Fludarabine With or Without Cyclophosphamide in Treating Patients With Chronic Lymphocytic Leukemia

Eastern Cooperative Oncology Group

Status and phase: Completed; Phase 3

Conditions: Leukemia

Treatments: Drug: cyclophosphamide; Drug: fludarabine phosphate

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00003764

E2997

SWOG-E2997

CALGB-10103

CDR0000066890

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known whether combining cyclophosphamide with fludarabine is more effective than fludarabine alone in treating chronic lymphocytic leukemia.

PURPOSE: Randomized phase III trial to study the effectiveness of fludarabine with or without cyclophosphamide in treating patients who have chronic lymphocytic leukemia that has not been treated previously.

Full description

OBJECTIVES:

• Compare the efficacy of fludarabine with or without cyclophosphamide in terms of complete remission rate and overall survival in patients with previously untreated B cell chronic lymphocytic leukemia (CLL).
• Compare the toxicities of these 2 regimens in this patient population.
• Determine whether the expression of proteins specifically implicated in the regulation of DNA damage induced apoptosis of lymphoid cells (i.e., p53; mdm2; GST; Bcl-2; Mcl-1; Bax; p27; and caspase-3) correlates with response to chemotherapy in these patients.
• Determine whether there is a relationship between clinical response or resistance and differential expression of genes in the CLL cells either at initiation of therapy or following relapse and progression.
• Correlate mutations in immunoglobulin heavy chain variable region genes with clinical response or resistance in this patient population.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to stage of disease (O-II vs III-IV). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive fludarabine IV over 30 minutes on days 1-5.
• Arm II: Patients receive fludarabine as in arm I plus cyclophosphamide IV over 1 hour on day 1.

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

Patients are followed every 3 months for 2 years and then every 6 months until disease progression.

PROJECTED ACCRUAL: A total of 280 patients will be accrued for this study over 2 to 2.5 years.

Enrollment: 280 estimated patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Diagnosis of chronic lymphocytic leukemia (CLL) of any stage as defined by the following:

  • Peripheral blood absolute lymphocyte count greater than 5,000/mm^3 within 14 days prior to study
  • Lymphocytes must be small to moderate size with no more than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically
  • Phenotypically characterized as B-CLL

• Must have one of the following characteristics indicating need for chemotherapy:

  • Progressive marrow failure (hemoglobin less than 10 g/dL and/or platelet count less than 100,000/mm^3)
  • Progressive lymphocytosis with an increase of more than 50% over a 2 month period or anticipated doubling time of less than 6 months
  • Massive (i.e., greater than 6 cm below left costal margin) or progressive splenomegaly
  • Massive nodes or clusters (i.e., greater than 10 cm in longest diameter) or progressive adenopathy
  • At least 10% weight loss within 6 months of study
  • Extreme fatigue
  • Fevers greater than 100.5 degrees F for 2 weeks without evidence of infection
  • Night sweats without evidence of infection

• No autoimmune anemia or autoimmune thrombocytopenia

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin no greater than 2 mg/dL unless secondary to tumor

Renal:

• Creatinine no greater than 2.0 mg/dL
• Creatinine clearance at least 40 mL/min if creatinine is greater than 1.5 mg/dL

Other:

• No other prior or concurrent malignancy within the past 2 years except basal cell carcinoma of the skin or carcinoma in situ of the cervix
• No active infection requiring oral or intravenous antibiotics
• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior cytotoxic chemotherapy

Endocrine therapy:

• No prior steroid treatment for CLL

Radiotherapy:

• Not specified

Surgery:

• Not specified