Inclusion Criteria:
* Patients have an established, pathologically confirmed diagnosis of newly diagnosed secondary acute myeloid leukemia (sAML) as defined by the 2016 World Health Organization criteria. Secondary AML includes:
* AML arising after an antecedent hematologic neoplasm including aplastic anemia (AA), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and overlap syndromes (MDS/MPN)
* AML with MDS defining cytogenetic changes as defined in Vardiman et al. Blood 2009 114 (5): 937-951 - Table 6. Please see appendix 14.6 for full table.
* Therapy-related AML
* Patients must not have received prior treatment for the diagnosis of secondary acute myeloid leukemia, with the exception of hydroxyurea and/or leukopheresis which are permitted until day 1 of study participation. Prior treatment for a diagnosis of MDS, MPN, or MDS/MPN overlap syndrome is allowed.
* Patients ≥ 18 years of age.
* ECOG PS ≤ 2
* Patient has ability to understand and the willingness to sign a written informed consent.
* Adequate organ function as defined by:
* serum creatinine level ≤ 2.0 mg/dL or a CrCl ≥ 30 ml/min (Cockcroft-Gault equation using actual body weight)
* alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 3 times the institutional upper limit of normal (ULN) unless considered due to leukemic involvement
* total bilirubin level ≤1.5 times the institutional upper limits of normal (ULN) (unless secondary to Gilbert syndrome, hemolysis, or suspected leukemic involvement).
* Patients must be non-fertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate during and for at least 6 months after completion of study therapy.
* Patients must be able to comply with the requirements for the entire duration of the study.
Exclusion Criteria:
* Diagnosed with acute promyelocytic leukemia (acute leukemia with recurrent genetic abnormalities - APL with t(15;17)(q22;q12);PML-RARA).
* Diagnosed with myeloid blast phase of chronic myeloid leukemia.
* Diagnosed with isolated extramedullary AML
* Diagnosed with acute leukemia of ambiguous lineage, acute biphenotypic or acute bilineal acute leukemia per the 2016 World Health Organization classification system.
* Patients with a white blood cell count (WBC) \>50,000 at the time of initiation of therapy will be excluded. Patients can consent and screen with a WBC \> 50,000 but will require cytoreduction (hydrea or leukopheresis) prior to day 1 of therapy.
* Receiving antileukemic therapy other than hydroxyurea. Patients may have received therapy with a hypomethylating agent (azacitidine or decitabine) for a prior diagnosis of myelodysplastic syndrome (MDS) or chemotherapy for a prior diagnosis of a myeloproliferative neoplasm or an MDS/MPN overlap syndrome. Likewise, patients may have received chemotherapy for a prior non-leukemic oncologic malignancy.
* Any prior therapy with a Bcl-2 antagonist.
* Any known allergy to the chemotherapeutic agents being investigated including fludarabine,cladribine, cytarabine, G-CSF and venetoclax.
* Clinical signs of active leptomeningeal leukemia or biopsy proven active leptomeingeal leukemia. A clinical history of previously treated leptomeningeal process is not exclusionary.
* Patients with known history of HIV, Hepatitis B, or Hepatitis C with the exception of those with an undetectable viral load within 3 months of screening. (Hepatitis B or C testing is not required). Subjects with serologic evidence of prior vaccination to HBV \[i.e., HBs Ag-, and anti-HBs+\] may participate.
* Having an active second malignancy requiring treatment--other than AML--within 3 months prior to the start of treatment, with the exception of basal cell carcinoma or squamous cell carcinoma of the skin, colon polyp, carcinoma in situ of the cervix, or DCIS/LCIS of the breast.
* Having an active uncontrolled infection (viral, bacterial or fungal), any other concurrent disease, or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator.
* Pregnant women or women who are breastfeeding. Women must be willing to not breast feed up until 30 days following the end of trial therapy.
* Men or women of childbearing potential must be willing to practice an effective method of birth control during treatment and up until 6 months following the end of trial therapy.
* Having received any live vaccines within 28 days prior to first study drug administration.
* Patient has received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
* Patient has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment.
* Patient has a cardiovascular disability status of New York Heart Association Class \> 2.
* Patient has a chronic respiratory disease that requires continuous supplemental oxygen.
* Patient has a malabsorption syndrome or other condition that precludes enteral route of administration of medications.
* Female subject that has positive results for a screening pregnancy test.
* Women of childbearing potential are defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception defined as:
* Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
* Female sterilization (surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.
* Male sterilization (at least six months prior to enrolling). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
* Use of a combination of any two of the following:
* Use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate \< 1%), for example hormonal vaginal ring or transdermal hormone contraception.
* Placement of an intrauterine device (IUD) or intrauterine system (IUS).
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/vaginal suppository.
* Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to enrolling. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of childbearing potential.
* If a study patient becomes pregnant or suspects being pregnant during the study or within 30 days after the final dose of trial therapy, the Study Doctor needs to be informed immediately.
* Malabsorption syndrome or other condition that would interfere with enteral absorption or an inability to take oral medications as prescribed.
