Venetoclax in Combination with Intensive Chemotherapy in Treating Patients with Acute Myelogenous Leukemia

Inclusion Criteria

• Patients with AML who are newly diagnosed according to the World Health Organization (WHO) 2016 classification and previously untreated with the exception of hydroxyurea. All-trans retinoic acid (ATRA) pretreatment for suspected acute promyelocytic leukemia (APL) for less than 5 days is allowed. Eligible patients with AML arising from an antecedent hematologic disease (AHD) including myelodysplastic syndrome (MDS), may have been treated for their prior hematologic disease (except for allogenic transplant).
• AML patients include de-novo AML, AML evolving from MDS or other AHD and AML after previous cytotoxic therapy or radiation (secondary AML). * For a diagnosis of AML, a bone marrow or peripheral blast count of 20% or more is required. * In AML with monocytic or myelomonocytic differentiation, monoblasts and promonocytes, but not abnormal mature monocytes, are counted as blast equivalents.
• Patients must be >= 18 and =< 60 years old
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Left ventricular ejection fraction (LVEF) >= 45% by multigated acquisition scan (MUGA) or echocardiography (ECHO) at screening.
• Calculated creatinine clearance >= 50 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.
• Aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) * Unless considered due to leukemic organ involvement.
• Alanine aminotransferase (ALT) =< 2.5 x ULN * Unless considered due to leukemic organ involvement.
• Total bilirubin =< 1.5 x ULN * Unless considered due to leukemic organ involvement. * Note: Subjects with Gilbert's Syndrome may have a total bilirubin > 1.5 x ULN per discussion with the overall study principal investigator (PI).
• Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug.
• Females of childbearing potential (i.e., not postmenopausal for at least 1 year or not surgically sterile) must have negative results by a serum pregnancy test performed within 7 days of day 1.
• Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.
• Subjects will be re-registered and receive high dose cytarabine-based consolidation including venetoclax with the following: * An induction response (complete response [CR]/complete response with incomplete bone marrow recovery [CRi] and including absolute neutrophil count [ANC] > 1000 and platelets [PLT] > 75000) for whom documented path report is submitted * Sufficiently fit (performance status < 3) * Starting at 1 dose level lower of venetoclax (thus starting at 200 mg /day [d]) than the induction MTD
• Consolidation should occur between 1-4 weeks following count recovery after induction and remission (must be confirmed by labs to document maximal response) is established. Count recovery is defined as ANC > 1000 and PLT > 75000. As of February 2024, phase 2 consolidation MTD has been established to be 400 mg. Phase 3: Expansion has been established to be 400mg (Induction) and 400mg (Consolidation). * Marrow Morphologic CR * ANC > 1000 * Plts > 75k * Investigator feels the patient is able to tolerate consolidation therapy

Exclusion Criteria

• Subject has acute promyelocytic leukemia, inversion16, t(8;21) or FLT3 mutant AML as described below; Contact PI with questions. * Inversion 16 and t(8;21): core binding factor (CBF) chromosomal abnormalities may be assessed by molecular (polymerase chain reaction [PCR]), metaphase cytogenetics, or fluorescence in situ hybridization (FISH). * FLT3: internal tandem duplication (ITD) or a point mutation in the TKD loop of variant allele fractions >= 5% by PCR, capillary electrophoresis, or next generation sequencing (NGS) panel capable of defining FLT3 allelic burden.
• Subject has known active central nervous system (CNS) involvement with AML.
• Subject has tested positive for human immunodeficiency virus (HIV) (due to potential drug-drug interactions between antiretroviral medications and venetoclax, as well as anticipated venetoclax mechanism-based lymphopenia that may potentially increase the risk of opportunistic infections). * Note: HIV testing is not required.
• Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required). Subjects with serologic evidence of prior vaccination to hepatitis B virus (HBV) [i.e., hepatitis B virus surface antigen negative (HBs Ag-), and anti-HBs+] are allowed.
• Subject has received the following within 7 days prior to the initiation of study treatment: * Strong or moderate CYP3A inducers. * Strong and moderate CYP3A inhibitors.
• Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit within 3 days prior to the initiation of study treatment.
• Subject has a cardiovascular disability status of New York Heart Association class >= 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
• Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
• Subject has chronic respiratory disease that requires continuous oxygen use.
• Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
• Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to uncontrolled systemic infection.
• Subject has a history of other malignancies prior to study entry, with the exception of: * Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; * Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; * Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. * Prior malignancies treated with (surgery+/- chemotherapy+/- radiation) that have remained disease free for at least two years after completion of therapy.
• Subject has a white blood cell count > 25 × 10^9/L. * Note: Hydroxyurea is permitted to meet this criterion.
• Subject treated with any form of chemotherapy, immunotherapy, or investigative agent within 1 month of enrollment.