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223 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 619. Acute Myeloid Leukemias: Disease Burden and Minimal Residual Disease in Prognosis and Treatment: Measurable Residual Disease in AML in 2024 and Beyond
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research, Measurable Residual Disease
Saturday, December 7, 2024: 2:00 PM

Sun Loo, MBBS, FRACP, FRCPA1,2, Harry Iland, MBBS, FRACP, FRCPA3, Ing Soo Tiong, FRACP, FRCPA, MPhil4,5,6, David Westerman, MBBS, FRCPA, FRACP4,5, Jad Othman, FRACP, FRCPA, MBBS7, Paula Marlton8*, Chong Chyn Chua, MBBS, FRACP, FRCPA2,9, Duncan Purtill, MBBS, FRACP, FRCPA10*, Hannah Rose11*, Shaun Fleming, MBBS, FRACP, FRACPA12*, Deepak Singhal, MBBS, MD, FRACP, FRCPA13*, Anoop K Enjeti, MBBS, FRCPA, MD, MRCP14,15, William S. Stevenson, MBBS, PhD7, Teng Fong Ng, BSc, MBBS, MRCP, FRACP, FRCPA16,17*, McCulloch Derek3*, Lachlin Vaughan, MBBS, PhD18*, Robin Gasiorowski, MA, FRACP, FRCPA, MBBS19, Adam Ivey, PhD20*, Amanda Souza21*, Revati Pattani, PhD21*, Natasha S. Anstee, PhD2,22*, Rachel Koldej, PhD23,24, David S. Ritchie, MBChB PhD23,24,25, Sanam Loghavi, MD26, Naval Daver, MD27, Courtney D. DiNardo, MD, MSc27, Andrew W. Roberts, MBBS, PhD1,22,28, Carolyn S. Grove, MBBS, FRACP, FRCPA, PhD29,30, John Reynolds, BSc, MSc, PhD31* and Andrew H Wei, MBBS, PhD, FRACP, FRCPA2,22,25

1Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia
2The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
3Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, Australia
4Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
5Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
6The Royal Melbourne Hospital, Melbourne, Australia
7Royal North Shore Hospital, Redfern, NSW, Australia
8Princess Alexandra Hospital and University of Queensland, Brisbane, QLD, Australia
9Monash Hospital and Monash University, Rosanna, VIC, Australia
10Haematology Department, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
11Department of Haematology, University Hospital Geelong, Geelong, Australia
12Department of Malignant Haematology & Stem Cell Transplantation, The Alfred Hospital, Melbourne, VIC, Australia
13Department of Haematology, Central Adelaide Local Health Network, Adelaide, SA, Australia
14Department of Haematology, Calvary Mater Hospital, Waratah, NSW, Australia
15School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, Australia
16Gold Coast University Hospital, Queensland, Australia
17Griffith University, QLD, Australia
18Westmead Hospital, Sydney, Australia
19Concord Hospital, University of Sydney, Concord, NSW, Australia
20Human Molecular Pathology, The Alfred Hospital, Melbourne, Australia
21Australasian Leukaemia and Lymphoma Group, Melbourne, Australia
22Department of Medical Biology, The University of Melbourne, Melbourne, Australia
23Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
24ACRF Translational Research Laboratory, The Royal Melbourne Hospital, Parkville, VIC, Australia
25Department of Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia
26Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
27Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
28The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
29Sir Charles Gairdner Hospital, Nedlands, Australia
30School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia
31Department of Malignant Haematology, Transplantation and Cellular Therapy Services, Alfred Health, Melbourne, Australia

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.

