Revumenib As Pre-Emptive Therapy for Measurable Residual Disease in NPM1 mutated or KMT2A-rearranged Acute Myeloid Leukemia: A Domain of the Multi-Arm ALLG AMLM26 Intercept Platform Trial

Introduction

ALLG AMLM26 INTERCEPT (Investigating Novel Therapy to Target Early Relapse and Clonal Evolution as Pre-emptive Therapy) is a multi-arm platform trial designed to obtain proof-of-concept for novel therapies targeting measurable residual disease (MRD) or early relapse in acute myeloid leukemia (AML) (ACTRN12621000439842). Patients (pts) are enrolled in first or second remission (CR1/2) and monitored with MRD technologies relevant to the patient e.g. RNA-based real time (RT-qPCR) for NPM1 mutation (NPM1m) or digital (RT-dPCR) for KMT2A-rearrangement (KMT2Ar). Pts with MRD or oligoblastic (5-15% marrow blasts) relapse were allocated to treatment with the menin inhibitor revumenib. We hereby present the first results from the AMLM26 INTERCEPT study reporting the safety and molecular efficacy of revumenib from the safety run-in cohort, delivered with pre-emptive intent to pts with MRD relapsed NPM1m or KMT2Ar AML.

Methods

MRD relapse was defined as ≥1 log₁₀ rise (from nadir or limit of detection) in peripheral blood or bone marrow, confirmed on repeat testing in the central laboratory. Revumenib at the recommended phase 2 dose of 276 mg BID (without strong CYP3A4 inhibitor) from the AUGMENT-101 study (NCT04065399) was initially tested as part of a safety run-in in pts with MRD relapse. Pts were evaluable if ≥75% of planned dose was delivered or if a dose limiting toxicity (DLT) occurred. DLTs were defined as G4 neutropenia/thrombocytopenia in the absence of disease persisting beyond day 42 of cycle 1 or ≥G3 non-hematologic toxicity related to study therapy. Marrow responses were assessed after cycles 1, 2, 3, 6, 12, and then every 6 months until 2 years, with peripheral blood monitoring every 2 months from cycle 6 for NPM1m or KMT2Ar MRD.

Results

Recruitment onto the platform commenced 16Aug2022, with recruitment onto the revumenib arm from 10Mar2023. With a data-cut on 18July2024, 75 pts with NPM1m and 10 with KMT2Ar AML have been registered for MRD monitoring and surveillance. Nineteen have been screened for the revumenib arm, of which 14 were deemed eligible and 5 screen failed (1 with >15% blasts, 2 started alternative therapy and 2 where a ≥1 log rise was not confirmed in the consecutive sample). Nine pts with MRD relapse (8 NPM1m and 1 KMT2Ar) were enrolled in the safety cohort and were DLT evaluable (another 5 eligible pts have been enrolled in the expansion phase).

Median age was 62 years (range 19-85), 7 were in CR1, 3 had prior venetoclax exposure and 6 prior intensive therapy. At baseline, the median neutrophil count was 1.7 x 10⁹/L (range 0.8-6.4) and platelets 169 x 10⁹/L (range 33-277). The median number of cycles delivered to date is 3 (range 1-12). DLTs included reversible G3 QTcF prolongation in 2/9 pts. With DLTs in 2/9 pts, neither de-escalation nor elimination were mandated and 276 mg BID was therefore considered safe for further expansion. In cycle 1, non-DLT treatment-emergent adverse events included ≥G3 thrombocytopenia in 56% [G3 in 3; G4 in 2], neutropenia in 44% [G3 in 2; G4 in 2], anemia in 11% and febrile neutropenia in 11%. Post cycle 1, ≥G3 treatment-emergent toxicities included G3 thrombocytopenia [11%] and G4 neutropenia [11%]. Overall, G3 thrombocytopenia developed between days 21-28 in 4 pts, with a median duration of 18 days (15-26). G3 thrombocytopenia recovered in two pts after ceasing revumenib. In 2 other pts, however, recovery occurred without treatment interruption. No differentiation syndrome was reported over a total of 36 cycles of therapy for all pts. In terms of efficacy within the NPM1m cohort, 5 of 8 had ≥1 log₁₀ MRD reduction, including 3 who have achieved MRD negativity within 6 cycles. Six of 9 pts have discontinued treatment (3 morphologic relapse, 1 MRD progression and 2 for allogeneic hematopoietic cell transplant). Treatment is ongoing in 3 pts.

Conclusions

The ALLG AMLM26 INTERCEPT study confirms that revumenib is safe and displays efficacy in pts with NPM1m MRD relapse. Accrual of pts with KMT2Ar driven MRD relapse is ongoing. The recommended dose for expansion is 276mg BID with plans to accrue 96 pts. In preliminary analysis, NPM1m ≥1 log₁₀ MRD reduction was recorded in 62.5% (n=5) of pts, including 37.5% (n=3) achieving MRD negativity. Further updates will be presented at the meeting.

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Revumenib, a menin inhibitor has been assessed in phase 2 clinical trials for the treatment of adult and pediatric relapsed or refractory KMT2A-rearranged acute leukemia. In this current trial (AMLM26), we report on the use of revumenib in measurable residual disease (MRD) relapse in patients with NPM1 mutant or KMT2A-rearranged acute myeloid leukemia.