Umbilical Cord Blood Transplantation in Treating Patients With Hematologic Cancer or Nonmalignant Hematologic Disease

OBJECTIVES:

• Determine the efficacy of umbilical cord blood transplantation, as measured by durable neutrophil engraftment, in patients with malignant or nonmalignant hematological disease.
• Determine the disease-free survival and long-term survival in patients treated with this regimen.
• Determine the incidence of neutrophil engraftment, primary and secondary graft failure, platelet engraftment, and RBC engraftment in patients treated with this regimen.
• Determine the incidence and severity of acute and chronic graft-versus-host disease, complications (infection, veno-occlusive disease, interstitial pneumonitis), relapse, other malignancies, lymphoproliferative disorders, and posttransplantation myelodysplasia in patients treated with this regimen.
• Determine the immune reconstitution in patients treated with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to disease group (malignant vs nonmalignant). Patients with malignant disease are further stratified according to quality of HLA match (1 or 2/6 vs 3/6 vs 4/6 vs 5/6 or 6/6), cell dose, and age.

Patients are assigned to one of three conditioning regimens, depending on disease.

• Group A (malignant disease ): Patients undergo total body irradiation (TBI) once on day -8 and twice daily on days -7 to -4. Male patients with acute lymphocytic leukemia (ALL) undergo radiotherapy boost to testes. Patients receive cyclophosphamide (CTX) IV on days -3 and -2 and methylprednisolone (MePRDL) IV and anti-thymocyte globulin (ATG) IV on days -3 to -1.
• Group B (inborn errors of metabolism/storage disease): Patients receive oral busulfan (BU) every 6 hours on days -6 and -5, CTX IV on days -4 and -3, and MePRDL IV and ATG IV every 12 hours on days -2 and -1.
• Group C (other nonmalignant diseases): Patients receive oral BU every 6 hours on days -9 to -6, CTX IV on days -5 to -2, and MePRDL IV and ATG IV on days -3 to -1.

Patients in all groups receive cord blood IV over a maximum of 30 minutes on day 0. Patients also receive MePRDL IV with the first half of the infusion administered immediately before the cord blood infusion and filgrastim (G-CSF) IV beginning 4 hours after transplantation and continuing until blood counts recover.

Patients are followed at 30, 60, and 90 days; at 6 months; and then annually thereafter.

PROJECTED ACCRUAL: Approximately 390 patients will be accrued for this study within 5 years.

DISEASE CHARACTERISTICS:

• One of the following diagnoses:

• Acute myeloid leukemia (AML), with or without myelodysplastic syndromes

• Not in first complete remission (CR)* with translocations t(8;21) and inv (16) unless failure of first-line induction therapy
• Not in first CR* with translocations t(15;17) abnormality unless:

• Failure of first-line induction therapy OR
• Molecular evidence of persistent disease
• Not in first CR with Down syndrome
• Patients with third or greater medullary relapse or refractory disease (other than primary induction failures) receive busulfan/melphalan conditioning regimen NOTE: * CR defined by no greater than 5% blasts in marrow
• Acute lymphocytic leukemia (ALL)

• Not in first CR OR
• High-risk ALL in first CR, with high risk defined as one of the following:

• Hypoploidy (no greater than 44 chromosomes)
• Pseudodiploidy with translocations or molecular evidence of t(9;22), 11q23, or t(8;14) (except B-cell ALL) with or without MLL gene arrangement
• Elevated WBC at presentation

• Age 6-12 months: greater than 100,000/mm^3
• Age 10-17 years: greater than 200,000/mm^3
• Age 18: greater than 20,000/mm^3
• Failed to achieve CR after 4 weeks of induction therapy
• Patients with B-ALL must not be in first CR, must meet at least one of the high-risk criteria specified above, or must not meet any of the following criteria:

• Translocation t(8;14)
• Blasts have surface immunoglobulins
• CD10 positive
• Patients with third or greater medullary relapse or refractory disease (other than primary induction failures) receive busulfan/melphalan conditioning regimen
• Chronic myelogenous leukemia, meeting criteria for 1 of the following:

