Haematologica. 2025;110(2):341-50. Perl AE, et al. Gilteritinib or chemotherapy for relapsed/refractory FLT3-mutated AML (ADMIRAL). N Engl J Med. 2019;381(18):1728-40. Schmid C, et al. Sequential therapy with FLAMSA chemotherapy and reduced-intensity conditioning for refractory AML: long-term results. Bone Marrow Transplant. 2017;52(3):404-10.