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

Treatment Protocol: Umbilical Cord Blood (UCB) Transplantation in Pediatric Patients With High Risk Leukemia and Myelodysplasia Using Conditioning Regimen Without Radiation

Unrelated Cord Blood (UCB) transplant in children is a viable stem cell transplant modality for patients with leukemia and myelodysplasia. UCB is now considered "Standard Of Care" in cases where a suitable living bone marrow donor is not available. The survival of UCB is similar to Matched Unrelated Marrow Transplant. This study is considered "Research" since UCB is not a licensed product and requires investigational new drug (IND). THERE ARE NO SPECIFIC RESEARCH QUESTIONS IN THIS PROTOCOL. This protocol merely provides UCB as a stem cell treatment modality to pediatric patients who may require it after a conditioning regimen that excludes Total Body Irradiation.

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:

  1. Ph+ ALL; or,
  2. 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,
  3. Hypodiploidy (< 44 chromosomes or DNA index < 0.81); or,
  4. End of induction M3 bone marrow; or,
  5. End of induction M2 with M2-3 at Day 42.

• High risk second remission, defined as:

  1. Bone marrow relapse < 36 months from induction; or,
  2. T-lineage relapse at any time; or,
  3. Very early isolated central nervous system (CNS) relapse (6 months from diagnosis); or,
  4. 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:

  1. Cardiac: Left ventricular ejection fraction at rest must be > 40%, or shortening fraction > 26%
  2. Hepatic: Bilirubin ≤ 2.5 mg/dL; and alanine transaminase (ALT), aspartate transaminase (AST) and Alkaline Phosphatase ≤ 5 x upper limit of normal (ULN)
  3. 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.
  4. 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.