Help guide our efforts to modernize
Send us your comments by March 14, 2020. Menu

Chemotherapy in Treating Patients With Newly Diagnosed 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: NCT00004218
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : December 18, 2013
Medical Research Council
Information provided by:
National Cancer Institute (NCI)

Brief Summary:

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. It is not yet known which regimen of chemotherapy is more effective for chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying chlorambucil to see how well it works compared to fludarabine and cyclophosphamide or fludarabine alone in treating patients with newly diagnosed chronic lymphocytic leukemia.

Condition or disease Intervention/treatment Phase
Leukemia Drug: chlorambucil Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: fludarabine phosphate Drug: prednisolone Drug: vincristine sulfate Phase 3

Detailed Description:


  • Compare the survival rate of patients with newly diagnosed chronic lymphocytic leukemia treated with chlorambucil alone vs fludarabine with or without cyclophosphamide.
  • Compare the response rate and duration of remission in patients treated with these regimens.
  • Compare the toxic effects of these regimens in these patients.
  • Compare the quality of life of patients treated with these regimens.
  • Determine the impact of the drug response information provided by the DiSC assay on response rate and survival in relapsed or nonresponding patients.
  • Assess the prognostic value of five genetic markers: trisomy 12 and deletions at 11q23, 13q14, p53, and 6q21 in patients treated with these regimens.

OUTLINE: This is a randomized study. Patients enter one of three treatment arms in the first randomization. Depending on response, some patients may also participate in a second randomization to one of two treatment arms.

  • First randomization:

    • Arm I: Patients receive oral chlorambucil daily for 7 days. Treatment repeats every 4 weeks until maximum response or up to 1 year.
    • Arm II: Patients receive fludarabine IV or orally daily for 5 days. Treatment repeats every 4 weeks for 3-8 courses.
    • Arm III: Patients receive cyclophosphamide IV and fludarabine IV for 3 days or orally daily for 5 days. Treatment repeats every 4 weeks for 3-8 courses.

Patients who relapse after being in remission for at least 1 year may repeat the initial therapy or may participate in a second randomization. Patients who experience progressive disease or relapse within 1 year after treatment proceed to a second randomization.

  • Second randomization:

    • Arm I: Treatment is guided by the results of the DiSC assay. Treatment may be one of the first-line treatments with fludarabine or standard CHOP chemotherapy repeated every 4 weeks (cyclophosphamide IV, doxorubicin IV, vincristine IV, and oral prednisolone on days 1-5) or any other therapy guided by the results of the DiSC assay.
    • Arm II: Treatment is physician's choice, which may include any of the options in arm I.

Quality of life is assessed prior to initial therapy; at 3, 6, and 12 months; and then annually thereafter.

Patients are followed annually for survival.

PROJECTED ACCRUAL: A total of 750 patients will be accrued for this study within 6-7 years.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Allocation: Randomized
Primary Purpose: Treatment
Official Title: Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide
Study Start Date : October 1999
Actual Study Completion Date : July 2007

Resource links provided by the National Library of Medicine

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.

Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Diagnosis of B-cell chronic lymphocytic leukemia (CLL) requiring therapy and meeting the following criteria:

    • Previously untreated disease
    • Peripheral blood morphology, excluding other leukemia and low-grade lymphoma in leukemic phase
    • Cell markers: CD5+, CD23+, SmIg (weak), CD79b-, FMC7-
    • Persistent lymphocytosis (greater than 10,000/mm^3)
    • At least 40% bone marrow infiltration
  • Stage 0 or I progressive disease indicated by at least one of the following:

    • Persistent rise in lymphocyte count with doubling time less than 12 months
    • Downward trend in hemoglobin and/or platelet count
    • At least 50% increase in size of liver and/or spleen and/or lymph nodes
    • Appearance of lymphadenopathy, hepatomegaly, or splenomegaly
    • Constitutional symptoms caused by disease

      • Pyrexia
      • Night sweats
      • Weight loss OR
  • Stage II or III



  • Not specified

Performance status:

  • Not specified

Life expectancy:

  • Not specified


  • See Disease Characteristics


  • Bilirubin no greater than 2 times upper limit of normal (ULN)*
  • SGOT/SGPT no greater than 2 times ULN* NOTE: * Unless due to CLL


  • Creatinine clearance at least 30 mL/min


  • No other cancer or life-threatening disease
  • Not pregnant
  • Fertile patients must use effective contraception during and for 6 months after study therapy


Biologic therapy

  • Not specified


  • Not specified

Endocrine therapy

  • No concurrent corticosteroids (e.g., dexamethasone) as antiemetics


  • 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): NCT00004218

Show Show 86 study locations
Sponsors and Collaborators
Leukemia Research Fund
Medical Research Council
Layout table for investigator information
Study Chair: Daniel Catovsky, MD Royal Marsden NHS Foundation Trust

Publications of Results:
Dearden CE, Wade RL, Else M, et al.: The combination of fludarabine and cyclophosphamide has a beneficial effect on the incidence of hemolytic anemia in chronic lymphocytic leukemia: results from the UK LRF CLL4 trial. [Abstract] Blood 110 (11): A-2044, 2007.

Publications automatically indexed to this study by Identifier (NCT Number):
Layout table for additonal information Identifier: NCT00004218    
Obsolete Identifiers: NCT00222599
Other Study ID Numbers: CDR0000067454
First Posted: January 27, 2003    Key Record Dates
Last Update Posted: December 18, 2013
Last Verified: January 2006
Keywords provided by National Cancer Institute (NCI):
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia
stage 0 chronic lymphocytic leukemia
Additional relevant MeSH terms:
Layout table for MeSH terms
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
Liposomal doxorubicin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors