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

Eligibility Criteria

• 1. Age ≥ 18 and ≤ 70 years. English and non-English speaking participants are eligible.
• 2. Participants 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
• 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. Participants must voluntarily sign an informed consent
• 5. Female participants 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)
• * Participants 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.
• 1. Age ≥ 18 and ≤ 65 years. English and non-English speaking participants are eligible.
• 2. Participants 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 3).
• 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 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
• 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. Participants must voluntarily sign an informed consent
• 5. Female participants 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)
• * Participants 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.
• 1. Participants is known to be positive for HIV.
• 2. Participants has cognitive impairments and/or is a prisoner.
• 3. Participants has acute promyelocytic leukemia
• 4. Participants 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: participants 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. Participants 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.