Introduction:

Venetoclax (Ven) plus intensive chemotherapy is a promising therapy for patients (pts) with untreated acute myeloid leukemia (AML) but has not been extensively studied in combination with the “7+3” regimen. In a phase 1b study at a tertiary academic center with an ethnically diverse patient population we evaluated the safety and efficacy of Ven plus daunorubicin (Dauno) and cytarabine (AraC) in newly diagnosed AML pts (NCT05342584).

Objectives:

The primary objective of this study is to determine the optimal dose of Ven in combination with Dauno and AraC chemotherapy. Secondary objectives are response per 2022 ELN, survival (OS), event-free survival (EFS) and duration of response (DoR). The data cutoff date for this analysis was 15 Feb 2024.

Methods:

Eligible pts must have a new diagnosis of AML, be 18-75 yrs of age and deemed fit for intensive chemotherapy. In a 3+3 design, Ven in escalating duration (400 mg D1-8 or -11 or -14, including 2-day ramp-up) is combined with AraC 100mg/m2 (D2-8) and Dauno 60mg/m2 (D2-4) in 2 separate age groups (≤60 and >60yrs); Dauno 90mg/m2 was initially studied in pts ≤60yrs, but since 04/2023 the dose is no longer explored. During consolidation, fixed dose Ven (200 mg x7days) is used in combination with age-adjusted intermediate doses of AraC (IDAC, 1.5g/m2 in <60yrs and 1g/m2 in ≥60yrs, every 12hrs on days 1,3,5). In the expansion phase, additional pts in each age group will undergo 1:1 randomization between the starting and highest tolerated dose determined during dose escalation, for a total of 20 pts per dose cohort in both phases.

Results:

Between 06 Jun 2022 and 15 Feb 2024, 34 AML patients enrolled and completed the induction phase. Twenty patients were treated in the younger and 14 in the older cohorts. Median age was 59 (27-71) years, and 19 patients (56%) were males. The majority of patients (n=21, 62%) belonged to ethnic/racial minority groups, with non-Hispanic blacks and Hispanics representing 24% (n=8) and 27% (n=9) of the total cohort, respectively. Thirteen patients (38%) were stratified as favorable, 6 (18%) as intermediate and 15 (44%) as adverse-risk AML by ELN 2022.

Fourteen pts were treated with Ven x 8d, 11 in Dauno60 and 3 in Dauno90 cohorts, 9 pts with Ven x11d and 11 pts with Ven x14d. No DLTs were observed. Febrile neutropenia (100%), sepsis (n=8, 24%) and enterocolitis (n=8, 24%) were the most common non-hematologic toxicities. There were no induction deaths. Delayed hematologic recovery was observed in only one patient who responded to therapy. For all responding patients, the median time to ANC≥0.5K/uL and ANC≥1.0K/uL was 26 and 27 days, respectively. The median time to PLT≥50K/uL and PLT≥100K/uL was 26 and 28 days, respectively. Median time to ANC≥1.0K/uL and PLT≥100K/uL was <30 days in each age-group and all three Ven-dose-cohorts with both age-groups combined.

Twenty-nine out of 34 patients (85.3%; 95% CI: 68.9% - 95.1%) achieved a composite complete remission (CRc: 28 CR + 1 CR with partial hematology recovery) with single induction. CRs were obtained in all Ven-dose cohorts. Of the 29 patients in CRc, 25 (86%; 95% CI: 68.3% - 96.1%) were measurable residual disease (MRD) negative (-) by multiparameter flow cytometry (MFC) and 23 (79.3%; 95% CI: 60.3% - 92.0%) by any MRD assay. With a median follow-up time of 9.6 months, the median EFS (mEFS) and OS (mOS) were not reached. Ten pts (29%) underwent allogeneic transplantation in first CR. Twenty-seven patients (79%) are alive and 22 of those (64%) remain in continuous MRD (-) CR. Of 5 pts with complex karyotype plus TP53 mutated AML, 3 did not respond and 2 had an early treatment failure.

Conclusions:

Ven plus “7+3” chemotherapy is a safe and highly efficacious induction regimen inducing deep remissions in AML, across the majority of molecular disease subsets. The optimal duration of Ven when combined with the “7+3” regimen remains to be determined and will be explored in the expansion phase of our study, where a 1:1 randomization dose finding design compares 8 and 14 days of Ven. The dose escalation phase of the trial has completed accrual and updated results will be presented at the meeting.

Disclosures

Shastri:NACE & PeerView: Honoraria; Jassen: Consultancy; Gilead, Rigel, Kymera: Consultancy; Kymera: Research Funding; Ryvu therapeutics: Research Funding; Geron: Speakers Bureau. Konopleva:AstraZeneca: Consultancy, Other: clinical trials, Research Funding; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees; Cellectis: Other: Clinical Trials; ImmunoGen: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Allogene: Research Funding; Boehringer: Consultancy; Immune Oncology: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Other: clinical trials; MEI Pharma: Consultancy, Research Funding; Precision Biosciences: Research Funding; Pfizer: Other: clinical trials; Redona: Consultancy; Sellas: Consultancy; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Vincerx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rafael Pharmaceutical: Research Funding; Reata Pharmaceutical: Other: IP; Sanofi Aventis: Consultancy, Other: clinical trials, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding. Feldman:Stelexis: Consultancy.

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2024
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