Introduction

Mutations in IDH1 or IDH2 occur in 15-20% of acute myeloid leukemia (AML) cases and promote leukemogenesis via production of the oncometabolite D-2-hydroxyglutarate, which disrupts metabolism and epigenetic regulation. Although treatment options for elderly and unfit AML patients have significantly improved — with many newer therapies now feasible in the outpatient setting — adverse events such as differentiation syndrome (DS) and febrile neutropenia still require careful patient monitoring. In the phase-3 AGILE-study, DS occurred in 14% of AML patients treated with ivosidenib, with a median onset of 19.5 days (range, 3–33), underscoring the importance of close monitoring during the initial weeks of therapy. We conducted a retrospective multicenter study to evaluate the clinical activity of IDH inhibitors in AML with particular focus on DS.

Methods

Eleven tertiary care centers across Germany participated in the study. Data were collected retrospectively through medical chart review. AML patients who received either enasidenib or ivosidenib outside of a clinical trial were included. Responses were evaluated according to ELN 2022 criteria, and baseline cytogenetics and next generation sequencing were performed per institutional standard and included in the analysis where available. The study was approved by the TUM institutional review board.

Results

Fifty-six patients were included in the analysis. Most patients (n=43, 77%) carried an IDH1 mutation and were treated with ivosidenib while 13 (23%) received enasidenib for IDH2-mutated AML. The median patient age was 73 years (range, 38-86) at the start of therapy, 64% were male. The median ECOG performance status was 1 (0-3). Most patients had a normal karyotype (n=29, 52%), a complex karyotype was present in 3 patients. Co-mutations were common, the most frequent being ASXL1 (n=16), NPM1 (n=15), and DNMT3A (n=15). Patients harbored a median of 3 co-mutations (range, 1–7). Of all patients, 59% (n=33) were treated in first line (1L), among those 32 (97%) with ivosidenib. Enasidenib was mostly given as monotherapy for relapsed AML (n=8) or as maintenance after transplant (n=4). Azacitidine was the most frequent combination partner (n=35, 63%), while decitabine or low-dose AraC were used infrequently. One patient received ivosidenib, azacitidine and venetoclax as a triplet. Among previously treated patients, 17 had received intensive chemotherapy and 7 patients had been treated with venetoclax-based regimens. The majority of 1L-treated patients (94%) had favorable risk according to ELN 2024. Among those who received intensive therapy in 1L, 53% (n=9) had adverse risk according to ELN 2022.

Clinically relevant DS occurred in 16 patients (29%), with a median onset at 11 days (range, 1–33) after therapy. All but one DS case occurred in patients treated with ivosidenib (94%), most of whom (80%) received it in the first-line setting. Notably, three patients developed a second episode of DS following re-exposure to ivosidenib, occurring at day 14 and day 20 (cycle 1), and at day 62 (cycle 2) of therapy. Among those patients, two were treated for relapsed AML. In two patients, DS was managed by withholding ivosidenib alone. Seven patients additionally received steroids; five received a combination of steroids and hydroxyurea (HU), and one patient was treated with HU alone. Data were unavailable for one patient. According to CTCAE v5.0, DS was defined as grade II in 8 patients, III in 5, IV in 1, and V (fatal) in 2 patients. Notably, both fatal DS events occurred in relapsed AML patients. Febrile neutropenia was observed in 29 patients (52%).

Excluding patients who received enasidenib as maintenance therapy, 29 patients (56%) achieved a complete remission (CR) or CR with incomplete count recovery after a median of 74 days (31–230). Of those patients, 26 (90%) were treated with ivosidenib (n=6 in 2L), and 3 had received enasidenib. At the time of data cutoff, patients who responded had received a median of 6 cycles (1-26).

Conclusions

In this real-world cohort, targeted therapy for IDH-mutant AML demonstrated promising clinical activity, similar to randomized controlled clinical trials. DS occurred more frequently than previously reported. While most cases resolved, two were fatal. We observed a broad time range of DS onset, not limited to the first treatment cycle or to one DS episode, highlighting the need for close patient monitoring.

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2025
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