Phase 1 Study of Venetoclax Combined with a 10-Day Regimen of Decitabine in Subjects with High-Risk Acute Myeloid Leukemia.

6547 Background: We and others have reported the antileukemic activity of a 10-day regimen of the hypomethylating agent (HMA), decitabine (DEC), in high-risk acute myeloid leukemia (AML). Venetoclax (VEN), at a standard (std) dose of 400 mg, combined with HMA, at a std schedule, has improved AML outcomes. We aimed to investigate the safety of adding VEN to the 10-day regimen of DEC and explore the effects of BCL2 inhibition on the immune repertoire. Methods: This was a multicenter, investigator-initiated, dose-escalation study in adults with high-risk AML defined as, disease with a TP53 mutation, adverse-risk cytogenetics or relapsed/refractory (R/R). Patients (pts) were naïve to HMA and VEN. The primary endpoint was to establish the maximum tolerated dose (MTD) of VEN when combined with a 10-day DEC schedule. Dose-limiting toxicities (DLT) were evaluated during cycle 1. In the absence of a DLT, 3-6 evaluable pts were enrolled per dose level (DL) or until the 400mg DL of VEN was reached (Table 1). Peripheral blood mononuclear cells (PBMCs) were isolated before and after treatment. Shifts in the immune landscape and BCL2 family expression were profiled with spectral flow cytometry. Results: 14 pts were enrolled, with a median age of 66.5 years (range 19-77); including 9 pts (64%) with R/R AML, 8 (57%) with adverse-risk cytogenetics and 6 (43%) with a TP53 mutation. One pt had a DLT at DL1, due to grade (G) 4 neutropenia and persistent marrow aplasia in the absence of leukemia beyond day 42. One patient with R/R AML and pre-existing elevated alanine aminotransferase (ALT) secondary to known graft-versus-host disease developed G2 ALT elevation. 3 pts were then enrolled at DL-1, before reescalation back up to DL1. 2 pts at DL1 were deemed not eligible for DLT evaluation, requiring an additional 2 pts enrolled at DL1, without DLT, to confirm safety. The MTD was determined to be DL2 (400 mg). 5 pts (36%) had a complete remission (CR) or CR with incomplete count recovery (CRi). Non-hematologic or infectious G1-2 toxicities included fatigue (43%), diarrhea (43%) and decreased appetite (36%). 1 pt died of suspected sepsis outside of the DLT evaluation period. 7 pts had serial PBMCs available for multiparameter flow cytometric immune and BCL2 family profiling. Of these, 3 responders had strong induction of BCL2 in CD4+/CD8+ lymphocytes and B cells after 1 cycle and were enriched for a population of “senescent” CD8+ T cells that had relatively low expression of coinhibitory markers (PD-1, LAG3, TIM3). Conclusions: A 10-day DEC+VEN regimen is feasible in high-risk AML, with myelosuppression being the major DLT. The recommended phase 2 dose is 400mg VEN (DL2), but responses were also seen at 200mg. The immune profile of responders have demonstrated intriguing patterns that merit investigation in a larger HMA+VEN cohort. Clinical trial information: NCT03844815 . DL DEC dose(D1-10)mg/m2 VEN dose (D1-21)mg # of pts DLT CR CRi No Response -1 15 100 3 0 0 0 3 1 20 200 8 1 1 3 4 2 20 400 3 0 0 1 2