αβT Cell/CD19+ B Cell Depletion for Alternative Donor Stem Cell Transplant for Children and Young Adults with Hematologic Malignancies

Inclusion Criteria

• Patients who will benefit from an allogenic stem cell transplant to treat underlying primary hematological malignancy as noted below and lacks a suitably available matched sibling donor
• Karnofsky Index or Lansky Performance Scale ≥ 60 % on pre-transplant evaluation. Karnofsky scores must be used for patients > 16 years of age and Lansky scores for patients ≤ 16 years of age
• Patient or legal guardian must give informed consent if patient is ≥ 18 years. Legal guardian must give informed consent (and patient must give assent if appropriate) if patient is < 18 years
• Adequate organ function as specified in our Institutional Standard of Care (within 4 weeks of initiation of preparative regimen). For patients receiving myeloablative conditioning (MAC) on this platform, they should meet organ function to tolerate MAC as per our Institutional standard of Care. Similar if patients are receiving reduced-intensity conditioning (RIC), they must meet the organ function criteria per our Institutional standard of Care
• High resolution HLA available
• Acute lymphoblastic leukemia (ALL) in complete remission (CR) ≥ 2 or high risk disease in CR1 marrow must be in morphologic remission (minimal residual disease positive [MRD+] acceptable) * The criteria for high-risk ALL in first CR are: ** MLL rearrangement with slow early response (defined as having M2 [5-25% blasts] or M3 [> 25% blasts on bone marrow examination on Day 14 of induction therapy]); or, ** Hypodiploidy (< 44 chromosomes or DNA index < 0.81); or, ** Induction failure (M3 on Day 29 or, M2/M3 or MRD ≥ 1% on Day 43) ** Persistent MRD of ≥ 0.01% at the end of consolidation
• Hodgkin’s lymphoma relapse post autologous stem cell transplant
• Non-Hodgkin lymphoma (NHL) in CR ≥ 2. Marrow in morphologic remission if applicable (e.g. Burkett’s leukemia/lymphoma)
• AML in CR1 if high risk by classification, MRD+ at the end of Induction I, or CR ≥ 2. Bone marrow may show CR (< 5% blasts) or, if chemotherapy refractory disease, < 25% morphologic blasts (M2 marrow). Both primary and secondary AML are eligible
• Chronic myeloid leukemia (CML) in chronic phase, accelerated phase, second chronic phase after blast crisis (active blast crisis will not be eligible). CML patients must have previously failed therapy with at least two tyrosine kinase inhibitors or are intolerant to tyrosine kinase inhibitors (TKI)
• Myelodysplastic syndrome: Patients with documented pre-leukemia (MDS) at any stage including refractory anemia (RA), refractory anemia with ringed sideroblasts, refractory anemia with excess blasts (RAEB), and RAEB in transformation will be eligible for inclusion
• For subjects having previously received CAR-T cells to treat primary disease, potential subjects must: * Be in remission but have reappearance of B-cell 30 days post- CAR T infusion OR * Be not in remission (CAR-T failure) at 30 days post-CAR T infusion OR * Be 60 days post-CAR T infusion if a) and b) are not applicable AND * Have resolved all CAR-T toxicities (except B-cell reappearance) AND * Meet other inclusion and restriction criteria defined in this list
• DONOR ELIGIBILITY:
• Age, size, and vascular access appropriate by Nationwide Children's Hospital (NCH) standard for peripheral blood stem cell (PBSC) collection
• The donor will be evaluated according to current NCH Institutional standard of Care and must meet all criteria
• The donor must be able and willing to undergo granulocyte colony-stimulating factor (G-CSF) mobilization ± plerixafor and stem cell apheresis
• HIV negative
• Not pregnant or lactating
• Must agree to donate PBSC
• Donor or legal guardian must give informed consent (and donor must give assent if appropriate)
• ALLOWED DONOR SOURCES: * Matched unrelated donors: HLA typing of at least 8 alleles is required. Donor must be matched at 8/8 alleles (HLA-A, -B, -C, -DRB1). Can be allele mismatched at DQ * Mismatched unrelated donor: 7/8 HLA allele or antigen mismatch (mismatch at any locus other than DQ i.e. A, B, C) * Haploidentical matched family members. Minimum match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1, -DQB1 alleles), but use of haploidentical donors with extra matches (e.g., 6, 7, or 8/10) encouraged * Recipient must not have high-level donor specific anti-HLA antibodies. High level donor specific antibodies may be defined as positive crossmatch test of any titer by solid phase assay. Recommended cut-off values are MFI > 1000 for donor specific antibody to HLA- A, -B, and DRB1 and MFI > 2000 for HLA-C, DQB1 and DPB1. Donor desensitization may be considered in circumstances when the patient has donor specific anti-HLA antibody (DSA) above the cut off values against the only available haploidentical donor. It is always recommended to choose donors whom the recipient does not have any DSA * Graft from umbilical cord blood, bone marrow and matched sibling donor (MSD) are not allowed as a source of stem cells. Patients with these donors available should use other approaches

Exclusion Criteria

• Patient does not have a suitable donor who is willing and able (meets donor criteria)
• Patient reports a history of allergic reactions to murine protein
• Pregnant or lactating females are ineligible as many of the medications used in this protocol could be harmful to unborn children and infants. Female patients of childbearing potential females ≥ 11 years of age or post- menarche and should have a negative pregnancy test
• Patients with HIV or uncontrolled fungal, bacterial or viral infections are excluded. Patients with history of fungal disease during induction therapy may proceed if they have a significant response to antifungal therapy with no or minimal evidence of disease remaining by CT evaluation. Viremia by polymerase chain reaction (PCR) analysis is not considered an active infection but may require immediate viral prophylaxis. Patients with possible fungal infections must have had at least 2 weeks of appropriate anti-fungal therapy and be asymptomatic
• Patients receiving umbilical cord blood and matched sibling donor transplants