Introduction Allo-SCT is the recommend curative approach for the majority of fit pts with AML and MDS, but relapse is common and represents a frequent challenge. Mutations in the IDH2 gene are found in 8% to 15% of pts with AML and about 5% with MDS and alter cell metabolism. Their recognition lead to the development of the the oral IDH2 inhibitor Enasidenib. Based on its clinical efficacy even as monotherapy, Enasidenib (Idhifa®) has been approved in the US for the treatment of R/R AML patients. Considering its favorable ratio of antileukemic efficacy and toxicity we sought to investigate Enasidenib as maintenance therapy after allo-SCT with the aim to prevent disease relapse.

Methods In this prospective, multicenter, non-randomized, open-label phase II trial pts with IDH2-mutated AML in morphological remission determined between d+25 to d+35 after allo-SCT could be included and should start Enasidenib maintenance therapy (up to twelve 28 day-cycles with 100 mg/d Enasidenib p. o.) until d+65. In case of relapse, intolerability or withdrawal of consent Enasidenib was stopped prematurely. Safety was the primary endpoint, while secondary endpoints included OS, RFS, relapse incidence, NRM, GvHD incidence and severity as well as hospitalizations.

Results Between 2020 to 2022 48 pts with AML (n=43, 90%), MDS (n=4, 8%) and CMML (n=1, 2%) were enrolled in 11 German transplant centers, of whom 47 initiated post-allo-SCT Enasidenib in median 51 days (range, 32-68) following allo-SCT. Median number of cycles per pt was 12 (range 1-12) with 24 pts (51%) receiving all 12 envisaged cycles. Dose adaptions of Enasidenib were required during therapy in 35 patients (74%) and 23 pts (49%) stopped Enasidenib prematurely after a median of 5 cycles (range 1-11) due to adverse events (AE, n=18, of which 44% were considered as drug-related), relapse (n=3) or patients' wish (n=2).

A total of 829 AE occurred during study treatment, of which 325 (39%) were considered to be drug-related. The only treatment-related toxicities occurring in more than 10% of patients at grade 3 or greater were neutropenia and thrombopenia. Overall, 25 patients (53%) had to be hospitalized at least once during treatment. During study, 21 pts (45%) developed aGvHD (Io 13%, IIo 9%, IIIo 17%, IVo 6%) and 23 pts (49%) developed cGvHD (mild 36%, moderate 45%, severe 18%).

The estimated 2-year cumulative incidence of relapse after allo-SCT was 17% with 3 pts (6%) relapsing while on maintenance therapy and 4 pts (9%) in median 5 months (range 1 to 7 months) after cessation of Enasidenib. NRM at 2 years was 9%, while 2-year RFS and OS after allo-SCT were 73% and 84%.

Conclusions Enasidenib is safe and tolerable with preliminary activity as maintenance after allo-SCT, which merits further validation by comparison with historical controls and ideally in prospective, randomized trials.

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2025
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