Umbilical Cord Blood Transplantation In Patients With Hematologic Malignancies Using A Myeloablative Preparative Regimen

In this study, participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT), who do not have a suitable human leukocyte antigen (HLA)-matched related/sibling donor (MSD), matched unrelated donor (MURD) or killer-immunoglobulin receptors (KIR) ligand mismatched haploidentical donor identified, will receive an umbilical cord blood transplantation (UCBT) using a myeloablative preparative regimen.

The preparative regimen includes fludarabine (75 mg/m2), fractionated total body irradiation (TBI) (10.0 Gy), and cyclophosphamide (120mg/kg) with mesna. Fludarabine will be given once a day at 25 mg/m2 for three days on day -10 to day -8, TBI will be given twice a day at 150 cGy for four days on day -7 to day -4, and cyclophosphamide will be given once a day for at 60mg/kg for two days on day -3 and day -2. Post-transplantation immunosuppression with cyclosporine and MMF will begin on day -3. Cord Blood infusion will occur on day 0 and G-CSF will start on day +1.

The primary objectives is to estimate the event-free survival (EFS) at one-year post-transplant for research participants with high-risk hematologic malignancies undergoing hematopoietic cell transplantation (HCT) using single unit umbilical cord blood (UCB).

Secondary objectives are:

* Describe the clinical outcome of patients undergoing a double unit UCBT.
* Estimate the incidence and severity of acute and chronic graft versus host disease (GVHD) of patients enrolled in the research arm.
* Estimate the incidence and time to neutrophil and platelet engraftment among patients enrolled in the research arm.
* Estimate the incidence of transplant related mortality (TRM) and transplant related morbidity in the first 100 days after transplantation among patients enrolled in the research

Exploratory Objectives are:

* Assess the relationship between pre-transplant minimal residual disease (MRD) with transplant outcomes.
* Record immune reconstitution parameters, including chimerism analysis, quantitative lymphocyte subsets, T cell receptor excision circle (TREC) and spectratyping. Immunophenotyping and functional assays of T, B and NK cells and lymphocytes will also be evaluated.
* Evaluate the determinants of engraftment.

Eligibility Criteria:
Inclusion Criteria:

* Age less than or equal to 21 years old.
* Has a partially HLA-matched single or double UCB product
* High-risk hematologic malignancy.
* High risk ALL in CR1, ALL in High risk CR2, ALL in CR3 or subsequent.
* AML in high risk CR1, AML in CR2 or subsequent
* AML in first relapse with \< 25% blasts in BM
* Therapy related AML, with prior malignancy in CR \> 12mo
* MDS, primary or secondary
* NK cell, biphenotypic, or undifferentiated leukemia in CR1 or subsequent.
* CML in accelerated phase, or in chronic phase with persistent molecular positivity or intolerance to tyrosine kinase inhibitor.
* Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous HCT, or unable to mobilize stem cells for autologous HCT.
* Non-Hodgkin lymphoma in CR2 or subsequent after failure of prior autologous HCT, or unable to mobilize stem cells for autologous HCT.
* JMML
* All patients with evidence of CNS leukemia must be treated and be in CNS CR to be eligible for study.

Patient must fulfill pre-transplant evaluation:

* Cardiac shortening fraction ≥ 26%.
* Creatinine clearance ≥ 70 ml/min/1.73m2.
* Forced vital capacity (FVC) ≥ 50% of predicted value or pulse oximetry ≥ 92% on room air.
* Karnofsky (≥ 16 years) or Lansky (\<16 years) performance score ≥ 70
* Bilirubin ≤ 2.5 mg/dL.
* Alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal for age.
* Aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age.

Exclusion Criteria:

* Patient has a suitable MSD, volunteer MURD, or KIR mismatched haploidentical donor available in the necessary time for stem cell donation.
* Patient has any other active malignancy other than the one for which HCT is indicated.
* Patient had a prior allogeneic HCT
* Patient had an autologous HCT within the previous 12 months.
* Patient is pregnant as confirmed by positive serum or urine pregnancy test within 14 days prior to enrollment.
* Patient is lactating
* Patient has Down Syndrome
* Patient has a current uncontrolled bacterial, fungal, or viral infection per the judgment of the PI.