Cord Blood Transplantation for the Treatment of Children and Young Adults with High Risk or Very High Risk Hematologic Malignancies

Inclusion Criteria

• COHORT 1 (HIGH RISK DISEASE): Patients with age ≤ 26 years at the time of informed consent with no available and suitably matched related or unrelated donor within 4 weeks, with one of the following diagnoses: * Acute myelogenous leukemia (AML): ** Complete first remission (CR1) with blast count < 5% by bone marrow morphology at high risk for relapse such as any of the following: *** Known prior diagnosis of myelodysplasia (MDS) *** High risk cytogenetics (e.g., those associated with MDS, abnormalities of 5, 7, 8, complex karyotype) and/or high-risk molecular abnormalities (e.g., TP53) *** Requirement for 2 or more inductions to achieve CR1 *** Therapy-related AML (t-AML) or therapy-related myeloid neoplasm (t-MN) (including after therapy for other malignancy, and/or gene therapy or cell therapy) *** Presence of Minimal/Measurable Residual Disease (MRD+) by cytogenetics, flow cytometry or molecular methods (at end of induction or end of consolidation) *** Other high-risk features not defined above. ** Complete second remission (CR2) or subsequent remission, with blast count < 5% by bone marrow morphology ** Presence of MRD by multiparameter flow cytometry at pre-transplant evaluation is acceptable. * Acute lymphoblastic leukemia (ALL): ** Complete first remission (CR1) with MRD negative status by multicolor flow cytometry, at high risk for relapse such as any of the following: *** Presence of any high risk cytogenetic abnormalities such as t(9;22), t(1;19), t(4;11) or other, KMT2A (11q23) or other high risk molecular abnormality *** Failure to achieve complete remission (CR) after four weeks of induction therapy (transplant to follow antibody therapy and/or chimeric antigen receptor (CAR) T cells) *** Persistence or recurrence of MRD on therapy (transplant to follow antibody therapy and/or CAR T cells) *** T-ALL in CR even with presence of MRD *** Other high-risk features not defined above ** Complete second remission (CR2) or subsequent remission with MRD negative status by multiparameter flow cytometry. *** Relapse in less than 36 months from CR1 *** Relapse for T-ALL ** Patients after antibody therapy (e.g., blinatumomab, inotuzumab, other) and/or CAR-T cell therapy that resulted in MRD negative status by multiparameter flow cytometry. * Other acute leukemias: ** Leukemias of ambiguous lineage or of other types with < 5% blasts by bone marrow morphology. ** Patients with persistent/relapsed disease with cytogenetic, flow cytometric or molecular aberrations in < 5% of cells. ** Chronic myelogenous leukemia: Patients with history of blast crisis or accelerated phase. ** Any leukemia that developed after gene therapy or cell therapy * Myelodysplastic Syndrome (MDS): ** Any International Prognostic Scoring System (IPSS) risk category with life-threatening cytopenia(s). ** Any IPSS risk category with high risk cytogenetic/molecular findings (5, 7, 8, complex karyotype, or TP53) * Non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) at high risk of relapse or progression if not in remission: ** Patients with aggressive histology (such as, but not limited to, diffuse large B-cell NHL, mantle cell NHL, and T-cell NHL) in CR. ** Patients with indolent B cell NHL (such as, but not limited to, follicular, small cell or marginal zone NHL) will have 2nd or subsequent progression with stable disease/ CR/ PR with no single lesion equal to or more than 5 cm. ** Patients with HL without progression of disease (POD) after salvage chemotherapy with no single lesion ≥ 5 cm
• COHORT 2 (VERY HIGH RISK DISEASE): * Patients in CR (bone marrow blasts < 5% by morphology) who had prior allogeneic transplant and disease recurrence. The second transplant will take place at least 4 months after the first. ** Acute myelogenous leukemia (AML) or Myelodysplastic Syndrome (MDS): Relapse after previous transplant, in CR after induction therapy. MRD positive status by multi-parameter flow cytometry is accepted. ** Acute lymphoblastic leukemia (ALL): Relapse after previous transplant, in CR after induction therapy and/or antibody therapy/CAR T cells. MRD positive status after targeted therapy, as evaluated by multi-parameter flow cytometry is accepted. ** Other: patients with leukemia or lymphoma, who, in the opinion of their physician, are not likely to have reduction in disease burden with further chemotherapy. * Patients with relapsed/refractory disease at either first or second allogeneic transplant, with up to 30% bone marrow blasts by multiparameter flow cytometry or morphology. ** Relapse after previous transplant with < 30% blasts by bone marrow morphology, or with cytogenetic, flow cytometric, or molecular abnormalities in < 30% of bone marrow cells, after induction therapy. ** Primary refractory or relapsed AML with < 30% blasts by bone marrow morphology or with cytogenetic, flow cytometric, or molecular abnormalities in < 30% of bone marrow cells
• Age 0-26 years at the time of informed consent
• Performance: Karnofsky (≥ 16 years) or Lansky score (< 16 years) of ≥ 70%
• Not pregnant and not nursing
• Bilirubin ≤ 1.5 mg/dL (unless benign congenital hyperbilirubinemia)
• Alanine aminotransferase (ALT) ≤ 3 x upper limit of normal
• Pulmonary function (forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1] and diffusion capacity of the lung for carbon monoxide [DLCO] corrected for hemoglobin) ≥ 50% predicted. * In young children unable to perform pulmonary function testing: pulse oximetry > 92% in room air, and a normal CT of the chest (if CT is not normal, the child needs to be evaluated and cleared by pediatric pulmonary physician)
• Left ventricular ejection fraction ≥ 50%
• Age-adjusted Hematopoietic Cell Transplantation-Comorbidity Index (aaHCT-CI) ≤ 7
• Female patients of childbearing potential must have a negative serum pregnancy test within 7 days of enrolment and must be willing to use an effective contraceptive method while enrolled in the study
• Serum creatinine (SCr) ≤ 1.5 x normal for age. If SCr is outside the normal range, then creatinine clearance (CrCl) > 50 mL/min (calculated or estimated) or estimated glomerular filtration rate (GFR) (mL/min/1.73m^2) >30% of predicted normal for age * 1 week: mean GFR plus or minus standard deviation: 40.6 +/- 14.8 * 2-8 weeks: mean GFR plus or minus standard deviation: 65.8 +/- 24.8 * > 8 weeks: mean GFR plus or minus standard deviation: 95.7 +/- 21.7 * 2-12 years: mean GFR plus or minus standard deviation: 133.0 +/- 27.0 * 13-21 years (males): mean GFR plus or minus standard deviation: 140.0 +/- 30.0 * 13-21 (females): mean GFR plus or minus standard deviation: 126.0 +/- 22.0

Exclusion Criteria

• Inadequate performance status/ organ function
• Active central nervous system (CNS) leukemic involvement
• Chloroma >2 cm
• Active and uncontrolled infection (bacterial/fungal/viral) at time of transplant
• HIV infection
• Seropositivity for human T-lymphotropic virus (HTLV)-1
• Pregnancy or breast feeding
• Patient or guardian unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, long-term follow up, and research tests
• Any abnormal condition or lab result that is considered by the principal investigator (PI) capable or altering patient’s condition or study outcome
• COHORT 2 (VERY HIGH RISK DISEASE): Allogeneic hematopoietic stem cell transplantation (HCT) in the preceding 4 months
• Prior checkpoint inhibitors/blockade in the last 12 months: eligibility to be discussed with study PI
• For patients with known hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection: * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load