P488: safety and efficacy of venetoclax plus “7 + 3” chemotherapy in newly diagnosed aml

Topic: 4. Acute myeloid leukemia - Clinical Background: Approximately 70% of patients (pts) with acute myeloid leukemia (AML) treated with the “7 + 3” regimen achieve complete remission (CR), with 30-50% of those attaining measurable residual disease (MRD) negative state by multiparameter flow cytometry (MFC). However, despite initial responses, the majority of pts eventually relapse. Venetoclax (Ven) added to intensive chemotherapy (IC) facilitates apoptosis of leukemic stem cells (LSC), and may result in deeper, more durable remissions. Moreover, IC induces MCL-1 downregulation and may overcome Ven resistance. We present initial results from an ongoing phase 1b study evaluating the safety and tolerability of different Ven doses combined with daunorubicin (Dauno)+ cytarabine (AraC) followed by high-dose cytarabine (HiDAC) chemotherapy in pts with newly diagnosed AML (NCT05342584). Aims: The primary objective of this study is to determine the optimal dose of Ven in combination with Dauno & AraC and HiDAC chemotherapy. Secondary objectives are response per 2022 ELN, survival (OS), event-free survival (EFS) and duration of response (DoR). A key exploratory objective is to assess rates of LSC eradication by means of MFC and single cell DNA (Tapestri, Mission Bio) and RNA sequencing (“high-resolution MRD assay”). 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, escalating total Ven doses (400 mg D1-8 or 11 or 14, including 2-day ramp-up) are combined with AraC 100mg/m2 (D2-8) and 2 doses of Dauno (60 and 90mg/m2, D2-4) in pts < 60yrs or Dauno 60mg/m2 (D2-4) alone in pts ≥60yrs. Overflow of additional 3 pts is allowed in lower-dose cohorts. During consolidation, Ven dose is escalated (200 -> 400mg x7days) in a similar 3 + 3 design in combination with age-adjusted HiDAC (1.5g/m2 in <60yrs and 1g/m2 in ≥60yrs, every 12hrs on days 1,3,5). In the expansion phase, additional 12 pts in each age group (<60 and ≥60yrs) will be treated at the dose determined during dose escalation. Dose-limiting toxicity (DLT) is defined as any ≥grade 3 non-heme toxicity not attributed to chemotherapy alone and/or failure to achieve ANC ≥ 500/mL and/or PLT≥ 50,000/mL by day 42 in pts without residual AML. A marrow exam, including an assessment of MRD by MFC with a sensitivity of 0.02%, is performed at the time of count recovery or by day 42. Results: Seventeen AML pts enrolled and 14 completed the induction phase to date, 3 are actively treated. Forty-one percent are females and 52% ethnic minorities. Six pts <60yrs of age were treated with Ven x 8d, 3 in Dauno60 and 3 in Dauno90 cohorts. From the 8 pts ≥60yo, 5 were treated with Ven x 8d and 3 with Ven x 11d plus Dauno60. No DLTs were observed. All except one pt (13/14, 93%) achieved a complete remission (CR) with single induction. Median time to ANC≥0.5K/uL and PLT≥50K/uL was 26 and 28 days, respectively. Of those in CR, all except one pt were MFC-MRD negative (12/14, 86%). Among 6/8 patients with available MRD PCR testing, 4 achieved molecular MRD-negative and 2 low-level molecular MRD CRs. With a median time on follow-up of 4.7 months, 11 of 14 (78.6%) patients are alive with no evidence of relapse. Table 1 summarizes patient characteristics, toxicity and outcomes. Summary/Conclusion: Ven 400mg in combination with “7 + 3” induction chemotherapy appears safe and highly effective in achieving deep remissions. Enrollment continues in the Dauno60 + Ven x11d and 14d cohorts. Updated results, as well as data on EFS, OS, DoR and rates of LSC elimination post-induction will be presented at the meeting.Keywords: Acute myeloid leukemia, AML