AUTHORS
Sun Loo, MBBS, FRACP, FRCPA, PhD, Harry Iland, MBBS, FRACP, FRCPA2, Adam Ivey, PhD3, Ing Soo Tiong, FRACP, FRCPA, MPhil, MBChB4, Jad Othman, MD5, Carolyn S. Grove, MBBS, PhD, FRACP, FRCPA6, Deepak Singhal, MD7, Paula Marlton, MBBS, FRACP, FRCPA8, Teng Fong Ng, MBBS, BSc, FRACP, FRCP, FRCPA, MRCP9, Anoop Enjeti, MD FRCP, FRCPA, PhD10, Chong Chyn Chua, MBBS BMedSc PhD FRACP FRCPA11, William Stevenson, MBBS, PhD12, Lachlin Vaughan, MBBS, FRACP, FRCPA13, Steven W. Lane, MD, PhD14, Courtney DiNardo, MD, MSCE15, Natasha S. Anstee, PhD16, Rachel Koldej, PhD17, Kah Lok Chan18, David Westerman, MBBS, FRACP, FRCPA19, Amanda Souza20, Revati Pattani21, John Reynolds, PhD22, Andrew H. Wei, MBBS, PhD23
AFFILIATIONS
1 Alfred Hospital and Monash University, Melbourne, Victoria, Australia, Northern Health, Epping, Victoria, Australia, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
2 Royal Prince Alfred Hospital, Sydney, New South Wales, Australia, The University of Sydney, Sydney, New South Wales, Australia
3 Alfred Hospital and Monash University, Melbourne, Victoria, Australia
4 Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia, The University of Melbourne, Melbourne, Victoria, Australia
5 Royal North Shore Hospital, Sydney, New South Wales, Australia, The University of Sydney, Sydney, New South Wales, Australia
6 Sir Charles Gairdner Hospital and PathWest Laboratory Medicine WA, Nedlands, Western Australia, Australia
7 Royal Adelaide Hospital and SA Pathology, Adelaide, South Australia, Australia
8 Princess Alexandra Hospital and The University of Queensland, Brisbane, Queensland, Australia
9 Gold Coast University Hospital and Griffith University, Gold Coast, Queensland, Australia
10 Calvary Mater Newcastle, Newcastle, New South Wales, Australia
11 Monash Health, Clayton, Victoria, Australia, Northern Health, Epping, Victoria, Australia, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
12 Royal North Shore Hospital, Sydney, New South Wales, Australia
13 The University of Sydney, Sydney, New South Wales, Australia, Westmead Hospital, Sydney, New South Wales, Australia
14 Metro North Health and QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
15 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
16 The University of Melbourne, Melbourne, Victoria, Australia, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
17 ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, Victoria, Australia, The University of Melbourne, Melbourne, Victoria, Australia
18 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia, The University of Melbourne, Melbourne, Victoria, Australia
19 Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia, The University of Melbourne, Melbourne, Victoria, Australia
20 Australasian Leukaemia & Lymphoma Group (ALLG), Melbourne, Victoria, Australia
21 Australasian Leukaemia & Lymphoma Group (ALLG), Melbourne, Victoria, Australia
22 Alfred Hospital, Melbourne, Victoria, Australia, Monash University, Melbourne, Victoria, Australia
23 Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia, The University of Melbourne, Melbourne, Victoria, Australia, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
ABSTRACT
Introduction
Although the menin inhibitor revumenib is approved for patients with relapsed/refractory NPM1 mutated (NPM1m) or KMT2A-rearranged (KMT2Ar) AML, response duration is short (4-6 months) (Issa, JCO 2024; Arellano, Blood 2025). Rising NPM1m MRD precedes morphological relapse by 3-4 months and we have previously established a novel high sensitivity digital PCR-based assay covering the commonest KMT2A fusions (Loo, Blood 2024). We previously reported that low-dose cytarabine + venetoclax (VEN) is efficacious in patients with NPM1m MRD relapse (55% MRD-negative) (Tiong, JCO 2024). AMLM26 INTERCEPT (ACTRN12621000439842) is an ongoing Australasian Leukaemia and Lymphoma Group (ALLG) cooperative multicenter AML platform trial evaluating MRD-guided novel therapies in patients with molecular relapse (≥1 log10 rise) or oligoblastic relapse (5-15% blasts). We previously reported the safety and preliminary efficacy of revumenib in 11 patients with NPM1m MRD relapse (Loo, ASH 2024). Here, we update these findings in NPM1m and, for the first time, patients with KMT2Ar MRD or oligoblastic relapse.
