Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative

  • Assent, when appropriate, will be obtained per institutional guidelines
• ≥ 70 years. Note: Patients ≥ 18 years and < 70 years with active, relapsed or refractory, or high-risk acute leukemia or MDS as defined below.
• Karnofsky performance status ≥ 70

• Eligible patients will have a histopathological confirmed diagnosis of hematologic malignancy in one of the following categories :

  • Acute myelogenous leukemia:

    • Patients with de novo or secondary disease in unfavorable risk group including poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for AML i.e., monosomal karyotype, -5,5q-,-7,7q-,11q23-non t(9;11), inv (3), t(3;3), t(6;9), t(9;22) and complex karyotypes (≥ 3 unrelated abnormalities), or all patient in intermediate risk groups accept patients with FLT3-NPM1+ disease, OR
    • Patients with a complete morphological remission (CR) with minimal residual disease (MRD)-positive status by flow cytometry (≥ 0.1% by flow cytometry) or cytogenetic after at least 2 prior induction therapies, OR
    • Patients with chemosensitive active disease defined as at least 50% reduction in their blast count after last treatment
  • Myelodysplastic syndrome in high-intermediate (int-2) and high-risk categories per Revised International Prognostic Scoring System- (IPSS-R)
  • Acute lymphocytic leukemia

• Evidence of CD38 expression by flow cytometry AND one of the below

  • Patients with de novo or secondary disease according to NCCN guidelines for ALL hypoploidy (< 44 chromosomes); t(v;11q23): MLL rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (≥ 30,000 for B lineage or ≥ 50,000 for T lineage); iAMP21loss of 13q, and abnormal 17p, OR
  • Patients with a complete response (CR) with MRD-positive status by flow cytometry (≥ 0.1% by flow cytometry) or cytogenetics after at least 2 prior induction therapies, OR
  • Patients with chemosensitive active disease defined as at least 25% reduction in their blast count after last treatment
  • Patients with myelofibrosis (primary or secondary, including post-polycythemia vera and post-essential thrombocythemia myelofibrosis) may be eligible for enrollment if they meet criteria for high-risk disease and are planned for allogeneic hematopoietic cell transplantation.

• Eligible patients include those with:

  • Accelerated-phase or blast-phase myelofibrosis, defined as 10% to 19% blasts or ≥20% blasts, respectively, in peripheral blood or bone marrow
  • High-risk chronic-phase primary or secondary myelofibrosis, defined as disease meeting transplant-appropriate risk criteria by a validated MF prognostic model, including DIPSS intermediate-2 or high-risk; DIPSS-plus intermediate-2 or high-risk; MIPSS70 intermediate, high, or very high-risk; MIPSS70-plus or MIPSS70-plus version 2.0 intermediate, high, or very high-risk; GIPSS intermediate-2 or high-risk; or MYSEC-PM intermediate-2 or high-risk for post-polycythemia vera or post-essential thrombocythemia myelofibrosis. Patients may also qualify based on adverse clinical, cytogenetic, or molecular features supporting high-risk disease biology and transplant candidacy, including complex karyotype, monosomal karyotype, very high-risk karyotype, high molecular risk mutations, transfusion-dependent anemia, thrombocytopenia, circulating blasts, constitutional symptoms, or symptomatic splenomegaly despite standard therapy
  • Suboptimal response, progression, or intolerance to prior JAK inhibitor therapy, defined as failure to achieve adequate spleen or symptom response after an appropriate trial of therapy, generally at least 12 weeks at an appropriate or maximally tolerated dose when clinically feasible; loss of prior spleen or symptom response; worsening splenomegaly; persistent or worsening constitutional symptoms attributable to MF; worsening cytopenias or transfusion dependence; progression to accelerated-phase or blast-phase disease; emergence of adverse cytogenetic or molecular features; or inability to continue JAK inhibitor therapy due to treatment-related toxicity. A minimum duration of JAK inhibitor exposure is not required when the treating investigator determines that continued therapy is not clinically appropriate due to rapidly progressive disease, accelerated-phase or blast-phase transformation, clinically significant cytopenias, intolerance, or urgent need to proceed to allogeneic HCT. The rationale for early determination of JAK inhibitor failure or inability to continue JAK inhibitor therapy will be documented in the medical record.

  • Persistent disease burden, including persistent splenomegaly, circulating or marrow blasts, transfusion dependence, cytopenias attributable to MF, leukocytosis, thrombocytopenia, adverse cytogenetic or molecular features, extramedullary hematopoiesis, or progression despite standard therapy, may support high-risk classification but does not constitute a separate eligibility criterion unless the patient also meets the defined advanced-phase, validated risk-model, or JAK inhibitor failure criteria above.

    **See Appendix F: Defined Risk Scoring Systems in MF

  • All patients must demonstrate CD38 expression on disease-relevant cell populations (bone marrow and/or peripheral blood) as assessed by flow cytometry or an equivalent validated assay prior to enrollment.

Clinical Laboratory and Organ Function Criteria (To be performed within 30 days prior to Day 1 of protocol therapy unless otherwise stated) or (acceptable windows for tests are indicated in the Study Calendar Section 10.0).

• A pretreatment measured creatinine clearance (absolute value) of ≥ 60 ml/minute (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Patients must have a serum bilirubin ≤ 2.0 mg/dl (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Patients must have a serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 times the institutional upper limits of normal (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Patients must have a serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 times the institutional upper limits of normal (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Ejection fraction measured by echocardiogram or multigated acquisition scan (MUGA) ≥ 50% (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Diffusion capacity of the lung for carbon monoxide (DLCO) > 50% predicted (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)
• Forced expiratory volume in 1 second (FEV1) > 50% predicted (To be performed within 30 days prior to day 1 of protocol therapy unless otherwise stated)

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
• DONOR SPECIFIC CRITERIA: All candidates for this study must have an human leukocyte antigen (HLA) (A, B, C, and DR) identical sibling who is willing to donate mobilized peripheral blood stem cells (preferred) or bone marrow, or have a 10/10 (A, B, C, DR and DQ) allele matched unrelated donor. DQ or DP mismatch is allowed per discretion of the principal investigator. City of Hope (COH) standards of practice (SOP) (B.001.11) will be used for allogeneic donor evaluation, selection, and consent. Donor screening will be in compliance with all requirements of Food and Drug Administration (FDA) regulation 21 CFR Part 1271 including donor screening for COVID-19 exposure or infection

Exclusion Criteria:

• Patients who had a prior allogeneic transplant
• Patients who have had prior radiotherapy
• Patients who have received prior radiopharmaceutical therapy
• Receiving any other investigational agents or concurrent biological, intensive chemotherapy or radiation therapy for the previous 2 weeks from conditioning
• Patients should have discontinued all previous intensive therapy, chemotherapy, or radiotherapy for 2 weeks prior to commencing therapy on this study. Note: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted. These include hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors (TKIs). FLT-3 inhibitors can also be given up to 3 days before conditioning regimen
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Patients with other active malignancies are ineligible for this study, other than non-melanoma skin cancers
• Patients should not have any uncontrolled illness including ongoing or active bacterial, viral or fungal infection
• The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the investigator (treating physician) would place the recipient at unacceptable risk
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)