Umbilical Cord Blood (UCB) Transplantation in Pediatric Patients With High Risk Leukemia and Myelodysplasia

The preparative regimen will consist of:

• Fludarabine: 25 mg/m2/day IV x 5 doses on Days -13, to -9
• Busulfan 1mg/kg IV every 6 hrs x 16 doses on Days -8 to -5
• Melphalan 45 mg/m2/day IV x 3 doses on days -4 to -2
• ATGAM 30mg/kg/day x 3 doses on Days -3 to -1
• Day 0 will be the day of the UCB Transplant
• The graft-versus-host-disease (GVHD) prophylaxis will be Cyclosporin A to maintain level 200-400 beginning on Day -3, through 200-400. Solumedrol at 1mg/kg/day on Day 1 until D+4, then solumedrol 2mg/kg/day until Day +19 or till absolute neutrophil count (ANC) reaches 500/mm2, then taper by 0.2 mg/kg/week.

Inclusion criteria

• Patients must be up to 21 years of age
• Patients cannot receive total body irradiation (TBI) because of:

• Young age - < 2 years at diagnosis of leukemia resulting in an age < 4 years at transplantation (due to risk of severe growth retardation and brain damage).
• Inability to tolerate TBI because of prior radiation or organ toxicity.
• Refractory/multiply relapsed leukemia, for which a traditional TBI/cyclophosphamide regimen would unlikely lead to a successful outcome.
• Patients must have a partially human leukocyte antigen (HLA)-matched UCB unit. Unit 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. The unit must deliver a pre-cryopreserved nucleated cell dose of at least 2.5 x 10^7 per kilogram.
• Acute myelogenous leukemia (AML) at the following stages:

• High risk first complete remission (CR1), defined as:

• Having preceding myelodysplasia (MDS)
• High risk cytogenetics (High-risk cytogenetics: del (5q) -5, -7, abn (3q), t (6;9) complex karyotype (>= 5 abnormalities)
• Requiring > 2 cycles chemotherapy to obtain CR;
• Second or greater CR.
• First relapse with < 25% blasts in bone marrow.
• Patients with therapy-related AML whose prior malignancy has been in remission for at least 12 months.
• Acute lymphocytic leukemia (ALL) at the following stages:
• High risk first remission, defined as:

• Ph+ ALL; or,
• Myeloid/lymphoid leukemia (MLL) rearrangement with slow early response [defined as having M2 (5-25% blasts) or M3 (>25% blasts on bone marrow examination on Day 14 of induction therapy)]; or,
• Hypodiploidy (< 44 chromosomes or DNA index < 0.81); or,
• End of induction M3 bone marrow; or,
• End of induction M2 with M2-3 at Day 42.
• High risk second remission, defined as:

• Bone marrow relapse < 36 months from induction; or,
• T-lineage relapse at any time; or,
• Very early isolated central nervous system (CNS) relapse (6 months from diagnosis); or,
• Slow reinduction (M2-3 at Day 28) after relapse at any time.
• Any third or subsequent CR.
• Biphenotypic or undifferentiated leukemia in any CR or if in 1st relapse must have < 25% blasts in bone marrow (BM).
• 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 must have a Karnofsky score ≥ 70% and patients < 16 years old must have a Lansky score ≥ 70%.
• Signed informed consent.
• Patients with adequate physical function as measured by:

• Cardiac: Left ventricular ejection fraction at rest must be > 40%, or shortening fraction > 26%
• Hepatic: Bilirubin ≤ 2.5 mg/dL; and alanine transaminase (ALT), aspartate transaminase (AST) and Alkaline Phosphatase ≤ 5 x upper limit of normal (ULN)
• Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or GFR) > 70 mL/min/1.73 m2.
• Pulmonary: Diffusing capacity of the lungs for carbon monoxide (DLCO), Forced expiratory volume in 1 second (FEV1), Forced vital capacity (FVC) (diffusion capacity) > 50% of predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% of room air.

Exclusion criteria

• Pregnant (B-positive 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 < 6 months prior to enrollment.
• Prior autologous transplant for the disease for which the UCB transplant will be performed.
• Allogeneic hematopoietic stem cell transplant < 6 months prior to enrollment.
• Active malignancy other than the one for which the UCB transplant is being performed within 12 months of enrollment
• Active CNS leukemia.
• Requirement of supplemental oxygen.
• HLA-matched related donor able to donate.