This phase II MyeloMATCH treatment trial compares cytarabine with daunorubicin versus cytarabine with daunorubicin and venetoclax versus venetoclax with azacitidine for the treatment of younger patients with intermediate risk acute myeloid leukemia (AML). Cytarabine is a drug that inhibits some of the enzymes needed for deoxyribonucleic acid (DNA) replication and repair and can slow or stop the growth of cancer cells. Daunorubicin is a drug that blocks a certain enzyme needed for cell division and DNA repair, and it may kill cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Azacitidine is a drug that interacts with DNA to activate tumor-suppressing genes, resulting in an anti-tumor effect. Adding venetoclax to cytarabine and daunorubicin, and adding venetoclax to azacitidine, may work better than the usual treatment of cytarabine with daunorubicin alone. To decide if they are better, the study doctors are looking to see if venetoclax increases the rate of elimination of AML in participants by 20% or more compared to the usual approach.
Participants must have been registered to master screening and re-assessment protocol (MYELOMATCH) prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox Protocol Assignment Team, prior to registration to this study. Participants must have agreed to have specimens submitted for translational medicine and must be offered the opportunity to submit biosamples for banking for future research as per MYELOMATCH
Note: Pre-enrollment/diagnosis labs must have already been performed under MYELOMATCH
Favorable cytogenetics: (t(8;21)q22;q22.1); RUNX1-RUNX1T1, inversion 16(p13.1;q22), t(16;16)(p13.1;q22); CBFB-MYH11
CEBPA biallelic mutations
Prior therapy for AML except for hydroxyurea and leukapheresis to control blood counts. The use of all-trans retinoic acid (ATRA) is permitted until a diagnosis of acute promyelocytic leukemia, if suspected, is ruled out
Patients who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to cytarabine, daunorubicin, azacitidine, venetoclax
Pregnant women are excluded from this study because venetoclax, cytarabine and azacitidine have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with venetoclax, cytarabine and azacitidine breastfeeding should be discontinued if the mother is treated with venetoclax, cytarabine and azacitidine. These potential risks may also apply to other agents used in this study
Parallel
Azacitidine
DrugGiven IV or SC
Biospecimen Collection
Procedure/SurgeryUndergo collection of blood samples
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Cytarabine
DrugGiven IV
Daunorubicin Hydrochloride
DrugGiven IV
Echocardiography Test
Procedure/SurgeryUndergo ECHO
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Venetoclax
DrugGiven PO
Measurable residual disease (MRD) undetectable complete remission (CR)
Will assess after one induction cycle with or without the addition of venetoclax or two cycles of venetoclax and azacitidine. MRD by flow cytometry will be considered undetectable if ≤ 10\^-3. The MRD negative CR will be assessed using European LeukemiaNet (ELN) 2017 criteria \[Döhner 2017\]. The analysis population for the primary outcome will be all randomized patients with the intent to treat population. The MRD undetectable CR rate will be the number of patients with MRD undetectable CR divided by the total number of patients. The differences of MRD undetectable CR rates between the experimental groups and the control group will be estimated and the corresponding one-sided 90% confidence limit will be calculated using Normal distribution approximation. MRD non-evaluable patients will be considered as MRD positive.
Frequency and severity of toxicities with each of the regimens
All patients who have received at least one dose of study treatment will be included in the safety analysis. Adverse events will be graded using the Common Terminology Criteria for Adverse Events version 5.0. The incidence of adverse events will be summarized by type severity and relationship to the study drugs. A Fisher's exact test will be used to compare toxicities between the two arms, if needed.
CR rates
Will be assessed per 2017 ELN guidelines and will be tabulated. Exact 95% confidence intervals will be calculated.
Complete remission with incomplete count recovery (CRi)
Will be assessed with and without MRD. Will be assessed per 2017 ELN guidelines and will be tabulated. Exact 95% confidence intervals will be calculated.
Event-free survival
Patients not known to have any of these events are censored on the date of last contact. Will be described by the Kaplan-Meier estimate. The stratified log-rank test using the stratification factor at randomization will be used to test the difference between each experimental arms to the control arms.
Comparative analysis by molecular characteristics
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