• Accelerated phase
• Chronic phase if 1 year from diagnosis without a matched unrelated bone marrow donor AND unresponsive to or unable to tolerate interferon
• Blast crisis, defined as greater than 30% promyelocytes plus blasts in bone marrow

• Patients receive busulfan/melphalan conditioning regimen
• Acute undifferentiated leukemia (AUL), infant leukemia, or biphenotypic leukemia

• Patients with third or greater medullary relapse or refractory disease (other than primary induction failures) receive busulfan/melphalan conditioning regimen
• Juvenile myelomonocytic leukemia meeting the following criteria:

• No Philadelphia chromosome
• Bone marrow blasts less than 30%
• Peripheral blood monocytes greater than 1,000/mm^3
• At least 2 of the following:

• Peripheral blood spontaneous growth and/or sargramostim (GM-CSF) hypersensitivity
• Increased hemoglobin F for age
• Clonal abnormalities (e.g., monosomy 7 or RAS mutations)
• Peripheral blood with myeloid precursors
• WBC greater than 10,000/mm^3
• Myelodysplastic syndromes defined by the following:

• Refractory anemia (RA)
• RA with ringed sideroblasts
• RA with excess blasts (RAEB)
• RAEB in transformation
• Chronic myelomonocytic leukemia
• Paroxysmal nocturnal hemoglobinuria
• Hodgkin's lymphoma or non-Hodgkin's lymphoma beyond first CR or primary induction failures AND chemosensitive (greater than 50% reduction in tumor mass size)
• Inborn error of metabolism including, but not limited to, Hurler's syndrome, adrenoleukodystrophy (ALD), Maroteaux-Lamy syndrome, globoid cell leukodystrophy, metachromatic leukodystrophy, fucosidosis, or mannosidosis

• For ALD patients over age 5, IQ must be at least 80
• For all other patients over age 5, IQ must be at least 70
• For all patients age 5 and under, developmental quotient or clinical neurodevelopmental examination should demonstrate potential for stabilization at a level of functioning where continuous life support (e.g., mechanical ventilation) would not be predicted to be required in the year after transplantation
• Combined immune deficiencies including, but not limited to:

• Severe combined immunodeficiency (SCID) requiring cytoreduction
• Wiskott-Aldrich syndrome
• Leukocyte adhesion defect
• Chediak-Higashi disease
• X-linked lymphoproliferative disease
• Adenosine deaminase deficiency
• Purine nucleoside phosphorylase deficiency
• X-linked SCID
• Common variable immune deficiency
• Nezelof's syndrome
• Cartilage hair hypoplasia
• No dyskeratosis congenita
• No ALL, AML, AUL, or biphenotypic leukemia in third or higher medullary relapse or refractory disease other than primary induction failure
• No primary myelofibrosis or myelofibrosis grade 3 or worse
• No active CNS leukemia involvement (CSF with WBC greater than 5/mm^3 and malignant cells on cytospin)
• No consenting 5/6 or 6/6 HLA-matched related donor available
• 3-6/6 HLA-matched unrelated umbilical cord blood donor available

PATIENT CHARACTERISTICS:

Age:

• See Disease Characteristics
• 18 and under

Performance status:

• Karnofsky 70-100%, if age 16 to 18
• Lansky 50-100%, if under age 16

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin less than 2.5 mg/dL
• SGOT less than 5 times upper limit of normal

Renal:

• Creatinine normal for age OR
• Creatinine clearance or glomerular filtration rate greater than 50% lower limit of normal for age

Cardiovascular:

• If symptomatic:

• LVEF greater than 40% (or shortening fraction greater than 26%) and improves with exercise OR
• Shortening fraction greater than 26%

Pulmonary:

• If symptomatic:

• DLCO, FEV_1, and FEC greater than 45% predicted OR
• Oxygen saturation greater than 85% on room air

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No uncontrolled viral, bacterial, or fungal infection

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characteristics
• At least 1 year since prior allogeneic stem cell transplantation (SCT) with cytoreductive preparative therapy
• At least 6 months since prior autologous SCT
• No concurrent thrombopoietic growth factors

Chemotherapy:

• See Disease Characteristics
• See Biologic therapy

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• Not specified