AlloHCT From Matched Unrelated Donors in Pts w/ Advanced Hematologic Malignancies & Disorders

OBJECTIVES:

Primary

• To determine the survival at day 100 of patients with relapsed, refractory, or poor-risk hematological malignancies treated with four different preparative regimens followed by allogeneic hematopoietic stem cell transplantation (HSCT) using two unrelated umbilical cord blood (UCB) units.

Secondary

• To determine the incidence and timing of neutrophil engraftment in patients treated with these regimens.
• To determine the incidence and timing of platelet engraftment in patients treated with these regimens.
• To determine the incidence and severity of acute and chronic graft-versus-host-disease (GVHD) in patients treated with these regimens.
• To determine the survival at day 180 in patients treated with these regimens.
• To determine the disease-free survival in patients treated with these regimens.
• To determine the incidence of primary and secondary engraftment failure in patients treated with these regimens.
• To determine the incidence of transplantation-related complications (e.g., infection, veno-occlusive disease of the liver, or organ toxicity) in these patients.
• To determine the incidence of post-transplantation-related lymphoproliferative disease, secondary myelodysplastic syndromes, or other secondary malignancies in these patients.
• To determine the incidence of relapse in patients treated with these regimens.
• To determine post-transplantation chimerism in patients treated with these regimens.
• To determine immune reconstitution in patients treated with these regimens.

OUTLINE: This is a multicenter study.

• Preparative regimens: Patients are assigned to 1 of 4 preparative regimens.

• Regimen 1 (for patients < 50 years of age and no contraindication to fractionated total-body irradiation (FTBI): Patients undergo FTBI 2-3 times a day on days -9 to -6 for a total of 11 fractions. Patients also receive cyclophosphamide IV over 2 hours on days -5 and -4 and fludarabine phosphate IV on days -5 to -2.
• Regimen 2 (for patients < 50 years of age and unable to tolerate FTBI due to prior dose-limiting radiotherapy or significant cardiotoxicity): Patients receive a test dose of busulfan on day -10 and then dose adjusted busulfan IV 3-4 times daily on days -9 to -6, melphalan IV on days -5 and -4, and fludarabine phosphate IV on days -5 to -2.
• Regimen 3* (for patients unable to tolerate regimen 1 or 2; no age exclusion): Patients receive fludarabine phosphate IV on days -8 to -4 and cyclophosphamide IV over 2 hours on day -3 and undergo TBI (single dose) on day -2.
• Regimen 4* (for patients unable to tolerate regimen 1 or 2): Patients receive fludarabine phosphate IV on days -7 to -3 and melphalan IV on day -2.

NOTE: *Treating physician decides the choice between regimen 3 and 4

• Umbilical cord blood (UCB) transplantation: Patients receive 2 combined units of UCB IV on day 0. Patients also receive G-CSF IV or subcutaneously beginning on day 5 (or later) and continuing until blood counts recover.
• Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV twice daily beginning on day -1 followed by a taper according to institutional guidelines. Patients also receive mycophenolate mofetil orally or IV beginning on day 0 and continuing until day 27 (or as clinically indicated).

After completion of study therapy, patients are followed periodically.

DISEASE CHARACTERISTICS:

• Histologically confirmed hematological or lymphatic malignancy, including any of the following:

• Acute myeloid leukemia

• Relapsed or primary refractory disease with < 10% blasts on peripheral blood smear
• In first remission with poor risk factors and molecular prognosis [i.e., AML with -5, -7, t(6;9), tri8, -11] (preparative regimen 3 or 4)
• Acute lymphocytic leukemia

• In second complete remission or higher OR in first remission with poor risk factors, including any of the following (preparative regimen 1 or 2):

• BCR/ABL by fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction
• t(9;22)(q34;q11) detected by cytogenetics
• Chromosomes < 44 by cytogenetics
• DNA index < 0.81 by flow cytometry
• Any rearrangement of chromosome 11 that results in disruption of MLL gene (11q23) by cytogenetics and SER
• In first remission with poor risk factors and molecular prognosis [ALL with Philadelphia chromosome-positive t(9;22), t(4;22), (q34;q11)] (preparative regimen 3 or 4)
• Chronic myelogenous leukemia

• In accelerated phase or greater (preparative regimen 1 or 2)
• In accelerated or second chronic phase (preparative regimen 3 or 4)
• Myelodysplastic syndromes

• With deletion of chromosome 7 or short arm of chromosome 5 (preparative regimen 1 or 2)
• In high and high-intermediate risk categories (preparative regimen 3 or 4)
• Non-Hodgkin lymphoma in relapse with marrow involvement
• Refractory chronic lymphocytic leukemia
• Patients deemed ineligible for conventional high-dose chemotherapy programs (i.e., regimens 1 or 2) due to any of the following concurrent medical conditions may be eligible for regimens 3 or 4 at the discretion of the treating physician and principal investigator (preparative regimen 3 or 4):

• LVEF < 50% and > 40%
• FEV1, FVC, or DLCO < 50%
• Bilirubin > 3 mg/dL
• Creatinine > 2 mg/dL
• Two partially HLA-matched umbilical cord blood (UCB) units available

• HLA-matched minimally at 4 of 6 HLA-A, HLA-B, and -DRB1 loci with the patient

• DRB1 matched by high resolution DNA typing
• HLA-A and HLA-B matched by low resolution at the "serological match" level
• Two pooled units with a nucleated cell number > 2.5 x 10^7/kg
• No available HLA-identical sibling or 1 antigen-mismatched related donor
• No available HLA-matched unrelated bone marrow donor

PATIENT CHARACTERISTICS:

• See Disease Characteristics
• Karnofsky performance status (PS) 60-100% OR Lansky PS 60-100% OR Zubrod PS 0-1
• Physiological age 60 or less (at any chronological age)
• Weight > 50 kg
• Creatinine normal for age OR creatinine clearance by 24-hour urine collection or glomerular filtration rate > 60 mL/min
• Bilirubin ≤ 1.5 mg/dL
• LVEF ≥ 50%
• DLCO ≥ 60% of predicted
• No HIV-1 infection
• No active uncontrolled infection
• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• Recovered from prior intensive chemotherapy