The purpose of this study is to see if see if adding the specific combination of donors can result in acceptable levels of survival without evidence of disease.

Cord blood (CB) and haplo-identical grafts are valuable alternative graft sources for patients with hematologic malignancies in need of allogeneic transplantation who lack human leukocyte antigen (HLA)-matched adult donors. In Black, Asian, Hispanic populations, the chance of finding a HLA matched donor is 23%, 41%, and 46%, respectively. These graft sources allow for greater HLA difference between donor and recipient, and increase the availability of donors, and therefore transplant, to these populations. Comparative retrospective analyses demonstrate similar results when compared to haplo/cord transplants. In this variant of the standard haplo/cord transplant, investigators will utilize post-transplant cyclophosphamide aGVHD prophylaxis after infusion of the haplo-identical graft and then infuse the CB graft after completion of post-transplant cyclophosphamide. Our hypothesis is that the combination of these two graft sources in which the haplo-identical graft is unmanipulated and the CB graft is infused after post-transplant cyclophosphamide, will be safe and result in effective disease eradication as measured by progression free survival in high risk patients.

Inclusion Criteria:

• Participants with the following hematologic malignancies:

  • Acute myelogenous leukemia (AML): High-risk AML including:

    • Antecedent hematological disease (e.g., myelodysplasia (MDS))
    • Treatment-related
    • Complete Remission (CR1) with poor or intermediate-risk cytogenetics or molecular markers (e.g. Flt 3 mutation, 11q23, del 5, del 7, TP53 mutations, complex cytogenetics)
    • Participants must be in CR1, CR2, CR3 or CRi

  • Acute lymphoblastic leukemia (ALL)

    • High-risk CR1 including:

      • Poor-risk cytogenetics (e.g., t(9;22)or 11q23 rearrangements)
      • Presence of minimal disease by flow cytometry or PCR or Clonoseq after 2 or more cycles of chemotherapy
      • No CR within 4 weeks of initial treatment

    • Participants in CR2 or beyond

    • Participants must be in CR1, CR2, CR3, or CRi

  • Myelodysplastic syndromes (MDS), Intermediate, High or Very High Risk by the revised international prognostic scoring system (IPSS-R) or treatment related MDS

  • High-risk lymphoma

• Age > 18 years

• Participants without a suitable HLA-matched related or unrelated donor CASE9Z24 Page 17 Version dated 12.16.2025

• Participants with the following suitable grafts:

  • A 4-8/8 HLA high resolution matched cord blood unit with a cell dose of 1.0x105 CD34 cells/kg.
  • A haplo-identical donor with a goal cell dose of > 4.0x106 CD34cells/kg (minimum 2 x106 CD34 cells/kg)

• Concurrent Therapy for Extramedullary Leukemia or CNS Lymphoma: Concurrent therapy or prophylaxis for testicular leukemia, CNS leukemia including standard intrathecal chemotherapy and/or radiation therapy will be allowed as clinically indicated. Such treatment may continue until the planned course is completed. Participants must be in CNS remission at the time of protocol enrollment if there is a history of CNS involvement. Maintenance therapy after transplant is allowed.

• Participants must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Participants with inadequate Organ Function as defined by:

  • Creatinine clearance < 40ml/min (Cockcroft-Gault)
  • Bilirubin > 2X institutional upper limit of normal unless Gilbert syndrome
  • AST (SGOT) > 3X institutional upper limit of normal
  • ALT (SGPT) > 3X institutional upper limit of normal
  • Pulmonary function: DLCOc < 60%
  • Cardiac: left ventricular ejection fraction < 40%
  • ECOG <2

• Participants with uncontrolled inter-current illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Pregnant or breastfeeding women are excluded from this study because chemotherapy involved with RIC have the significant potential for teratogenic or abortifacient effects.

• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.

• Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.

• Prior autologous stem cell transplant or CAR-T within the preceding 6 months or prior allogeneic transplant.

All IPD that underlie results in publication

Compiled and analyzed participant data will be published upon study completion. Publisher may request Protocol and Statistical Analysis Plan.