Combination Navitoclax, Venetoclax and Decitabine for Advanced Myeloid Neoplasms

Inclusion Criteria: * 18 years or older * Subjects must have a diagnosis of one of the following: * Myelofibrosis in accelerated phase (AP-MF), defined by WHO as 10-19% blasts in either bone marrow or blood. There is no requirement for prior therapy. * Myelofibrosis in blast phase (BP-MF), defined as ≥ 20% blasts in either bone marrow or blood. There is no requirement for prior therapy. * Untreated secondary AML (s-AML), which includes subjects with therapy-related disease or known antecedent MDS or MDS/MPN. All these subjects must be ineligible or not recommended for any available approved therapy as determined by the treating provider. For subjects with known antecedent MDS or MDS/MPN, they must have received prior HMA therapy (minimum number of cycles are not required in this setting). * MDS/MPN overlap syndromes (e.g. CMML) with ≥ 5% blasts in either bone marrow or blood. No requirements for prior therapy. * MDS with excess blasts defined as ≥ 5% blasts in either bone marrow or blood must be ineligible for any available approved therapy including intensive chemotherapy and immediate allogeneic stem cell transplant per treating investigator and must meet at least one of the following criteria: 1) persistent disease despite prior exposure to venetoclax plus HMA for at least 3 cycles, 2) disease progression per IWG 2006 criteria on venetoclax plus HMA or on M15-954 protocol, or 3) persistent disease after at least four cycles of any HMA-based therapy. * ECOG performance status ≤ 2 (see Appendix A) * Baseline platelet count ≥ 25 x 109/L * Subjects must have adequate organ function as defined below: * Aspartate transaminase (AST) and alanine transaminase (ALT) \< 3 x ULN * Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) * Subject must have adequate renal function as demonstrated by a creatinine clearance ≥ 45 mL/min; calculated by the Cockcroft Gault formula * aPTT ≤ 1.5 x ULN * INR ≤ 1.5 x ULN * Prior treatment-related toxicities must be grade 1 or baseline except for alopecia. * Moderate/strong inhibitors of CYP3A are allowed if they cannot be substituted; however, patients must be on these agents for at least 2-3 days prior to treatment start. (See section 5.5 for details on concomitant medications and dose adjustment.) * If female, subject must be either : * Postmenopausal (surgically sterile or age \> 55 years with no menses for 12 or more months without an alternative medical cause or age greater than or equal to 55 or less with no menses for 12 or more months without an alternative medical cause and an FSH level \> 40 IU/L); or * Of children bearing potential. These subjects must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Subject must agree to have a negative urine or serum beta-HCG test result during screening and repeated within 7 days prior to study drug (local labs are allowed) to be eligible. * Subject must voluntarily sign and date an informed consent * Subjects must be able to swallow pills Exclusion Criteria: * Subject cannot have had prior navitoclax or any BCL-XL therapy. Otherwise, there are no restrictions on any other prior therapies. Prior venetoclax is allowed. * Subject is eligible and willing to receive intensive chemotherapy for their specific disease. * Anti-leukemic therapy within 14 days of first day of study treatment except for hydroxyurea. If on hydroxyurea, then subject needs to be off hydroxyurea at least 3 days prior to first dose of study treatment. If on venetoclax, then a wash-out period of at least five times the half-life of the treatment. * Subject with known and active concurrent malignancy requiring treatment. Subjects with basal or squamous skin cancers or carcinomas in situ are allowed. Exception: hormonal or topical therapies are allowed. * Subject has known active/uncontrolled HIV and on contraindicated medication due to drug-drug CYP inducer interaction. HIV testing is not required. * Subject has known and active CNS involvement with AML. * Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: * Uncontrolled and/or active systemic infection (viral, bacterial or fungal). Controlled infections are allowed. * Chronic, active hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. Subjects that have prior HCV that has been definitively treated with negative HCV viral load prior to study initiation and no evidence of cirrhosis are allowed to participate. * Recent diagnosis of myocardial infarction or worse heart failure within the last six months. * Treatment with any moderate or strong CYP3A inducers (see Appendix D for examples) within 7 days prior to the first dose of study drug. * Administration or consumption of any of the following within 3 days prior to the first dose of study drug: * Grapefruit or grapefruit products * Seville oranges (including marmalade containing Seville oranges) * Star fruit * White blood cell count (WBC) greater than or equal to 25 x 109/L. Exception: Subjects with myelofibrosis or MDS/MPN overlap syndrome may enter study with WBC greater than or equal 25 x 109/L on the first day of therapy only if the absolute blast count is \< 5 x 109/L; hospitalization for subjects with this particular disease subset is required during dose ramp-up of venetoclax for TLS monitoring. This criterion is intended to exclude AML patients at high risk of TLS, but permit entry of patients with MF or CMML who frequently have leukocytosis without AML transformation who are at low risk for TLS. * Ongoing requirement for anticoagulation with the exception of low-dose anticoagulation medications used to maintain patency of a central venous catheter or for deep venous thrombosis prophylaxis. Antiplatelet agents such as aspirin and clopidogrel are not allowed if platelet count \< 50 x 109/L. * Known history of immune thrombocytopenia that previously required therapy. * Known history of platelet refractoriness and HLA alloimmunization prior to study start. * History of serious or life-threatening bleeding in last 12 months that has not been definitively treated. * Uncontrolled, systemic infection (viral, bacterial, or fungal). Antibiotic use is permitted. (See Section 5.5 for concomitant drugs) * Active and known SARS-CoV-2 infection. * If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, then the subject must undergo molecular (e.g. PCR) testing to rule out SARS-CoV-2 infection. * Subjects positive for active SARS-CoV-2 infection may re-screen after they meet either criteria A or B indicating SARS-CoV-2 infection has resolved with viral clearance: A) ≥14 days since first the PCR test result in an asymptomatic subject; OR B) ≥14 days since recovery, defined as resolution of fever without use of anti-pyretics and improvement in symptoms. * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the subject inappropriate for enrollment into this study. * Vaccination with live, attenuated vaccines ≤4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study. All other recommended vaccinations including COVID19 is permitted.