Disclosures: Loo: Abbvie: Honoraria; Astellas: Other: Consultancy. Iland: SYROS Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tiong: Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Jazz: Honoraria. Othman: Pfizer: Honoraria; Astellas: Honoraria; Jazz: Honoraria. Marlton: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, BeiGene: Speakers Bureau; Menarini: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas; Janssen; BeiGene; AstraZeneca; Otsuka; AbbVie; Menarini; Pfizer; MSD; Jazz; Novartis: Membership on an entity's Board of Directors or advisory committees. Chua: Otsuka: Honoraria, Speakers Bureau; AbbVie: Honoraria; Sumitomo-pharma: Honoraria; Bristol Myer Squibb: Speakers Bureau; Pfizer: Honoraria. Fleming: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead/Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Enjeti: Jazz: Honoraria; RACE Oncology: Consultancy, Honoraria; Amgen: Honoraria; AbbVie: Speakers Bureau; Servier: Honoraria; Astellas: Honoraria, Speakers Bureau; Amgen: Honoraria; Otsuka: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ng: University hospital Geelong: Other: Project Grant; WA Health: Other: Fellowship Grant; Spinnaker Health Research foundation: Research Funding. Anstee: AbbVie: Patents & Royalties: as an employee of WEHI receives milestone and royalty payments related to the development of Venetoclax.. Ritchie: BMS: Research Funding; Novartis: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Loghavi: Pathology Education Partners; VJ HemeOnc, College of American Pathologists, OncLive, ICCS, MD Education, NCCN, MashUp Media, NCTN, Aptitude Health: Honoraria; Guidepoint; QualWorld; Gerson Lehrman Group, AlphaSight, Arima, Qiagen, Opinion Health: Consultancy; Astellas, Amgen: Research Funding; Abbvie: Current holder of stock options in a privately-held company; Syndx, Servier, BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie, Daiichi Sankyo, BluePrint Medicine, Caris Diagnostics, Recordati, Servier: Consultancy. Daver: Syndax: Consultancy; Gilead: Consultancy, Research Funding; Trovagene: Research Funding; Trillium: Consultancy, Research Funding; Arog: Consultancy; Servier: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; KITE: Research Funding; Novartis: Consultancy; Genentech: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Shattuck Labs: Consultancy; Menarini Group: Consultancy; Pfizer: Consultancy, Research Funding; Hanmi: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Jazz: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding. DiNardo: GSK: Consultancy, Honoraria; Cleave: Research Funding; GenMab: Consultancy, Honoraria, Other: data safety board; Loxo: Research Funding; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Schrodinger: Consultancy, Honoraria; Astex: Research Funding; Gilead: Consultancy; Amgen: Consultancy; Rigel: Research Funding; ImmuneOnc: Research Funding; Genetech: Honoraria; Foghorn: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Riegel: Honoraria; Immunogen: Honoraria; Notable Labs: Honoraria; AstraZeneca: Honoraria; Jazz: Consultancy, Honoraria; Stemline: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding. Roberts: AbbVie: Patents & Royalties: Patent assigned to AbbVie, Research Funding. Grove: AbbVie: Other: institutional consultancy payment; Otsuka Australia Pharmaceutical: Other: institutional consultancy payment; Astellas Pharma: Other: institutional consultancy payment; institutional payment for educational event. Reynolds: Telethon Kids Institute (Australia): Membership on an entity's Board of Directors or advisory committees; Sandoz AG: Other: Equity ownership; Novartis Australia: Honoraria; Novartis AG: Other: Equity ownership; NHMRC: Research Funding; MRFF: Membership on an entity's Board of Directors or advisory committees, Research Funding; Monash University: Consultancy; Janssen: Research Funding; HaemaLogiX: Consultancy; Australasian Myeloma Research Consortium (AMaRC): Membership on an entity's Board of Directors or advisory committees; Australasian Leukaemia and Lymphoma Group: Consultancy; Abbvie: Research Funding. Wei: Servier Pharmaceuticals LLC, Shoreline Biosciences: Consultancy; AbbVie Inc, Amgen Inc, Astex Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Janssen Biotech Inc, Novartis, Servier Pharmaceuticals LLC, Syndax Pharmaceuticals: Research Funding; AbbVie Inc, Astellas, Bristol Myers Squibb, Novartis, Servier Pharmaceuticals LLC: Speakers Bureau; AbbVie Inc, Agios Pharmaceuticals Inc, Amgen Inc, Astellas, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Gilead Sciences Inc, Janssen Biotech Inc, MacroGenics Inc, Novartis, Pfizer Inc, Roche Laboratories Inc, Servier Pharmaceuticals LLC, Shoreli: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: 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.

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