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217 A Phase II Randomized Trial Comparing Low-Dose Cytarabine and Venetoclax +/- Midostaurin in Non-Adverse Cytogenetic Risk Acute Myeloid Leukemia: The ALLG AMLM25 Intervene Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemias: Commercially Available Therapies: Impact of Molecularly-Targeted Agents in AML
Hematology Disease Topics & Pathways:
Research, Clinical trials, Combination therapy, Apoptosis, Elderly, Clinical Research, Treatment Considerations, Adverse Events, Biological Processes, Molecular biology, Study Population, Human
Saturday, December 7, 2024: 2:00 PM

Chong Chyn Chua, MBBS, FRACP, FRCPA1,2,3, Blake Hsu4*, Anoop K Enjeti, MBBS, FRCPA, MD, MRCP5,6, Ashish Bajel, MBBS, FRACP, FRCPA7,8, Paula Marlton9*, Shaun Fleming, MBBS, FRACP, FRACPA10*, Devendra Hiwase, MD, MBBS, PhD, FRACP, FRCPA11, Chun Kei Kris Ma, BSc MBBS PhD FRACP FRCPA12, Peter J. Browett13, Travis Perera, MBChB14,15*, Carolyn S. Grove, MBBS, FRACP, FRCPA, PhD16, Shuhying Tan, FRACP, FRCPA, MBBS17*, Jad Othman, FRACP, FRCPA, MBBS18, Julian Cooney, FRACP, FRCPA, MBBS,19*, Hannah Rose20*, Edward S Morris21*, Rachel Koldej, PhD22,23, David S. Ritchie, MBChB PhD22,23,24, Kate Mason25*, Natasha S. Anstee, PhD2,26*, John Reynolds, BSc, MSc, PhD27,28* and Andrew H Wei, MBBS, PhD, FRACP, FRCPA2,24,29

1Monash Hospital and Monash University, Rosanna, VIC, Australia
2The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
3Northern Hospital, Epping, VIC, Australia
4Department of Haematology, Christchurch Hospital, Christchurch, New Zealand
5Department of Haematology, Calvary Mater Hospital, Waratah, NSW, Australia
6School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, Australia
7Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia
8Department of Medicine, University of Melbourne, Melbourne, Australia
9Princess Alexandra Hospital and University of Queensland, Brisbane, QLD, Australia
10Department of Malignant Haematology & Stem Cell Transplantation, The Alfred Hospital, Melbourne, VIC, Australia
11Royal Adelaide Hospital, Adelaide, SA, Australia
12Westmead Hospital, Westmead, NSW, Australia
13Dept of Molecular Medicine and Pathology, Auckland Hospital and The University of Auckland School of Medicine, Auckland, New Zealand
14Te Rerenga Ora Wellington Blood & Cancer Centre, Te Whatu Ora Health New Zealand Capital Coast & Hutt Valley, Wellington, New Zealand
15Wellington Blood and Cancer Centre, Wellington Hospital, Wellington South, New Zealand
16Department of Haematology, Sir Charles Gairdner Hospital and PathWest, Perth, Australia
17Department of Haematology, St Vincent’s Hospital, Melbourne, Australia
18Royal North Shore Hospital, Redfern, NSW, Australia
19Fiona Stanley Hospital, Perth, Western Australia, Australia
20Department of Haematology, University Hospital Geelong, Geelong, Australia
21Department of Haematology, Townsville Hospital, Townsville, Australia
22Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
23ACRF Translational Research Laboratory, The Royal Melbourne Hospital, Parkville, VIC, Australia
24Department of Clinical Haematology, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, VIC, Australia
25Australasian Leukaemia Lymphoma Group, Melbourne, Australia
26Department of Medical Biology, The University of Melbourne, Melbourne, Australia
27Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
28Department of Malignant Haematology, Transplantation and Cellular Therapy Services, Alfred Health, Melbourne, Australia
29The University of Melbourne, Melbourne, VIC, Australia

Background

For fit patients (pts), combining kinase inhibitors (midostaurin, quizartinib) with intensive chemotherapy is standard of care for FLT3mutated AML. New studies also suggest a role for kinase inhibitors (e.g. quizartinib) in modifying disease history in pts with FLT3wild-type AML (Montesinos et al, EHA 2023). Clonal evolution of kinase-activating mutations, including FLT3-ITD is an important mechanism of treatment failure in pts with non-adverse (NON-ADV) cytogenetic risk AML receiving frontline therapy with azacitidine and venetoclax (AZA-VEN) (DiNardo and Tiong et al, Blood 2020). Incorporating kinase inhibitors (e.g. gilteritinib) into less-intensive VEN-based regimens in unfit, older pts has been challenging, with cumulative myelosuppression a dominant issue (Short et al, JCO 2024). Gilteritinib is known to have a long half-life (~113 hrs), which may contribute to its negative impact on marrow recovery when directly combined with chemotherapy and VEN. We hypothesized that myelosuppression could be lessened by using a FLT3 inhibitor with a short half-life (e.g. midostaurin, MIDO) administered sequentially after, rather than concurrently with chemotherapy. The phase 1b/2 INTERVENE study was conducted across 19 sites in Australia and New Zealand to establish the safety and efficacy of a triplet regimen involving low dose cytarabine (LDAC), VEN and MIDO (LVM) in older unfit pts with NON-ADV AML. A phase 1b dose-finding study confirmed safety in 18 pts and determined the recommended phase 2 dose (RP2D) of LVM to be LDAC 20 mg/m2 SQ D1-10, VEN D1-28 with dose ramp-up to 600mg D and MIDO 50 mg BD D11-28 (Chua et al, ASH 2022). INTERVENE was designed to seamlessly transition to a randomized phase 2 expansion comparing the RP2D of LVM with LDAC+VEN (LV), the focus of the current report.

