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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00003764
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : January 28, 2010
National Cancer Institute (NCI)
Cancer and Leukemia Group B
Southwest Oncology Group
Information provided by:
Eastern Cooperative Oncology Group

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Leukemia Drug: cyclophosphamide Drug: fludarabine phosphate Phase 3

Detailed Description:


  • 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: Randomized
Primary Purpose: Treatment
Official Title: Phase III Randomized Trial of Fludarabine and Cyclophosphamide Versus Fludarabine for Previously Untreated Chronic Lymphocytic Leukemia
Study Start Date : December 1999
Actual Primary Completion Date : November 2005

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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



  • 18 and over

Performance status:

  • ECOG 0-2

Life expectancy:

  • Not specified


  • See Disease Characteristics


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


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


  • 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


Biologic therapy:

  • Not specified


  • No prior cytotoxic chemotherapy

Endocrine therapy:

  • No prior steroid treatment for CLL


  • Not specified


  • Not specified

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00003764

Show Show 218 study locations
Sponsors and Collaborators
Eastern Cooperative Oncology Group
National Cancer Institute (NCI)
Cancer and Leukemia Group B
Southwest Oncology Group
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Study Chair: Ian W. Flinn, MD, PhD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Chair: Michael R. Grever, MD Ohio State University Comprehensive Cancer Center
Study Chair: Mohamad A. Hussein, MD The Cleveland Clinic

Publications of Results:
Grever MR, Dewald GW, Neuberg DS, et al.: Select high risk genetic features predict earlier progression following chemotherapy in chronic lymphocytic leukemia: prospective randomized trial (Intergroup E2997) to evaluate justification for risk-adapted therapy. [Abstract] J Clin Oncol 24 (Suppl 18): A-6521, 342s, 2006.
Flinn IW, Kumm E, Grever MR, et al.: Fludarabine and cyclophosphamide produces a higher complete response rate and more durable remissions than fludarabine in patients with previously untreated CLL: Intergroup trial E2997. [Abstract] Blood 104 (11): A-475, 2004.
Grever MR, Lucas DM, Dewald GW, et al.: Outcome of treatment with fludarabine versus fludarabine and cyclophosphamide in chronic lymphocytic leukemia (CLL) is adversely impacted by high risk genetic features: results from ECOG 2997. [Abstract] Blood 104 (11 Pt 1): A-3487, 2004.

Other Publications:
Dewald GW, Paietta E, Goloubeva O, et al.: Correlation of interphase fluorescence in situ hybridization (FISH) anomalies with cell morphology and immunophenotyping in chronic lymphocytic leukemia (B-CLL). [Abstract] Blood 100 (11 pt 1): A-2334, 2002.

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Group Chair, Eastern Cooperative Oncology Group Identifier: NCT00003764    
Other Study ID Numbers: CDR0000066890
First Posted: January 27, 2003    Key Record Dates
Last Update Posted: January 28, 2010
Last Verified: January 2010
Keywords provided by Eastern Cooperative Oncology Group:
stage 0 chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antiviral Agents
Anti-Infective Agents