Venetoclax in Combination with Azacitidine followed by Donor Lymphocyte Infusion for the Treatment of Patients with Very High-Risk Acute Myeloid Leukemia Undergoing Donor Stem Cell Transplant

PRIMARY OBJECTIVE:

I. Determine the safety profile, maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of venetoclax in combination with azacitidine followed by prophylactic / preemptive DLI as post-transplant therapy in patients with very high-risk AML.

SECONDARY OBJECTIVES:

I. Determine recurrence-free survival (RFS) in patients with very high-risk AML treated with venetoclax in combination with azacitidine followed by DLI as post-transplant prophylactic / preemptive therapy.

II. Determine overall survival (OS) in patients with very high-risk AML treated with venetoclax in combination with azacitidine followed by DLI as post-transplant prophylactic / preemptive therapy.

III. Determine treatment related mortality (TRM) in patients with very high-risk AML treated with venetoclax in combination with azacitidine followed by DLI as post-transplant therapy.

IV. Determine cumulative incidence of acute and chronic graft versus host disease (GVHD) in patients with very high-risk AML treated with venetoclax in combination with azacitidine followed by DLI as post-transplant prophylactic / preemptive therapy.

EXPLORATORY OBJECTIVES:

I. Determine the impact of cytogenetic and molecular abnormalities on survival endpoints and other clinical endpoints of interest in patients with very high-risk AML receiving venetoclax in combination with azacitidine followed by DLI as post-transplant prophylactic / preemptive therapy.

II. Evaluate the impact of measurable residual disease (MRD) status on survival and other clinical endpoints of interest in patients with very high-risk AML receiving venetoclax in combination with azacitidine followed by DLI as post-transplant prophylactic / preemptive therapy.

III. Assess markers of T-cell maturation, functional immunity and regulatory T-cell subsets in patients with very high-risk AML receiving venetoclax in combination with azacitidine followed by DLI as post-transplant prophylactic / preemptive therapy.

OUTLINE: This is a dose-escalation study of venetoclax in combination with fixed-dose azacitidine and DLI followed by a dose-expansion study.

Patients undergo standard of care allogeneic HCT on day 0. Starting 42-100 days after HCT, patients receive venetoclax orally (PO) once daily (QD) on days 1-7, 1-14 or 1-21 of each cycle, and azacitidine subcutaneously (SC) or intravenously (IV) on days 1-5 of cycles 1-6. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive DLI IV after cycle 3, and patients with persistent MRD may receive additional infusions after cycles 5 and 7. Additionally, patients undergo multigated acquisition scan (MUGA) or echocardiography, blood sample collection, and bone marrow (BM) biopsy and aspiration pre-HCT and on study.

After completion of study treatment, patients are followed up every 3 months for up to 1 year.