Venetoclax Basket Trial for High Risk Hematologic Malignancies

Inclusion Criteria Cohort A Inclusion Criteria: * MDS, AML arising from MDS (MDS/AML), therapy related myeloid neoplasm (tMDS/AML) meeting at least one of the following criteria: * MDS with excess blasts (\>10%) * MDS with blasts \<10% with high-risk features * MDS refractory to initial treatment * Relapsed MDS * MDS/AML: May be newly diagnosed or relapsed/refractory disease. * Therapy related myeloid neoplasm (tMDS/AML): May be initial or relapsed/refractory disease. * Note: MDS or MDS/AML may be derived from a germline predisposition to myeloid malignancy as long as that condition does not confer increased toxicity to treatment. * Age ≤ 40 years of age, except the following subjects that must be \<18 years to enroll * Subjects with MDS/AML that have not received prior therapy * Subjects enrolled onto Dose level -2. * Lansky/Karnofsky performance status ≥ 50% * Participants must have fully recovered from the acute toxic effects of all and meet all of the following criteria: * Myelosuppressive chemotherapy: 14 days, or 5 half-lifes (whichever is shorter) must have elapsed since the completion of myelosuppressive therapy. Individuals may have received any of the following medications without a "wash-out" period * Standard maintenance therapy: dexamethasone/prednisone, vincristine, 6MP, low dose methotrexate) * Hydroxyurea * Intrathecal chemotherapy with methotrexate, hydrocortisone and/or cytarabine. * Radiation therapy (XRT): * Total Body Irradiation (TBI) or cranial radiation therapy: Must have been completed more than 90 days prior to study entry * XRT for chloroma does not require a washout period. * Palliative XRT does not require a washout * Small molecule inhibitors (BCR-ABL or FLT3 inhibitors, for example): 7 days, or 5 half-lifes, whichever is shorter) must have elapsed since the completion of therapy. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. * Immunotherapy: At least 30 days after the administration of any type of immunotherapy, including, but not limited to, tumor vaccines, chimeric antigen receptor (CAR) therapy, other immune effector cell therapy and checkpoint inhibitors. * Monoclonal antibodies: At least 3 half-lives of the antibody * Prior hematopoietic stem cell transplant (HSCT): * Allogeneic HSCT \> 90 days of study entry * No evidence of graft-versus-host-disease (GVHD) * Adequate organ function, as defined by * Serum alanine aminotransferase (ALT) ≤5X upper limit of normal (ULN) * Direct bilirubin ≤ 3X * Ejection fraction ≥ 50% or shortening fraction of ≥ 24% on screening echocardiogram. * Female participants of childbearing potential must have a negative urine or serum HCG prior to study entry and at the start of therapy. All females of childbearing potential must refrain from breastfeeding during study participation, and all male and females of childbearing potential must agree to use an effective form of contraception (abstinence, hormonal, or barrier) prior to study entry, for duration of participation, and for a minimum of 30 days following the last dose of treatment. Cohort B Inclusion Criteria * MDS, MDS/AML, therapy related myeloid neoplasm (tMDS/AML) that is derived from the following germline disorders: * Dyskeratosis Congenita or associated telomeropathies * Fanconi Anemia * Nijmegen Breakage * Other related disorders with high risk of toxicity may be eligible for this cohort after discussion with the Sponsor-Investigator. * And meets at least one the following disease characteristics: * MDS with excess blasts (\>10%) * MDS with blasts \<10% with high-risk features * MDS refractory to initial treatment * Relapsed MDS * MDS/AML: May be newly diagnosed or relapsed/refractory disease. * Therapy related myeloid neoplasm (tMDS/AML): May be initial or relapsed/refractory disease. * Age ≤ 40 years of age * Lansky/Karnofsky performance status ≥ 50% * Participants must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study and meet all of the following criteria: * Myelosuppressive chemotherapy: 14 days, or 5 half-lifes (which ever is shorter) must have elapsed since the completion of myelosuppressive therapy. Individuals may have received any of the following medications without a "wash-out" period * Standard maintenance therapy: dexamethasone/prednisone, vincristine, 6MP, low dose methotrexate * Hydroxyurea * Intrathecal chemotherapy with methotrexate, hydrocortisone and/or cytarabine. * Radiation therapy (XRT): * Total Body Irradiation (TBI) or cranial radiation therapy: Must have been completed more than 90 days prior to study entry * XRT for chloroma does not require a washout period. * Palliative XRT does not require a washout * Small molecule inhibitors (BCR-ABL or FLT3 inhibitors, for example): 7 days, or 5 half-lifes, whichever is shorter) must have elapsed since the completion of therapy. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. * Immunotherapy: At least 30 days after the administration of any type of immunotherapy, including, but not limited to, tumor vaccines, chimeric antigen receptor (CAR) therapy, other immune effector cell therapy and checkpoint inhibitors. * Monoclonal antibodies: At least 3 half-lives of the antibody * Prior hematopoietic stem cell transplant (HSCT): Must meet all of the following conditions: * Allogeneic HSCT \> 90 days of study entry * No evidence of graft-versus-host-disease (GVHD) * Adequate organ function, as defined by * Serum alanine aminotransferase (ALT) ≤5X upper limit of normal (ULN) * Direct bilirubin