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

• The clinical outcome of patients undergoing a double unit UCBT will be described by engraftment, relapse/death status [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  For patients enrolled in the observation arm their clinical outcomes such as engraftment, acute and chronic GVHD, relapse/death status, and transplant related mortality/morbidity will be described.
• The incidence and severity of acute and chronic GVHD of patients enrolled in the research arm will be estimated . [ Time Frame: 1 years ] [ Designated as safety issue: No ]
  The cumulative incidence of acute and chronic GVHD will be estimated using Gray's method and death is the competing risk event.
• Time to neutrophil and platelet engraftment as well as the incidence of engraftment among patients enrolled in the research arm will be estimated. method [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  A descriptive statistics for time to engraftment for patients that achieve neutrophil and platelet engraftment will be provided. The cumulative incidence of engraftment will be estimated .
• The incidence of TRM and transplant related morbidity in the first 100 days after transplantation among patients enrolled in the research arm will be estimated . [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  The cumulative incidence of TRM and transplant related morbidity will be estimated .TRM is death occurring in patients in continuous complete remission.

• The clinical outcome of patients undergoing a double unit UCBT will be described by engraftment, relapse/death status [ Time Frame: 19 years ] [ Designated as safety issue: No ]
  For patients enrolled in the observation arm their clinical outcomes such as engraftment, acute and chronic GVHD, relapse/death status, and transplant related mortality/morbidity will be described.
• The incidence and severity of acute and chronic GVHD of patients enrolled in the research arm will be estimated using Gary's method [ Time Frame: 19 years ] [ Designated as safety issue: No ]
  The cumulative incidence of acute and chronic GVHD will be estimated using Gray's method and death is the competing risk event.
• Time to neutrophil and platelet engraftment as well as the incidence of engraftment among patients enrolled in the research arm will be estimated by using gray's method [ Time Frame: 19 years ] [ Designated as safety issue: No ]
  A descriptive statistics for time to engraftment for patients that achieve neutrophil and platelet engraftment will be provided. The cumulative incidence of engraftment will be estimated using the Gray's method .
• The incidence of TRM and transplant related morbidity in the first 100 days after transplantation among patients enrolled in the research arm will be estimated by Gray's method [ Time Frame: 19 years ] [ Designated as safety issue: No ]
  The cumulative incidence of TRM and transplant related morbidity will be estimated using the same method. TRM is death occurring in patients in continuous complete remission.Death before day +100 and due to other reasons are the competing risk events when estimating the cumulative incidence of TRM and transplant related morbidity, respectively.

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)(13.2 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 165 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.
• Characterize the pharmacokinetics of mycophenolate mofetil (MMF).

• Hematologic Malignancies
• Disorder Related to Transplantation
• Hematopoietic Malignancy

• Research Arm

  Participant with high-risk hematologic malignancies undergoing Hematopoietic Cell Transplantation, who do not have a suitable Human Leukocyte Antigen -matched related/sibling donor, Matched Unrelated Donor or Killer immunoglobulin receptors ligand mismatched haploidentical donor identified, will receive a single UCB unit.

  Intervention: Preparative Regimen

  Intervention: Genetic: Preparative Regimen
• Observation Arm

  Patients requiring two UCB units will be eligible for UCBT01 on the observational arm.

  Intervention: Preparative Regimen

  Intervention: Genetic: Preparative Regimen

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.