Frontline Aspacytarabine with Venetoclax for Older/Unfit Patients with Acute Myeloid Leukemia: Preliminary Results of a Phase 1 Study

Introduction: Venetoclax (VEN), a selective BCL2 inhibitor, in combination with hypomethylating agents (HMA) or low-dose cytarabine is currently the standard of care for first line treatment of older/unfit patients with acute myeloid leukemia (AML). This, however, requires indefinite cycles of treatment and results in prolonged cytopenias. Aspacytarabine (ASPA, formerly BST-236), a novel pyrimidine antagonist, is a cytarabine prodrug designed to enable high cytarabine dose treatment with reduced systemic toxicity, that was previously proven safe and effective for the treatment of AML in adults unfit for intensive chemotherapy. Given excellent outcomes with intensive chemotherapy with VEN, we hypothesized that higher cytarabine dose using ASPA and VEN followed by a limited consolidation with ASPA may provide superior outcomes than the current standard.

Aims: To assess the safety and efficacy of VEN plus ASPA induction treatment regimen in older/unfit AML patients followed by limited consolidation course(s) with ASPA alone.

Methods: A phase I/II dose escalation and expansion study using 1 or 2 induction courses with intravenous (IV) ASPA 2.3 or 4.5 g/m ² daily for 6 consecutive days plus VEN at a dose of 200 mg or 400 mg for 7 days without azole antifungals. Followed by up to 3 consolidation courses with single agent ASPA 2.3/4.5 g/m ²/day for 6 days, in patients with newly diagnosed AML unfit for intensive chemotherapy. Patients with secondary AML are allowed. MRD was evaluated centrally by flow cytometry at Dr. Wood's laboratory, with a sensitivity of 0.1%.

Results: Two cohorts are completed with 7 patients enrolled. Table 1 details the cohort treatment. Baseline characteristics and outcome are provided in Table 2. To date, the combination is well-tolerated. As expected, all patients had cytopenia (16% grade 4, and 84% grade 3 and lower), following the induction treatment and non-hematological grade ≥3 reported in more than 1 patient were pneumonia and sepsis both reported in 2 patients). One death occurred in cohort 1: an 80 year-old patient with a cardiac medical history died at home on day 27 of induction, prior to bone marrow analysis, but with full count recovery; death was deemed unrelated to study treatment. One 79-year-old patient from cohort 2 discontinued the study following the 1 ^st consolidation, while in CR _MRD-, due to prolonged laryngitis. In the first, cohort, 1 patient attained a CR _MRD- after 1 induction course, and this response is still maintained 6 months from study entry (after 3 consolidation courses of ASPA monotherapy). In the second cohort, all 3 patients' disease entered a CR after 1 course of ASPA and VEN Two achieved CR _MRD-, and the 3 ^rd patient is currently receiving a second induction course, as per protocol. All responding patients had a full count recovery within 35 days and disease continues to be in CR.

Conclusions: The combination induction regimen of ASPA and VEN followed by consolidation with ASPA alone, is a promising therapy. The regimen is tolerable, and all patients in cohort 2 have attained a CR with 2/3 MRDneg and the third with treatment ongoing. This treatment may overcome the limitations of prolonged cytopenia and indefinite therapy with HMA/VEN along with a high CR rate. This study is ongoing, and updates will be provided at the conference.