Clinical Trial Finder

Inclusion Criteria:

Phase

• II. 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. Participants with myelodysplastic syndrome or CMML and one of the following high-risk features: 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.

Phase

• III. 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 Or. Patients with myelodysplastic syndrome and one of the following high-risk features: 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. 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 8/8 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.

Exclusion criteria:

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 < 65% 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. Prior gemtuzumab ozogamicin and/or inotuzumab ozogamicin use. 10. 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. 11. Prior autologous or allogeneic stem cell transplantation.

Phase 2 Portion. Primary Objective 1) To obtain preliminary evidence of efficacy as defined by 1-year progression free survival. Secondary Objectives. To determine: 1. Safety of this regimen as per NCI toxicity criteria. 2. Time to neutrophil and platelet engraftment. 3. Incidence of acute and chronic GVHD. 4. Relapse incidence. 5. Non-relapse mortality. 6. Overall survival. 7. Graft versus host disease-relapse free survival (GRFS) Phase 3 Portion. Primary Objective. 1) To compare progression free survival between two arms Arm 1 Standard of Care: fludarabine + IV busulfan (FluBu) versus Arm 2 Experimental: Venetoclax + Fractionated busulfan, cladribine, and fludarabine. Secondary Objectives To compare following between two arms. 1. Safety of this regimen as per NCI toxicity criteria. 2. Time to neutrophil and platelet engraftment. 3. Incidence of acute and chronic GVHD. 4. Relapse incidence. 5. Non-relapse mortality. 6. Overall survival. 7. Graft versus host disease-relapse free survival (GRFS)

Arms

Experimental: Treatment (venetoclax, busulfan, fludarabine, cladribine)

Patients receive venetoclax PO QD on days -22 to -3, busulfan IV over 3 hours on days -20, -13, -6, -5, -4, and -3, and fludarabine phosphate IV over 1 hour and cladribine IV over 2 hours on days -6 to -3 in the absence of disease progression or unacceptable toxicity. Patients then undergo stem cell transplantation over 1-2 hours on day 0.

Interventions

Drug: - Busulfan

Given IV

Drug: - Cladribine

Given IV

Drug: - Fludarabine Phosphate

Given IV

Procedure: - Hematopoietic Cell Transplantation

Undergo stem cell transplantation

Drug: - Thiotepa

Given IV

Drug: - Venetoclax

Given PO