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

Prior treatment

• 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 (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.
• 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
• Prior allogeneic stem cell transplantation.

Other illness

• Subject is known to be positive for HIV.
• 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.

Lab values

• Cardiac history of CHF requiring treatment or Ejection Fraction \< 50% or unstable angina;

Other

• Subject has cognitive impairments and/or is a prisoner.
• Subject has acute promyelocytic leukemia
• Subject has known active CNS involvement with AML.
• Corrected DLCO \< 50% or FEV1 \<65%.

• Phase II
• Age ≥ 18 and ≤ 70 years. English and non-English speaking patients are eligible.
• 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 (see Appendix 2)
  • 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. See Appendix 3 for details.
  • AML secondary to MDS or MPD
  • Therapy-related AML.
  • 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:
  • Poor or Very poor cytogenetic risk group as per 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% BM blasts at transplant
  • Therapy-related MDS
• HLA-identical sibling or a minimum of 7/8 matched unrelated donor, or a haploidentical related donor available
• Subject must voluntarily sign an informed consent
• Female subjects of childbearing potential must have negative results for pregnancy test
• 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
• Age ≥ 18 and ≤ 65 years. English and non-English speaking patients are eligible.
• 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 (see Appendix
  • Measurable residual disease positive (MRD +) including MRD + any time after induction therapy.
  • 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.
  • 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 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
• HLA-identical sibling or a minimum of 7/8 matched unrelated donor
• Subject must voluntarily sign an informed consent
• Female subjects of childbearing potential must have negative results for pregnancy test
• 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.