Cord Blood Transplant, Cyclophosphamide, Fludarabine, and Total-Body Irradiation in Treating Patients With High-Risk Hematologic Diseases

Inclusion Criteria:

• Patients aged 6 months to =< 65 years at time of consent.

• Acute myelogenous leukemia (AML):

• Complete first remission (CR1), complete second remission (CR2) or greater (CR2+), must have < 5% marrow blasts at the time of transplant.

• Patients in morphologic remission with persistent cytogenetic, flow cytometric,or molecular aberrations are eligible.

• Acute lymphoblastic leukemia (ALL):

• Complete first remission (CR1) at high risk for relapse such as any of thefollowing:

• Presence of any high-risk cytogenetic abnormalities such as t(9;22),t(1;19), t(4;11) or other MLL rearrangements (11q23) or other high-riskmolecular abnormality.

• Failure to achieve MRD- complete remission after induction therapy.

• Persistence or recurrence of minimal residual disease on therapy.

• Any patient unable to tolerate consolidation and/or maintenancechemotherapy as would have been deemed appropriate by the treatingphysician.

• Other high-risk features not defined above.

• Complete second remission (CR2) or greater (CR2+).

• Note: ALL with less than 5% blasts at time of transplant but persistentcytogenetic, flow cytometric or molecular aberrations are eligible.

• Other acute leukemias: Acute leukemias of ambiguous lineage or mixed phenotype withless than 5% blasts. Leukemias in morphologic remission with persistent cytogenetic,flow cytometric or molecular aberrations are eligible.

• Chronic Myeloid Leukemia (CML): Excluding refractory blast crisis. To be eligible infirst chronic phase (CP1) patient must have failed or be intolerant to tyrosinekinase inhibitor therapy.

• Myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD) other thanmyelofibrosis:

• MDS/MPD overlap syndromes without myelofibrosis.

• MDS/ MPD patients must have less than 10% bone marrow myeloblasts and absoluteneutrophil count (ANC) > 0.2 (growth factor supported if necessary) attransplant work-up.

• Non-Hodgkin lymphoma (NHL) at high-risk of relapse or progression if not inremission:

• Eligible patients with aggressive histology (such as, but not limited to,diffuse large B-cell NHL, mantle cell NHL, and T-cell histology) in CR byPET/CT imaging.

• Eligible patients with indolent B-cell NHL (such as, but not limited to,follicular, small cell or marginal zone NHL) will have 2nd or subsequentprogression with PR or CR by PET/CT imaging.

• Blastic plasmacytoid dendritic cell neoplasm (BPDCN) in morphologic remission.

• Only for adult patients, to prevent graft rejection, patients who received onlynon-lymphodepleting agents for their malignancy (hypomethylating agents, venetoclax,hydroxyurea, TKIs etc.), or patients who received lymphodepleting chemotherapy > 3months prior to scheduled admission, may receive fludarabine 25 mg/m^2 daily x 3days for lymphodepletion 14-42 days (aiming for 2-4 weeks) at the discretion of theprincipal investigator (PI).

• For patients > 18 years old, Karnofsky score ≥ 70%. For patients =< 18 years old,Lansky score ≥ 50%.

• Calculated creatinine clearance > 70 ml/min.

• Bilirubin < 1.5 mg/dL (unless benign congenital hyperbilirubinemia or hemolysis).

• Alanine transaminase (ALT) < 3 x upper limit of normal (ULN).

• For patients > 18 years old, pulmonary function (spirometry and corrected diffusingcapacity for carbon monoxide [DLCO]) > 60% predicted. For patients =< 18 years old,or any patient unable to perform pulmonary function tests, O2 saturation > 92% onroom air.

• Left ventricular ejection fraction > 50%.

• Albumin > 3.0 g/dL.

• For patients > 18 years old, Hematopoietic Cell Transplantation Comorbidity index (HCT-CI) =< 5.

• UCB units will be selected according to current umbilical cord blood graft selectionalgorithm. One or two UCB units may be used to achieve the required cell dose.

• The UCB graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient. This mayinclude 0-2 antigen mismatches at the A or B or DRB1 loci. Unit selection based oncryopreserved nucleated cell dose and HLA-A, B, DRB1 using intermediate resolutionA, B antigen and DRB1 allele typing.

Exclusion Criteria:

• Diagnosis of myelofibrosis or other malignancy with moderate-severe bone marrowfibrosis.

• Patients persistent with central nervous system (CNS) involvement in cerebrospinalfluid (CSF) or CNS imaging at time of screening0

• Prior checkpoint inhibitors/ blockade in the last 12 months.

• Two prior stem cell transplants of any kind.

• One prior autologous stem cell transplant within the preceding 12 months.

• Prior allogeneic transplantation.

• Prior involved field radiation therapy that would preclude safe delivery of 400cGytotal body irradiation (TBI) in the opinion of radiation oncology.

• Active and uncontrolled infection at time of transplantation.

• HIV infection.

• Inadequate performance status/ organ function.

• Pregnancy or breast feeding.

• Patient or guardian unable to give informed consent or unable to comply with thetreatment protocol including appropriate supportive care, long-term follow-up, andresearch tests.