P524: pharmacodynamically defined metronomic dosing of decitabine and venetoclax in acute myeloid leukemia

Background: Hypomethylating agents (HMAs) (5-azacytidine or decitabine) combined with venetoclax (Ven) have become the new standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, myelosuppression and infectious complications are common adverse events of currently approved HMA/Ven regimens, requiring dose interruptions/delays that often undermine treatment goals. Previous studies have identified the minimum dose of decitabine needed to deplete DNA methyltransferase-1 (DNMT1) without causing cytotoxicity (Saunthararajah, 2015). Administration of a single venetoclax dose synergizes with low dose weekly decitabine by inhibiting de-novo pyrimidine synthesis - a major mechanism of resistance to HMAs (Awada, 2020). Thus, once weekly low dose decitabine combined with a single weekly dose of venetoclax may reduce toxicity while maintaining efficacy. Here, we report initial results of an ongoing Phase II clinical trial evaluating tolerability and efficacy of a metronomic dosing of decitabine and venetoclax for treatment of older patients with AML. Aims: The primary endpoint of this study is percentage of patients who are able to continue on treatment during the 12-week induction period without dose interruptions or delays. The key secondary endpoints include best overall response, rate of Grade >≥3 adverse events, infections, and hospitalizations. Correlative studies evaluate DNMT1 depletion in bone marrow at the time of diagnosis and at week 12. Methods: This is a single arm open-label Phase II clinical trial (NCT05184842). Patients >≥18 years old with a diagnosis of AML, MDS, MDS/MPN and MDS/AML not fit for intensive chemotherapy were eligible. Subcutaneous decitabine and oral venetoclax were administered on the same day, once a week at 0.2mg/kg and 400mg, respectively. A bone marrow exam and measurable residual disease (MRD) assessment by multiparametric flow cytometry (MFC) were performed following 12-week induction period. Results: Between June 2022 and February 2023, 18 patients were enrolled on this study, these included AML (n=12), MDS (n=2), CMML (n=2), MDS/MPN (n=2). Herein we report findings on AML patients. Of 12 AML patients, 9 have completed the 12-week induction period and are evaluable for safety and response (1 lost to follow-up; 2 not yet evaluable). The median age was 75 years old (63-83). Four patients (44%) were adverse risk by 2022 European Leukemia Net (ELN) criteria. All patients were able to complete all 12 weeks of treatment without dosing interruptions or delays. There were no Grade >≥ 3 therapy related adverse events. Only 1/9 (11%) patients required hospitalization at any point while on therapy. At the end of induction, 5 patients (56%) achieved a complete remission (CR), which in 3 patients was MRD negative by MFC. Four (44%) patients had progression of disease (POD) after a median of 72 days. 30 and 60-day mortality was zero. After median follow-up time of 4.1 months, all 5/9 (56%) responding patients remain in remission and on study. Studies evaluating DNMT1 staining on bone marrow samples from patients treated on this study are ongoing. Summary/Conclusion: In this interim analysis we demonstrate tolerability and preliminary efficacy of metronomic dosing of decitabine and venetoclax, by allowing frequent sustained drug exposure often not possible with standard HMA/Ven regimens. Data on correlation of clinical response to DNMT1 depletion from bone marrow samples obtained pre and post therapy will be presented. Enrollment continues to further define the safety and efficacy.Keywords: Myelodysplastic syndrome, Venetoclax, Acute myeloid leukemia, decitabine