This multicenter, open-label phase II study combines CLAG-based therapy with or without venetoclax in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) in order to improve measurable residual disease (MRD) clearance and event-free survival. Investigators hypothesize that the addition of venetoclax to CLAG-M in patients with relapsed or refractory AML is safe, and superior to CLAG-M alone in improving patient outcomes.

Inclusion Criteria:

• Provision of signed and dated informed consent form.
• Ability to understand and stated willingness to comply with all study procedures and availability for the duration of the study.
• Adults aged ≥18 years - 80 years.
• Patients with documented refractory or relapsed AML: Refractory disease is defined as failure to achieve CR (i.e., <5% blasts in BM or blood) with or without normal restoration of hematopoiesis (Cri) after at least 1 cycle of intensive induction therapy (or 2 cycles of non-intensive induction). Relapse: Recurrence of disease after achieving remission, meeting one or more of the following criteria: ≥ 5% blasts in the marrow or peripheral blood, extramedullary disease.
• Secondary AML arising out of MDS previously treated with HMA, HMA + venetoclax (if > 3 months from venetoclax exposure), and/or 1 cycle of induction chemotherapy.
• Extramedullary AML with marrow involvement is allowed as long as concurrent medullary AML is present.
• ECOG performance status ≤ 2.
• Participants must have adequate organ function as defined within the protocol.
• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Testing is not mandatory.
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and have an undetectable HCV viral load. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Testing is not mandatory.
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 4 months after completion of study drug administration.

Exclusion Criteria:

• Venetoclax-refractory disease or recent venetoclax exposure < 3 months prior to first dose of study therapy.
• Prior treatment with a high-dose cytarabine-containing regimen (e.g., no prior CLAG/FLAG/MEC/CLIA/HAM, etc.).
• Allogeneic stem cell transplant in the past 3 months.
• Less than 14 days from last AML-directed therapy or five half-lives, whichever is shorter, not including hydroxyurea.
• Known history of prior TP53 mutation (results from any myeloid mutation panel are not required for screening eligibility).
• Active CNS involvement by AML.
• WBC count ≥25k at the time study treatment begins.
• Uncontrolled intercurrent systemic illness that would limit compliance.
• Concurrent malignancy in addition to AML that requires active treatment with some exceptions.
• Immunosuppressive therapy in the past 14 days except for prednisone at ≤ 10 mg/day or equivalent AND no active or uncontrolled graft-versus-host disease (GvHD).
• Participants who have not recovered from adverse events (Aes) due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1), with the exception of alopecia.
• Participants who are receiving any other investigational agents.
• Participants with psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with active heart disease that limits the use of mitoxantrone or recent (<6 months) history of an acute cardiovascular event (STEMI, NSTEMI).
• Pregnant women are excluded from this study because venetoclax, cladribine, and cytarabine are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these drugs, breastfeeding should be discontinued.