Preemptive Treatment With Venetoclax Plus Azacitidine in Patients Diagnosed With Acute Myeloid Leukemia (AML) With Persistence or Reappearance of Measurable Residual Disease (MRD) After Frontline Chemotherapy and High-level MRD Prior to Allogeneic Hematopoietic Cell Transplantation (alloHCT)
The VERDI study is an investigator-initiated, multicenter, multicohort, phase II trial with combination of venetoclax + azacitidine for patients treated for AML under according to an intensive chemotherapy protocol (CETLAM-20) failing to achieve or maintain MRD negativity at pre-established time-points: at chemotherapy completion for ELN favorable subtypes, and prior to alloHCT for non-favorable European LeukemiaNet (ELN) AML patients. The primary objective is to determine Ven/Aza treatment activity in MRD clearance in patients diagnosed with AML with persistent MRD or MRD reappearance after frontline chemotherapy, or prior to alloHCT.
• Patients must have confirmation of with acute myeloid leukemia (AML) with persistent measurable residual disease (MRD) or MRD reappearance after frontline intensive chemotherapy (including at least one cycle of cytarabine and anthracycline), and prior to allogeneic hematopoietic cell transplantation (allo-HCT).
‣ In patients with NPM1 mutation, qRT-PCR of NPM1 will be the method used to establish a molecular failure, defined as failure to achieve molecular response after consolidation therapy (NPM1mut/ABL1·100 \> 0.1) or MRD reappearance after molecular response. All cases of molecular failure must be confirmed with a second MRD assessment in 2 to 4 weeks.
⁃ In patients with core-binding factor AML, qRT-BCR of RUNX1-RUNX1T1 and CBFb-MYH11 transcripts will be used. Patients failing to achieve a major MRD reduction after consolidation therapy (i.e., RUNX1-RUNX1T1/ABL1·100\>0.1 or CBFb-MYH11/ABL1·100\>0.1), a log increase in MRD between two positive samples or confirmed MRD reappearance after molecular response will be considered as molecular failures and could be included in the trial.
⁃ In the remaining cases, an appropriate leukemia-associated immunophenotype (LAIP) measured by multiparameter flow cytometry will be used for MRD surveillance. A cutoff of 0.1% will be used to define MRD positivity.
• Age ≥18 years.
• Without clinical signs of active central nervous system disease.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤2 or Karnofsky performance status (KPS) equivalent.
• Patients must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.
• Patients must have adequate liver function as demonstrated by:
‣ aspartate aminotransferase (AST) ≤ 3.0 × upper limit normal (ULN)
⁃ alanine aminotransferase (ALT) ≤ 3.0 × ULN
⁃ bilirubin ≤ 1.5 × ULN, unless due to Gilbert\'s syndrome
• Non-sterile male patients must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 3 months after the last dose of study drug. Male patients must agree to refrain from sperm donation from initial study drug administration until 3 months after the last dose of study drug.
• WOCBP must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting therapy; 2) throughout the entire duration of treatment; 3) during dose interruptions; and 4) for at least 6 months after discontinuation of therapy (last dose of study drug).
• Patients must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed screening procedures.