Fludarabine and Cyclophosphamide With or Without Oblimersen in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

OBJECTIVES:

• Compare the complete response and nodular partial response of patients with relapsed or refractory chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide with or without oblimersen.
• Compare the overall response rate, response duration, survival, and time to progression in patients treated with these regimens.
• Compare the clinical benefit and safety of these regimens in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to disease response to prior fludarabine-containing therapy (responsive vs refractory), number of prior regimens (1-2 vs 3 or more), and duration of response to last prior therapy (more than 6 months vs 6 months or fewer). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oblimersen IV continuously on days 1-7 via an infusion pump (ending on day 8) and fludarabine IV over 20-30 minutes and cyclophosphamide IV over 30-60 minutes on days 5-7. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 11 and continuing until blood counts recover.
• Arm II: Patients receive fludarabine IV over 20-30 minutes followed by cyclophosphamide IV over 30-60 minutes on days 1-3. Patients also receive G-CSF SC beginning on day 7 and continuing until blood counts recover.

Treatment in both arms continues every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed at 1 month and then every 2 months for 2 years.

PROJECTED ACCRUAL: A total of 200 patients (100 per arm) will be accrued for this study within 1 year.

DISEASE CHARACTERISTICS:

• Diagnosis of relapsed or refractory chronic lymphocytic leukemia (CLL) requiring therapy

• Primary resistance, defined as disease progression without response during at least 2 courses of myelosuppressive therapy OR
• Relapsed disease, defined as a response (remission or plateau) followed by relapse on or off prior therapy
• At least 1 prior regimen must have contained fludarabine
• Intermediate or high-risk CLL

• Intermediate-risk disease must satisfy at least 1 of the following criteria for active disease:

• Massive or progressive splenomegaly and/or lymphadenopathy

• Spleen tip greater than 6 cm below costal margin
• More than 10% weight loss within the past 6 months
• Grade 2 or 3 fatigue
• Fevers greater than 100.5 degrees F or night sweats for more than 2 weeks without evidence of infection
• Progressive lymphocytosis with an increase of more than 50% over a 2-month period or an anticipated doubling time of less than 6 months
• Worsening anemia or thrombocytopenia
• Measurable disease with all of the following:

• Absolute lymphocytosis greater than 5,000/mm^3
• Lymphocytosis of small to moderate-size lymphocytes with less than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically determined by manual differential
• Bone marrow aspirate smear with at least 30% nucleated cells that are lymphoid or a bone marrow core biopsy showing lymphoid infiltrates compatible with CLL
• Normocellular or hypercellular bone marrow
• Lymphocyte immunophenotype that shows a predominant B-cell monoclonal population
• No Rai stage 0 CLL or stable CLL not requiring therapy
• No secondary leukemia or history of antecedent hematologic disorder prior to initial onset of CLL (e.g., myelodysplasia)

PATIENT CHARACTERISTICS:

Age:

• Over 18

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics
• Platelet count at least 50,000/mm^3 (hematopoietic growth factor or transfusion independent)
• Negative Coombs' test
• No bleeding or coagulation disorder
• No history of hemolytic anemia, including autoimmune hemolytic anemia
• No history of autoimmune thrombocytopenia

Hepatic:

• Albumin at least 3.0 g/dL
• Bilirubin no greater than 2 mg/dL
• AST no greater than 1.5 times upper limit of normal (ULN) (5 times ULN if due to CLL)
• PT no greater than 1.5 times ULN OR
• INR no greater than 1.3
• PTT no greater than 1.5 times ULN
• No chronic hepatitis or cirrhosis

Renal:

• Creatinine no greater than 2.0 mg/dL

Cardiovascular:

• No uncontrolled congestive heart failure
• No active symptoms of coronary artery disease (i.e., uncontrolled arrhythmia or recurrent chest pain despite prophylactic medication)
• No New York Heart Association class III or IV disease
• No cardiovascular signs or symptoms grade 2 or greater

Other:

• Able to maintain an ambulatory infusion pump
• HIV negative
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No known hypersensitivity to phosphorothioate-containing oligonucleotides, fludarabine, or cyclophosphamide
• No concurrent medical disease that would preclude study participation
• No uncontrolled seizure disorder
• No unresolved serious infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior autologous or allogeneic stem cell transplantation
• At least 3 weeks since prior immunologic therapy, cytokine therapy, vaccine therapy, or other biologic therapy for CLL and recovered
• No concurrent interleukin-11

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks since prior chemotherapy and recovered

Endocrine therapy:

• No concurrent corticosteroid therapy

Radiotherapy:

• At least 3 weeks since prior radiotherapy for CLL and recovered

Surgery:

• No prior organ allograft
• At least 3 weeks since prior major surgery for CLL and recovered

Other:

• At least 3 weeks since other prior therapy for CLL and recovered
• No other concurrent investigational therapy
• No concurrent therapeutic anticoagulation
• No concurrent immunosuppressive drugs