Single Versus Double Umbilical Cord Blood Transplantation in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)

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; ALT, AST and 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: DLCO, FEV1, FEC (diffusion capacity) 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