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 therapyand one of the following high-risk features:

3. ELN17 adverse risk prognostic group irrespective of remission status (seeAppendix 2)

4. Measurable residual disease positive (MRD +)

5. Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, orrelapsed disease. See Appendix 3 for details.

6. AML secondary to MDS or MPD

7. Therapy-related AML.

8. Not in complete remission after one course of induction therapy Or Patients with myelodysplastic syndrome or CMML and one of the following high-riskfeatures:

9. Poor or Very poor cytogenetic risk group as per IPSS-R

10. Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN1) or DNMT 3a orASXL1 or RUNX1

11. Maximum IPSS-R >3.5 between diagnosis and the start of the preparative regimen.

12. ≥ 5% BM blasts at transplant

13. Therapy-related MDS

14. HLA-identical sibling or a minimum of 7/8 matched unrelated donor, or ahaploidentical related donor available

15. Subject must voluntarily sign an informed consent

16. Female subjects of childbearing potential must have negative results for pregnancytest

17. 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 ofnon-hepatic origin)

• Subject must have adequate renal function as demonstrated by a creatinineclearance ≥ 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 therapyand one of the following high-risk features:

3. ELN22 adverse risk prognostic group irrespective of remission status (seeAppendix

4. Measurable residual disease positive (MRD +) including MRD + any time afterinduction therapy.

5. Not in complete remission including complete remission without count recovery (Cri) and/or morphologic leukemia free state (MLFS), primary refractory, orrelapsed disease. See Appendix 4 for details.

6. AML secondary to MDS or MPD

7. Therapy-related AML.

8. Not in complete remission after one course of induction therapy

9. Second or higher complete remission Or Patients with myelodysplastic syndrome and one of the following high-risk features:

10. Poor or Very poor cytogenetic risk group as per IPSS-R

11. Mutated P53 or Ras pathway genes (CBL, NRAS, KRAS, NF1, PTPN11) or ASXL1 orRUNX1 or moderate high, or high, or very high-risk group as per IPSS-M

12. Maximum IPSS-R >3.5 between diagnosis and the start of the preparative regimen.

13. ≥ 5% BM blasts at transplant

14. Therapy-related MDS Or Patients with CMML

15. HLA-identical sibling or a minimum of 7/8 matched unrelated donor

16. Subject must voluntarily sign an informed consent

17. Female subjects of childbearing potential must have negative results for pregnancytest

18. 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 ofnon-hepatic origin)

• Subject must have adequate renal function as demonstrated by a creatinineclearance ≥ 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, butnot limited to:

6. Uncontrolled and/or active systemic infection (viral, bacterial or fungal)

7. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note:subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis Bsurface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitisB core (HBc) antibody negative) or positive anti-HBc antibody from intravenousimmunoglobulins (IVIG) may participate.

8. Cardiac history of CHF requiring treatment or Ejection Fraction < 50% or unstableangina;

9. Corrected DLCO < 50% or FEV1 <65%.

10. Administration or consumption of any of the following within 3 days prior to thefirst 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 medicalcondition or psychiatric disorder that can interfere with safety or with obtaininginformed consent or compliance with study procedures.

10. Prior allogeneic stem cell transplantation.