Inclusion Criteria:
* Patients aged ≥ 18 years old.
* Patients with any of the following hematologic malignancies for which allo-HCT is indicated, including:
* Acute myeloid leukemia (AML) with intermediate or high-risk features in CR1.
* Relapsed AML in ≥ CR2.
* Acute leukemias of ambiguous lineage in ≥ CR1.
* Acute lymphoid leukemia (ALL) in CR1 with clinical, flow cytometric, or molecular features indicating a high risk for relapse, or ALL in ≥ CR2.
* CML meeting one of the following criteria:
* Failed response to or intolerant to BCR-ABL tyrosine kinase inhibitors (TKIs).
* CML with BCR-ABL mutation consistent with poor response to TKIs (e.g., T315I mutation)
* CML in accelerated phase or blast crisis with \<10% blasts after therapy, or in second chronic phase.
* Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or MDS/MPN overlap syndromes with least one of the following:
* Revised International Prognostic Scoring System risk score of intermediate or higher at the time of transplant evaluation.
* Life-threatening cytopenias.
* Karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia, including abnormalities of chromosome 7 or 3, mutations of TP53, or complex or monosomal karyotype.
* Therapy related disease or disease evolving from other malignant processes.
* Chronic myelomonocytic leukemia (CMML-1 or CMML-2).
* Severe aplastic anemia.
* Relapsed Hodgkin lymphoma meeting both of the following criteria:
* Responding to therapy prior to enrollment.
* Relapse after autologous HCT or are ineligible for autologous HCT.
* Relapsed non-Hodgkin lymphoma meeting both of the following criteria:
* Responding to therapy prior to enrollment.
* Relapse after prior autologous HCT or are ineligible for autologous HCT.
* High-risk multiple myeloma following autologous HCT or relapsed multiple myeloma following autologous HCT with chemosensitive disease.
* Adequate organ function is required, defined as follows:
* Serum bilirubin ≤ 2 mg/dL, unless benign congenital hyperbilirubinemia. Patients with hyperbilirubinemia related to paroxysmal nocturnal hemoglobinuria or other hemolytic disorders are eligible with PI approval.
* AST, ALT, and alkaline phosphatase \< 3 times the upper limit of normal unless thought to be disease-related.
* Creatinine clearance ≥ 50 ml/min (calculated by Cockcroft Gault)
* LVEF ≥ 45% by MUGA or resting echocardiogram.
* Pulmonary function (FEV1 and corrected DLCO) ≥ 50% predicted.
* Adequate performance status of ECOG ≤ 2.
* Each patient must be willing to participate as a research subject and must sign an informed consent form.
Exclusion Criteria:
* Patients with active extramedullary disease.
* Patients with active central nervous system malignancy.
* Active and/or uncontrolled infection at the time of allo-HCT.
* Patients who have undergone previous allo-HCT.
* Patients who have undergone previous autologous HCT within the last 6 months, with the exclusion of high-risk multiple myeloma patients.
* Patient seropositivity for HIV I/II and/or HTLV I/II.
* Females who are pregnant or breastfeeding.
* Patients unwilling to use contraception during the study period.
* Patient or guardian unable to give informed consent or unable to comply with the treatment protocol.
Donor Inclusion and Exclusion Criteria:
* Must be a 10/10 HLA genotypically matched related or unrelated donor at A, B, C, DRB1, and DQB1 loci, as tested by DNA analysis.
* Able to provide informed consent for the donation process per institutional standards.
* Meet standard criteria for donor collection as defined by the National Marrow Donor Program Guidelines.
