Single vs Double Umbilical Cord Blood Transplants in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)
Condition: Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Natural Killer Cell Lymphoblastic Leukemia/Lymphoma
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
Intervention: Single Umbilical Cord Blood Unit Transplant; Double Umbilical Cord Blood Unit Transplant; Total Body Irradiation; Cyclophosphamide; Fludarabine; Cyclosporine A; Mycophenolate Mofetil
Intervention description: Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF; Unrelated donor, double umbilical cord blood unit; Conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF; The TBI will be delivered from either a linear accelerator or cobalt source at a dose rate of between 4 and 26 cGy/minute using energies of between 1 and 25 MV.; Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush on Days -3 and -2.; Fludarabine 25 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days -10 through -8. Fludarabine will not be dose adjusted for body weight.; CSA will be administered beginning on Day -3 and doses will be adjusted to maintain a level of 200-400 ng/mL by TDX method (or 100-250 ng/mL by Tandem MS or equivalent level for other CSA testing methods). CSA can be administered per institutional practice.; MMF will be given at a dose of 1 gram IV q 8 hours if > 50 kg or 15 mg/kg IV q 8 hours if < 50 kg beginning the morning of Day -3.
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Cyclophosphamide; Fludarabine; Cyclosporins
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 224.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Double cord blood

Summary:

      This study is a Phase III, randomized, open-label, multi-center, prospective study of single
      umbilical cord blood (UCB) transplantation versus double UCB transplantation in pediatric
      patients with hematologic malignancies.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Two partially HLA-matched UCB units. Units must be HLA-matched minimally at 4 of 6
             HLA-A and B (at intermediate resolution by molecular typing) and DRB1 (at high
             resolution by molecular typing) loci with the patient, and the units must be
             HLA-matched at 3 of 6 HLA- A, B, DRB1 loci with each other (using same resolution of
             molecular typing as indicated above). Two appropriately HLA-matched units must be
             available such that one unit delivers a pre-cryopreserved nucleated cell dose of at
             least 2.5 x 10^7 per kilogram and the second unit at least 1.5 x 10^7 per kilogram.

          -  Acute myelogenous leukemia (AML) at the following stages:

               1. High risk first complete remission (CR1), defined as the following:

                    -  Having preceding myelodysplasia (MDS)

                    -  High risk cytogenetics (high risk cytogenetics: del (5q) -5, -7, abn (3q), t
                       (6;9) complex karyotype [at least 5 abnormalities],)the presence of a high
                       FLT3 ITD-AR (> 0.4)

                    -  Requiring more than 1 cycle of chemotherapy to obtain complete remission
                       (CR);

                    -  FAB M6

               2. Second or greater CR

               3. First relapse with less than 25% blasts in bone marrow

               4. Morphologic complete remission with incomplete blood count recovery

          -  Therapy-related AML for which prior malignancy has been in remission for at least 12
             months

          -  Acute lymphocytic leukemia (ALL) at the following stages:

               1. High risk first remission, defined as one of the following conditions:

                    -  Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)

                    -  Mixed lineage leukemia (MLL) rearrangement with slow early response (defined
                       as having M2 [5-25% blasts] or M3 [more than 25% blasts on bone marrow
                       examination on Day 14 of induction therapy])

                    -  Hypodiploidy (less than 44 chromosomes or DNA index less than 0.81)

                    -  End of induction M3 bone marrow

                    -  End of induction M2 with M2-3 at Day 42

                    -  Evidence of minimal residual disease (MRD). If a patient's only high risk
                       criterion is MRD, approval by a protocol chair or protocol officer is
                       required for enrollment. For COG centers, this will only be for MRD greater
                       than 1 percent by flow MRD at the end of extended induction.

               2. High risk second remission, defined as one of the following conditions:

                    -  Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)

                    -  Bone marrow relapse less than 36 months from induction

                    -  T-lineage relapse at any time

                    -  Very early isolated central nervous system (CNS) relapse (6 months from
                       diagnosis)

                    -  Slow reinduction (M2-3 at Day 28) after relapse at any time

                    -  Evidence of minimal residual disease (MRD). If a patient's only high risk
                       criterion is MRD, approval by a protocol chair or protocol officer is
                       required for enrollment. For COG centers, this will only be for MRD greater
                       than 1 percent by flow MRD at the end of extended induction.

               3. Any third or subsequent CR

          -  NK cell lymphoblastic leukemia in any CR

          -  Biphenotypic or undifferentiated leukemia in any CR or if in first relapse must have
             less than 25% blasts in bone marrow (BM)

          -  Myelodysplastic syndrome (MDS) at any stage

          -  Chronic myelogenous leukemia (CML) in chronic or accelerated phase

          -  All patients with evidence of CNS leukemia must be treated and be in CNS CR to be
             eligible for study.

          -  Patients 16 years old or older must have a Karnofsky score of at least 70% and
             patients younger than 16 years old must have a Lansky score of at least 70%.

          -  Patients with adequate physical function as measured by:

               1. Cardiac: Left ventricular ejection fraction greater than 40% or shortening
                  fraction greater than 26%

               2. Hepatic: Bilirubin no more than 2.5 mg/dL; alanine aminotransferase (ALT),
                  aspartate aminotransferase (AST), and alkaline phosphatase (ALP) no more than 5
                  times the upper limit of normal (ULN)

               3. Renal: Serum creatinine within normal range for age, or if serum creatinine is
                  outside normal range for age, then renal function (creatinine clearance or GFR)
                  greater than 70 mL/min/1.73 m^2

               4. Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced
                  expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater
                  than 50% of predicted value (corrected for hemoglobin); if unable to perform
                  pulmonary function tests, then O2 saturation greater than 92% of room air

        Exclusion Criteria:

          -  Pregnant (β-positive human chorionic gonadotropin [HCG]) or breastfeeding

          -  Evidence of HIV infection or HIV positive serology

          -  Current uncontrolled bacterial, viral, or fungal infection (currently taking
             medication and progression of clinical symptoms)

          -  Autologous transplant less than 12 months prior to enrollment

          -  Prior autologous transplant for the disease for which the UCB transplant will be
             performed

          -  Prior allogeneic hematopoietic stem cell transplant

          -  Active malignancy other than the one for which the UCB transplant is being performed
             within 12 months of enrollment

          -  Inability to receive TBI

          -  Requirement of supplemental oxygen

          -  HLA-matched related donor able to donate