Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS
Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 18 and ≤ 70 years
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.
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
- 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.
Exclusion criteria:
- Subject is known to be positive for HIV.
- Subject has cognitive impairments and/or is a prisoner.
- Subject has acute promyelocytic leukemia
- Subject 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: 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 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
Sites / Locations
- M D Anderson Cancer CenterRecruiting
Arms of the Study
Arm 1
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.