Combination Chemotherapy Followed By Umbilical Cord Blood Transplantation in Treating Patients With Hematologic Cancer or Severe Aplastic Anemia

OBJECTIVES:

• Determine the incidence and severity of acute toxicity in patients with hematologic malignancies or severe aplastic anemia treated with a non-myeloablative conditioning regimen followed by umbilical cord blood transplantation.
• Determine the incidence and severity of acute and chronic graft-versus-host-disease in patients treated with this regimen.
• Determine the incidence of relapse, disease-free survival, and overall survival of patients treated with this regimen.
• Determine the survival rate at 100 days post-transplantation in patients treated with this regimen.
• Determine the incidence of regimen-related complications (infection, hepatic veno-occlusive disease, and interstitial pneumonitis) in patients treated with this regimen.
• Determine the incidence of primary and secondary graft failure in patients treated with this regimen.
• Determine the rates and kinetics of donor-derived lymphoid, myeloid, neutrophil, RBC, and platelet engraftment in patients treated with this regimen.

OUTLINE: Patients receive a non-myeloablative conditioning regimen comprising fludarabine IV over 30 minutes on days -8 to -4, cyclophosphamide IV over 2 hours on days -3 to -2, and anti-thymocyte globulin (ATG) IV over at least 4 hours on days -2 to -1. Patients unable to tolerate ATG may receive methylprednisolone IV over 1 hour on days -3 to -1.

Patients undergo multiple unit umbilical cord blood transplantation on days 0-1. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 7 and continuing until blood counts recover.

Patients are followed monthly for 6 months; at 9, 12, 14, 16, 18, and 24 months; and then annually thereafter.

PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• One of the following histologically confirmed diagnoses:

• Acquired severe aplastic anemia

• Meets at least 2 of the following criteria:

• Granulocyte count less than 500/mm^3
• Platelet count less than 20,000/mm^3
• Absolute reticulocyte count less than 20,000/mm^3 (after correction for hematocrit)
• Unresponsive to OR recurrent disease after prior treatment with anti-thymocyte globulin and/or cyclosporine
• Acute myeloid leukemia (AML), meeting 1 of the following criteria:

• Failed induction therapy
• In first complete remission (CR) with any of the following high-risk features:

• Stem cell or biphenotype classification (M0)
• Erythroleukemia (M6)
• Acute megakaryocytic leukemia (M7)
• Cytogenetic markers indicative of poor prognosis
• t(15;17) translocation and failed first-line induction therapy OR there is molecular evidence of persistent disease
• t(8;21) and inv(16) translocations and failed first-line induction therapy
• In early relapse*
• In second or subsequent remission
• Recurrent disease after prior autologous stem cell transplantation (SCT) NOTE: *No refractory relapse
• Acute lymphoblastic leukemia, meeting 1 of the following criteria:

• In early relapse*
• In second or subsequent remission
• In first CR with the following high-risk features:

• t(4;11) or t(9;22) translocation
• Hyperleukocytosis (initial WBC greater than 30,000/mm^3)
• Failed to achieve CR by day 28 of standard induction therapy
• Recurrent disease after prior autologous SCT NOTE: *No refractory relapse
• Chronic myelogenous leukemia

• Chronic or accelerated phase that has failed medical management
• Blastic phase allowed after reinduction chemotherapy induces chronic phase
• Myelodysplastic syndromes meeting 1 of the following criteria:

• Refractory to medical management
• Presence of cytogenetic abnormalities predictive of transformation to acute leukemia, including the following:

= 5q- = 7q-

• Monosomy 7 and trisomy 8
• Evidence of evolution to AML (e.g., refractory anemia with excess blasts [RAEB], or RAEB in transformation)

• Chronic lymphocytic leukemia

• Refractory to treatment including fludarabine-based therapy
• Recurrent disease after prior autologous SCT
• Multiple myeloma

• Recurrent disease after prior autologous SCT
• Beyond first CR or failed induction therapy
• Disease is sensitive to pretransplantation cytoreduction
• Hodgkin's lymphoma

• Beyond first CR or failed induction therapy
• Disease is sensitive to pretransplantation cytoreduction
• Non-Hodgkin's lymphoma (NHL)

• Recurrent disease after prior autologous SCT
• Beyond first CR or failed induction therapy
• Disease is sensitive to pretransplantation cytoreduction
• Mantle zone NHL allowed after induction therapy
• Myeloproliferative disorders

• Refractory to medical management
• Allografting required unless grade 3 or greater myelofibrosis by bone marrow biopsy

• No HLA-matched sibling donor available
• Ineligible for a myeloablative conditioning regimen due to advanced age (over 55), extensive prior therapy, and/or other comorbidities
• If under age 55, must meet at least 1 of the following criteria:
• Received extensive prior therapy
• Organ toxicity or infection precluding eligibility for allogeneic transplantation with full ablation conditioning

• Availability of 2-5 umbilical cord blood units that are at least a 4/6 HLA match
• No active CNS disease
• No primary or grade 3 or 4 myelofibrosis

PATIENT CHARACTERISTICS:

Age

• Any age

Performance status

• Karnofsky 70-100% (for patients 16 years of age and older)
• Lansky 50-100% (for patients under 16 years of age)

Life expectancy

• At least 3 months

Hematopoietic

• See Disease Characteristics

Hepatic

• ALT/AST less than 4 times normal
• Bilirubin less than 2.0 mg/dL (unless due to hepatic infiltration by primary malignancy)

Renal

• Creatinine clearance greater than 40 mL/min

Cardiovascular

• Shortening fraction or ejection fraction greater than 40% of normal value for age by echocardiogram or radionuclide scan

Pulmonary

• FVC and FEV_1 greater than 60% of predicted
• DLCO greater than 60% of predicted (adult patients)
• Clearance by pulmonologist required if patient cannot perform pulmonary function tests

Other

• Not pregnant or nursing
• No uncontrolled active infection (viral, bacterial, or fungal)
• HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• More than 3 months since prior autologous stem cell transplantation

Chemotherapy

• See Disease Characteristics
• At least 4 weeks since prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• Recovered from prior therapy
• No other concurrent investigational agents that would preclude study participation or increase risk to patient

• Investigational diagnostic procedures allowed