Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) remains a mainstay in the treatment of acute myeloid leukemia (AML), with post HSCT relapse being a challenge. Several studies reported promising efficacy and an acceptable safety of post-transplant prophylaxis to prevent such relapses, mainly using FLT3 inhibitors (FLT3i), whereas the use of hypomethylating agents (HMA) such as azacitidine (AZA) or decitabine (DEC) remains controversial. Nonetheless, multiple questions remain unanswered, including which patient would benefit the most from such treatments, the optimal prophylactic agent, timing of initiation, as well as duration of prophylaxis.

Methods: We performed a registry-based multicenter analysis from the European Society for Blood and Marrow Transplantation with approval of the Acute Leukemia Working Party, evaluating the utilization of HMA or FLT3i as post HSCT prophylaxis. We included adult patients (> 18 years) who received their first HSCT for AML in first complete remission (CR1) during 2010-2022, and who received post HSCT prophylaxis with any FLTi or HMA within 180 days post HSCT in absence of molecular or hematological relapse before prophylactic treatment.

Results: We identified a total of 317 patients who fulfilled the inclusion criteria. Post HSCT FLT3i maintenance was given to 171 patients (51% had NPM1 mutation). Of this group, 17% had secondary AML, 9% had adverse (adv) risk cytogenetics (CG) by ELN2022, 25% were minimal measurable disease (MRD) positive pre HSCT and 136 patients (80%) received FLT3i before transplant (midostaurin in 106 of those). Median age at HSCT was 51, median year of HSCT was 2020 (2019-2022). Overall, 63% received myeloablative conditioning (MAC), and 97% peripheral blood stem cells (PBSC) from matched related (31%), unrelated (26%) or haploidentical (22%) donors. The median time to initiation of post HSCT FLT3i was 74 days [Interquartile range (IQR) 50-111], 35% had prior graft-versus-host disease (GVHD), and 98% were MRD negative at first post HSCT evaluation. The median duration of FLT3i prophylaxis was 364 days (IQR 98-675). Sorafenib was used in 58%, midostaurin in 30%, gilteritinib in 11% while 3 patients received sorafenib and midostaurin. After a median follow up of 3 years, the 2-year overall survival (OS) and leukemia free survival (LFS) from time of initiation of prophylaxis were 87% (95% CI 81-91) and 82% (95% Ci 75-87) respectively, and were not significantly affected by age or MRD status at HSCT, use of FLT3i before HSCT, type of FLT3i (2-year OS and LFS: 88% and 81% for sorafenib; 91% and 87% for midostaurin; 70% and 70% for gilteritinib; p=0.13 and 0.28), or presence of GVHD before prophylaxis. Pretransplant MRD positivity increased the 2-year relapse incidence (21% versus 8%; p=0.03). For the HMA group, post-transplant maintenance was used in 146 patients (135 received AZA and 11 DEC). Of those, 39% had secondary AML, 30% had adv risk CG, 8% FLT3 ITD and 7% NPM1 mutation, with only 23 patients having received HMA prior to HSCT. The median age at HSCT was 55, median year of HSCT 2018 (2016-2021), with 46% of patients having received MAC, and 94% PBSC from a matched related (35%), unrelated (34%) or haploidentical donor (22%). HMA maintenance was initiated at a median of 69 days (IQR 52-97) with 48% of patients having GVHD before maintenance. At HSCT, 66% had MRD negativity, while 97% were MRD negative at first evaluation post HSCT. The median duration of HMA prophylaxis was 172 days (IQR 86-343). The 2-year OS and LFS for this group were 77% (95% CI 69-83) and 72% (64-78) respectively. Both OS and LFS were improved in those with GVHD prior to initiation of maintenance [2-year OS 91% (95% CI 78-97) versus (vs) 71% (95% CI 60-79); p=0.03, and 2-year LFS 85% (95% CI 72-93) vs 66 (95% CI 55-74); p=0.02], but were not significantly affected by age, type of AML, CG or pretransplant MRD status. The 2-year molecular LFS was negatively affected by adv CG (56% vs 73%; p=0.047) and positively affected by presence of GVHD before maintenance (83% vs 61%; p=0.007).

Conclusion: This large study further strengthens the role of sorafenib and other FLT3i as standard post HSCT maintenance with 2-year LFS exceeding 80%, not affected by pretransplant use of FLT3i or MRD status. Encouraging results were also observed with HMA maintenance, with 2-year LFS exceeding 70%, particularly for patients who had GVHD prior to initiation of maintenance.

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2025
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