• Age 18 years and older.

• Patients must have a prior diagnosis of one of the following:

‣ (Note: Mutational and cytogenetic studies performed at sites other than Dana-Farber Cancer Institute or Brigham and Women's Hospital will require review of the outside cytogenetic and/or molecular pathology reports by the overall PI.)

• High-risk MDS, which is defined as one of the following subsets:

‣ IPSS Intermediate-2 or higher

⁃ Presence of a mutation in TP53

⁃ Prescence of mutation in the RAS pathway including NRAS, KRAS, PTPN11, CBL, NF1, RIT1, FLT3, and KIT

⁃ Therapy-related MDS

∙ High-risk AML, which is defined as one of the following subsets:

‣ AML with adverse risk disease according to ELN guidelines including one of the following features:

• a history of mutation in TP53, RUNX1, or ASXL1

∙ t(6;9)(p23;q34.1); DEK-NUP214

∙ t(v;11q23.3); KMT2A rearranged

∙ t(9;22)(q34.1;q11.2); BCR-ABL1

∙ inv(3)(q21.3q26.2) or t(3;3)(q21.3;26.2); GATA2,MECOM(EVI1)

∙ -5 or del(5q)

∙ -7

∙ -17/abn(17p)

∙ Complex karyotype

∙ Monosomal karyotype

∙ Wild-type NPM1 and FLT3-ITDhigh

⁃ Secondary AML, which is defined as a history of antecedent hematologic disorder (an MPN or MDS), a diagnosis of therapy-related myeloid neoplasm including t-MDS and t-AML, or AML with myelodysplasia-related changes, OR

⁃ Secondary-type AML, which is defined by the presence of a mutation in any of the following eight genes with high specificity for the presence of antecedent myelodysplastic syndrome including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2

⁃ Patients with AML with evidence of measurable residual disease by multiparameter flow cytometry (≥ 0.1%) despite morphologic remission on the pre-transplant/screening bone marrow biopsy. Review required by overall PI.

∙ High-risk chronic myelomonocytic leukemia (CMML) or MDS/MPN unclassifiable (MDS/MPN-U), which is defined by the presence of trisomy 8, chromosome 7 abnormalities or complex karyotype (3 or more abnormalities); or by the presence of a mutation in ASXL1

⁃ Measurable disease is not required for eligibility.

⁃ Patient is determined to be a suitable candidate for an allo-HCT using a reduced intensity conditioning (RIC) regimen using peripheral blood stem cell as stem cell source.

⁃ Patient must have a matched related or an 8/8 unrelated donor option for his/her allo-HCT.

⁃ Patient must have an ECOG performance status ≤ 2

⁃ There are no limitations or minimum on the amount of prior therapy for patient's advanced myeloid malignancy. Prior exposure to venetoclax is allowed.

⁃ Patient must have normal organ function as defined below:

• Total bilirubin ≤ 2.0 x institutional upper limit of normal (In patients with Gilbert's Syndrome, Total Bilirubin ≥ 2.0 is permitted.)

∙ AST(SGOT)/ALT(SGPT) ≤ 3 × institutional upper limit of normal

∙ Creatinine clearance ≥ 30 mL/min using Cockcroft Gault formula

⁃ The effects of venetoclax on the developing human fetus are unknown. For this reason, women of child-bearing potential and men 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of venetoclax administration. For women who are of child-bearing potential, they must have a negative serum beta-HCG (human chorionic gonadotropin) test to be eligible.

⁃ Ability to understand and the willingness to sign a written informed consent document