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

Inclusion Criteria:

Phase II

Age ≥ 18 and ≤ 70 years. English and non-English speaking participants are eligible.

Participants 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

Participants 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
Participants must voluntarily sign an informed consent
Female participants 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)
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.

Phase III

Age ≥ 18 and ≤ 65 years. English and non-English speaking participants are eligible.

Participants 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

Participants 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 8/8 matched unrelated donor
Participants must voluntarily sign an informed consent
Female participants 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)
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.

Exclusion criteria:

Participants is known to be positive for HIV.
Participants has cognitive impairments and/or is a prisoner.
Participants has acute promyelocytic leukemia
Participants has known active 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 (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.
Cardiac history of CHF requiring treatment or Ejection Fraction < 50% or unstable angina;
Corrected DLCO < 65% or 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
Prior gemtuzumab ozogamicin and/or inotuzumab ozogamicin use
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.