Venetoclax with Busulfan, Thiotepa, Cladribine, and Fludarabine for the Treatment of High-Risk Acute Myeloid Leukemia or Myelodysplastic Syndrome

Inclusion Criteria

• PHASE II: Age ≥ 18 and ≤ 70 years. English and non-English speaking patients are eligible
• PHASE II: Patients with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features: * ELN17 adverse risk prognostic group irrespective of remission status * Measurable residual disease positive (MRD +) * Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, or relapsed disease * Acute myeloid leukemia (AML) secondary to myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPD) * Therapy-related AML * Not in complete remission after one course of induction therapy OR Patients with myelodysplastic syndrome or chronic myelomonocytic leukemia (CMML) and one of the following high-risk features: * Poor or very poor cytogenetic risk group as per Revised International Prognostic Scoring System (IPSS-R) * Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a or ASXL1 or RUNX1 * Maximum IPSS-R > 3.5 between diagnosis and the start of the preparative regimen * >= 5% bone marrow (BM) blasts at transplant * Therapy-related MDS
• PHASE II: HLA-identical sibling or a minimum of 7/8 matched unrelated donor, or a haploidentical related donor available
• PHASE II: Subject must voluntarily sign an informed consent
• PHASE II: Female subjects of childbearing potential must have negative results for pregnancy test
• PHASE II: Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x upper limit of normal (ULN)
• PHASE II: Bilirubin < 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
• PHASE II: 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: Age >= 18 and =< 65 years. English and non-English speaking patients are eligible
• PHASE III: Patients with acute myeloid leukemia who have previously received induction therapy and one of the following high-risk features: * ELN22 adverse risk prognostic group irrespective of remission status * Measurable residual disease positive (MRD +) * Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, or relapsed disease * AML secondary to MDS or MPD * Therapy-related AML * Not in complete remission after one course of induction therapy * Second or higher complete remission OR Patients with myelodysplastic syndrome and one of the following high-risk features: * Poor or very poor cytogenetic risk group as per IPSS-R * 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 Molecular International Prognostic Scoring System (IPSS-M) IPSS-M * Maximum IPSS-R > 3.5 between diagnosis and the start of the preparative regimen * >= 5% BM blasts at transplant * Therapy-related MDS OR Patients with CMML
• PHASE III: HLA-identical sibling or a minimum of 8/8 matched unrelated donor
• PHASE III: Subject must voluntarily sign an informed consent
• PHASE III: Female subjects of childbearing potential must have negative results for pregnancy test
• PHASE III: Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 X ULN
• PHASE III: Bilirubin < 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
• PHASE III: 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

• Subject is known to be positive for human immunodeficiency virus (HIV)
• Subject has cognitive impairments and/or is a prisoner
• Subject has acute promyelocytic leukemia
• Subject has known active central nervous system (CNS) involvement with AML
• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: * Uncontrolled and/or active systemic infection (viral, bacterial or fungal) * Chronic hepatitis B virus (HBV) or hepatitis C (hepatitis C virus [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
• Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction < 50% or unstable angina
• Corrected diffusion capacity of the lung for carbon monoxide (DLCO) < 50% or forced expiratory volume in 1 second (FEV1) < 65%
• 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
• 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
• Prior allogeneic stem cell transplantation