A Phase I Trial to Evaluate the Safety and Efficacy of Addition of Novel Anti-leukemia Agents to Flu/Mel RIC Transplant for High-risk Myeloid Malignancies
The purpose of this study is to determine the safety of adding Decitabine and Venetoclax to patients undergoing reduced intensity allogenic transplantation for treatment of hematologic malignances with Fludarabine and Melphalan.
• Adult male or female, age 18-75 years
• Patients must have a related or unrelated peripheral blood stem cell donor. Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) resolution, and -DRB1 at high resolution using DNA-based typing, and must be willing to donate peripheral blood stem cells and meet institutional criteria for donation. Unrelated donor must the following: have Optimum: HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1; Minimum: HLA-A, -B, -C, -and DRB1 matching at high resolution using DNA-based typing and be willing to donate peripheral blood stem cells and be medically eligible to donate stem cells according to National Marrow Donor Program (NMDP) criteria.
• A candidate for reduced intensity preparative regimen, based on age≥60, or HCT-CI of ≥4, or considered by the treating physician to have high risk for toxicity with myeloablative preparative regimen.
• Cardiac function: Ejection fraction \>40%
• Calculated creatinine clearance greater than 50 mL/minute (using the Cockcroft-Gault formula and actual body weight).
• Pulmonary function: DLCO ≥50% (adjusted for hemoglobin) and FEV1≥50%
• Liver function: total bilirubin \< 1.5x the upper limit of normal and ALT/AST \< 2.5x the upper normal limit. Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the defined bilirubin value up to \<3mg/dl.
• Female subjects (unless postmenopausal for at least 1 year before the screening visit, or surgically sterilized), agree to practice two effective methods of contraception or agree to complete abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant.
• Male subjects (even if surgically sterilized), of partners of women of childbearing potential must agree to practice effective barrier contraception or abstain from heterosexual intercourse from the time of signing the informed consent through 12 months post-transplant.
⁃ Karnofsky performance status KPS ≥ 70 (Appendix B)
⁃ Patients must have a diagnosis of one of the following:
‣ AML: A. Any AML with active disease (defined as ≥ 5% blasts in the marrow), with no available re-induction strategies, or further therapy is not felt to be effective by treating physician.
⁃ B. Any AML with adverse risk disease, therapy-related or secondary-AML in CR1 or beyond C. AML with intermediate risk disease that is MRD+ in CR1 or beyond D. Any AML in CR2 or beyond (regardless of MRD) E. Marrow blast percentage needs to be 20-25% and total WBC counts needs to be ≤ 25000/µl before the start of the conditioning regimen. It is acceptable to use hydroxyurea or low dose cytarabine to maintain this WBC count.
‣ MDS:
⁃ MDS with IPSS-M ≥ high and/or with ≥5% blasts in the bone marrow with no available pre-transplant strategies, or further therapy is not felt to be effective by treating physician.- MDS/MPN:
‣ MDS/MPN \>5% blasts and spleen \< 22 cm with no available pre-transplant strategies, or further therapy is not felt to be effective by treating physician.
⁃ Subject is willing and able to sign informed consent and abide by the protocol requirements.