Mitoxantrone for Venetoclax Resistant Acute Myeloid Leukemia

Inclusion Criteria: 1. Subject must have confirmation of non-APL AML by WHO criteria and have been treated with first-line venetoclax/HMA (azacitidine or decitabine). 2. Subject must have relapsed disease per IWG criteria or disease refractory to first line venetoclax/HMA defined by less than a PR response after ≥ 1 complete cycle of venetoclax/HMA. 3. Subject must have either measurable residual disease (MRD+), as measured by FDA-approved flow cytometric test performed by Hematologics (cohort 3 and 4) or relapsed/refractory disease (cohort 1 and 2). 4. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤ 2. 5. Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 60 mL/min, calculated using the formula CKD-EPI Creatinine Equation 6. Subject must have adequate heart function as measured by left ventricular ejection fraction (LVEF) \>50%, assessed by multigated acquisition (MUGA) or echocardiogram (ECHO) within 1 month prior to study day 1 7. Subject must have adequate liver function as demonstrated by: 1. aspartate aminotransferase (AST) ≤ 3.0 × ULN\* 2. alanine aminotransferase (ALT) ≤ 3.0 × ULN\* 3. bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome\* * Unless considered due to leukemic organ involvement 8. Non-sterile male subjects must use contraceptive methods with partner(s) at least prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug. No contraception is required if male subjects are surgically sterile (vasectomy with medical assessment confirming surgical success) or if the male subject has a female partner who is postmenopausal or permanently sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 9. Female subjects must be either: 1. Postmenopausal; defined as Age \> 60 years with no menses for 12 or more months without an alternative medical cause; OR 2. Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy); OR 3. If subject is of childbearing potential, use of contraception is required while on study treatment and for 6 months after the last dose. 10. Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed procedures. Exclusion Criteria: 1. Subject has known active CNS involvement from AML. 2. Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to: 1. Significant active cardiac disease within the previous 6 months including: New York Heart Association heart failure \> class 2, unstable angina, or myocardial infarction. 2. Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia. 3. Subject has a malabsorption syndrome or other condition that precludes enteral route of administration. This includes history of inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis), celiac disease (e.g. sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity. 4. Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal). Uncontrolled is defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment. 5. Subject has a history of other malignancies prior to study entry, with the exception of: 1. Adequately treated in situ carcinoma of the breast or cervix uteri 2. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin 3. Prostate cancer not requiring therapy beyond hormonal therapy 4. Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent 6. Subject has a white blood cell count \> 25 × 109/L. Note: hydroxyurea or apheresis are permitted to meet this criterion (cohort 3 only). 7. Pregnant or breast-feeding females. 8. Known or suspected hypersensitivity to azacitidine or mannitol. 9. Any prior exposure to an anthracycline or anthracenedione