Venetoclax to Improve Outcomes of Fractionated Busulfan Regimen in Patients With High-Risk AML and MDS
This phase II trial studies the effect of venetoclax together with busulfan, cladribine, and fludarabine in treating patients with high-risk acute myeloid leukemia or myelodysplastic syndrome who are undergoing stem cell transplant. Chemotherapy drugs, such as venetoclax, busulfan, cladribine, and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding venetoclax to the current standard of care stem cell transplant regimen of busulfan, fludarabine, and cladribine may help to control high-risk acute myeloid leukemia or myelodysplastic syndrome.
• 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.