Methods

Pts aged ≥60 years (y) unfit for intensive chemotherapy with treatment naïve NON-ADV cytogenetic risk AML (excluding APL or core-binding factor) were randomised 2:1 to receive LVM or LV. Posaconazole antifungal prophylaxis was permitted with dose adjustment of VEN to 50 mg daily and MIDO to 50 mg daily due to increased risk of cardiac toxicities in older populations. The primary endpoint was CR/CRi by end of C4 utilizing dual criteria for proof of concept. Secondary endpoints included other measures of response, duration of response and survival. Exploratory endpoints included FLT3-ITD measurable residual disease (MRD) by PCR-NGS (sensitivity 10-5). First patient was 10MAR2021, with data cut-off 31MAY2024.

Results

124 pts were randomized with 117 commencing study therapy (76 LVM, 41 LV). Median follow up was 13.4 months. Median age was 74y (range 60-89, 81% ≥70y) and 66% were male. In the LVM vs LV arms, secondary AML was present in 38% vs 26%, prior AZA exposure in 14% vs 3%, adverse European LeukemiaNet 2022 risk in 53% vs 56%, FLT3-ITD in 27% vs 23% and FLT3-TKD in 3% vs 3%, respectively.

Overall, 30-day mortality was 6% (4% LVM vs 10% LV): 4 due to infections, 3 due to progressive AML. In the LVM and LV arms, the most frequent non-hematological adverse events in cycle 1 (C1) were nausea (47% vs 22%, G3+ 1% vs 0%), constipation (29% vs 0%, no G3+) and cardiac symptoms (7% vs 5%, G3+ 4% vs 0%). G3 febrile neutropenia occurred in 28% vs 17%.

Regarding deliverability, the median number of cycles received was 5.5 (range 1-24) for LVM and 4 (range 1-31) for LV. For pts achieving CR/CRi/CRh, the proportion receiving >6 cycles in the LVM and LV arms was 62% vs 56%, including 38% vs 36% receiving >12 cycles, respectively. For pts in remission, the proportion with delayed treatment (commencing next cycle >day 42) in LVM vs LV were 24% vs 7% at the end of C1, declining to 13% vs 13% at the end of C6, and 11% vs 9% at the end of C12, respectively, with no evidence of cumulative delays after successive treatment cycles.

Of 96 patients dosed and completing at least 4 cycles of therapy or off therapy prior to C4, overall response rates (ORR: CR/CRi) were 70% in the LVM arm and 64% in the LV arm. The final analysis of response will be presented at the conference. Among pts with FLT3 mutation, ORR in the LVM and LV arms were 86% vs 50%, respectively. FLT3­-ITD MRD clearance was observed in 9/15 (60%) in the LVM arm and 1/4 (25%) in the LV arm.

Conclusion

In unfit, older pts ≥60 years with newly diagnosed NON-ADV cytogenetics AML, LDAC-VEN-MIDO, with sequential delivery of MIDO after LDAC was well tolerated, with promising clinical and molecular responses in FLT3 mutated AML.

Disclosures: Chua: Sumitomo-pharma: Honoraria; Bristol Myer Squibb: Speakers Bureau; AbbVie: Honoraria; Otsuka: Honoraria, Speakers Bureau; Pfizer: Honoraria. Enjeti: AbbVie: Speakers Bureau; Jazz: Honoraria; RACE Oncology: Consultancy, Honoraria; Amgen: Honoraria; Servier: Honoraria; Otsuka: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria; Astellas: Honoraria, Speakers Bureau. Bajel: Takeda: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Glaxo-Smith-Kline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marlton: Otsuka: 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; Jazz: 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; Menarini: 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; 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; AbbVie, BeiGene: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fleming: Gilead/Kite: 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; BMS: 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; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hiwase: Abbvie: Honoraria; Astella Pharma: Honoraria; Otsuka: Honoraria. Perera: AbbVie: Honoraria. Grove: Otsuka Australia Pharmaceutical: Other: institutional consultancy payment; Astellas Pharma: Other: institutional consultancy payment; institutional payment for educational event; AbbVie: Other: institutional consultancy payment. Othman: Jazz: Honoraria; Astellas: Honoraria; Pfizer: Honoraria. Ritchie: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; BMS: Research Funding. Anstee: AbbVie: Patents & Royalties: as an employee of WEHI receives milestone and royalty payments related to the development of Venetoclax.. 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: AbbVie Inc, Amgen Inc, Astex Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Janssen Biotech Inc, Novartis, Servier Pharmaceuticals LLC, Syndax Pharmaceuticals: Research Funding; Servier Pharmaceuticals LLC, Shoreline Biosciences: Consultancy; 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: This presentation will focus on the ALLG INTERVENE clinical trial combining LDAC+venetoclax+midostaurin. Although venetoclax and midostaurin are individually FDA-approved in some indications, the combinations examined in this clinical trial have not been approved by FDA.

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*signifies non-member of ASH