Methods
AMLM26 INTERCEPT involves 15 sites in Australia and 1 in the US (MD Anderson). MRD is centrally monitored using RT-qPCR/dPCR for NPM1m AML and multiplex or fusion-specific RT-dPCR for KMT2Ar AML. Revumenib was administered at 276 mg twice daily (without a strong CYP3A4 inhibitor). The primary endpoint was MRD clearance. Secondary endpoints included MRD response, duration of MRD clearance, safety, overall survival and progression-free survival including MRD/morphologic relapse as events.
Results
Thirty-one patients (23 NPM1m, 8 KMT2Ar) received at least one dose of revumenib by data cut-off and comprise the safety cohort. Median age was 59 (range 19-86), 87% were in first remission, 55% had received prior intensive chemotherapy, 52% prior VEN and 29% prior allogeneic hematopoietic cell transplant (HSCT). Median time from MRD failure to commencement of revumenib was 48 days (range 12–125). At baseline, median MRD level prior to initiation of revumenib was 0.486% NPM1m/ABL1 (range 0.06–36.3) and 1.67% (range 0.07–33.98) for KMT2Ar.
Baseline cytopenias prior to commencing revumenib were infrequent; grade 3 (G3) neutropenia and thrombocytopenia at screening were 3% and 13%, respectively (nil grade 4). Including all dosed patients, median number of revumenib cycles received was 3 (range 1-16). Treatment-emergent G3+ neutropenia and thrombocytopenia in cycle 1 developed in 11 patients (35%; G3 in 3, G4 in 8, for both parameters). Median duration of G3+ thrombocytopenia was 16.5 days (range 6–44), with recovery to G2 after a median of 21 days (range 9–54). Seven patients required temporary dose interruption; one discontinued treatment due to prolonged cytopenia with marrow reticulin fibrosis, which resolved spontaneously off therapy. One patient required dose reduction for prolonged G4 thrombocytopenia lasting 15 days, with recovery to G2 after 30 days. G3+ non-hematologic adverse events were uncommon and included QTcF prolongation (6.4%; nil G4) and febrile neutropenia (3%). No differentiation syndrome was recorded.
In the NPM1m cohort (n=23, all MRD relapse), 20 were evaluable for response (3 had response outcomes pending). MRD response (≥1 log10 reduction) was 60% (12/20), with 45% (9/20) achieving MRD negativity. Median time to MRD clearance was 3 cycles (range 1–6). Patients with MRD response had lower baseline MRD levels than non-responders (median NPM1m/ABL1 0.27% vs 15.2%). Among 9 patients with prior VEN exposure, 6 (67%) achieved MRD response. At data cut-off, 4 patients remained on treatment, while 19 discontinued (9 for HSCT; 10 with MRD or morphologic relapse). Median duration of MRD-negative remission was not reached. With a median follow-up time of 24 months, 2-year OS was 73.6% (not censored at treatment discontinuation).
Among the KMT2Ar cohort (n=8; 6 MRD, 2 oligoblastic relapse), 6/8 (75%) achieved MRD-negative remission. Responses were rapid, with median time to MRD clearance of 2 cycles (range 1–3).
Conclusions
For patients with NPM1m or KMT2Ar AML experiencing MRD or oligoblastic relapse, revumenib is associated with a favorable safety profile and robust clinical efficacy, as evidenced by ~45% MRD-negative response for NPM1m and ~75% MRD-negative response for KMT2Ar. Recruitment and follow-up are ongoing.
DISCLOSURES
Sun Loo, MBBS, FRACP, FRCPA, PhD: Syndax Pharmaceuticals - Honoraria; Abbvie - Consultancy (Includes expert testimony); Servier - Consultancy (Includes expert testimony); Astellas - Consultancy (Includes expert testimony)