Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS

Inclusion Criteria: Phase II 1. Age ≥ 18 and ≤ 70 years. English and non-English speaking patients are eligible. 2. Patients with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features: 1. ELN17 adverse risk prognostic group irrespective of remission status (see Appendix 2) 2. Measurable residual disease positive (MRD +) 3. Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, or relapsed disease. See Appendix 3 for details. 4. AML secondary to MDS or MPD 5. Therapy-related AML. 6. Not in complete remission after one course of induction therapy Or Patients with myelodysplastic syndrome or CMML and one of the following high-risk features: 1. Poor or Very poor cytogenetic risk group as per IPSS-R 2. Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a or ASXL1 or RUNX1 3. Maximum IPSS-R \>3.5 between diagnosis and the start of the preparative regimen. 4. ≥ 5% BM blasts at transplant 5. Therapy-related MDS 3. HLA-identical sibling or a minimum of 7/8 matched unrelated donor, or a haploidentical related donor available 4. Subject must voluntarily sign an informed consent 5. Female subjects of childbearing potential must have negative results for pregnancy test 6. Adequate hepatic and renal function per local laboratory reference range as follows: * Aspartate transaminase (AST) and alanine transaminase (ALT) \< 3.0X ULN * Bilirubin \<1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) * Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 50 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection. Phase III 1. Age ≥ 18 and ≤ 65 years. English and non-English speaking patients are eligible. 2. Patients with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features: 1. ELN22 adverse risk prognostic group irrespective of remission status (see Appendix 2. Measurable residual disease positive (MRD +) including MRD + any time after induction therapy. 3. Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, or relapsed disease. See Appendix 4 for details. 4. AML secondary to MDS or MPD 5. Therapy-related AML. 6. Not in complete remission after one course of induction therapy 7. Second or higher complete remission Or Patients with myelodysplastic syndrome and one of the following high-risk features: 1. Poor or Very poor cytogenetic risk group as per IPSS-R 2. Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN11) or ASXL1 or RUNX1 or moderate high, or high, or very high-risk group as per IPSS-M 3. Maximum IPSS-R \>3.5 between diagnosis and the start of the preparative regimen. 4. ≥ 5% BM blasts at transplant 5. Therapy-related MDS Or Patients with CMML 3. HLA-identical sibling or a minimum of 7/8 matched unrelated donor 4. Subject must voluntarily sign an informed consent 5. Female subjects of childbearing potential must have negative results for pregnancy test 6. Adequate hepatic and renal function per local laboratory reference range as follows: * Aspartate transaminase (AST) and alanine transaminase (ALT) \< 3.0X ULN * Bilirubin \<1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) * Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 50 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection. Exclusion criteria: 1. Subject is known to be positive for HIV. 2. Subject has cognitive impairments and/or is a prisoner. 3. Subject has acute promyelocytic leukemia 4. Subject has known active CNS involvement with AML. 5. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: 1. Uncontrolled and/or active systemic infection (viral, bacterial or fungal) 2. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. 6. Cardiac history of CHF requiring treatment or Ejection Fraction \< 50% or unstable angina; 7. Corrected DLCO \< 50% or FEV1 \<65%. 8. Administration or consumption of any of the following within 3 days prior to the first dose of study drug: * grapefruit or grapefruit products * Seville oranges (including marmalade containing Seville oranges) * star fruit 9. Patients with cognitive impairments and/or any serious unstable pre-existing medical condition or psychiatric disorder that can interfere with safety or with obtaining informed consent or compliance with study procedures. 10. Prior allogeneic stem cell transplantation.