Adding Venetoclax to the High-dose Chemotherapy Regimen Prior to Mismatche Allogeneic Stem Cell Transplant

A Phase II Trial of Venetoclax-Enhanced Reduced Intensity HLA-Mismatched Allogeneic Transplant for Ultra-High-Risk Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Patients eligible for a mismatch allogeneic stem cell transplant will receive Venetoclax daily for 7 days prior to transplant in addition to the following chemotherapy regimen: Decitabine daily for 5 days, Fludarabine daily for 5 days, and Busulfan daily for 2 days followed by 1 day of total body irradiation. Stem cell transplant will occur thereafter.

Inclusion Criteria:

• Availability of a 4/8 - 6/8 HLA-matched related donor or a 7/8 HLA-matched unrelated donor
• Receiving first allogeneic transplant
• KPS >/= 70%
• MDS associated with TP53 mutation AND R-IPSS high or very high risk at diagnosis OR
• AML with adverse risk cytogenetics or molecular abnormalities according to the 2017 ELN risk stratification OR pre-transplant MRD by either flow cytometry, cytogenetics or FISH
• Less than 5% myeloblasts in the marrow pre-transplant

Exclusion Criteria:

• Poor cardiac function defined as LVEF <45%
• Poor pulmonary function defined as FEV1, FVC, or DLCO <50% predicted
• Poor liver function defined as bilirubin >/=2.5mg/dL, AST/ALT >3xULN
• Poor renal function defined as creatinine >/=2.0mg/dL or CrCl <40mL/min
• Ongoing or active systemic infection, active Hepatitis B or C virus infection, or known HIV positivity
• Patient requiring treatment with a moderate or strong inhibitor or inducer of CYP3A4 or a P-gp inhibitor within 7 days prior to starting preparative chemotherapy through Day +4 post-transplant