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Clinical Trials (PDQ®)

  • First Published: 2/1/2000
  • Last Modified: 2/14/2012

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Clinical Trials (PDQ®)

Phase III Randomized Study of Chlorambucil Alone Versus Fludarabine With or Without Cyclophosphamide in Patients With Newly Diagnosed Chronic Lymphocytic Leukemia. Note: The information about this trial has not been updated by the sponsor/principal investigator/lead organization. cannot verify the accuracy of the information.

Alternate Title
Basic Trial Information
Entry Criteria
Expected Enrollment
Published Results
Trial Contact Information
Registry Information

Alternate Title

Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia. Note: The information about this trial has not been updated by the sponsor/principal investigator/lead organization. cannot verify the accuracy of the information.

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosedNot specifiedOtherLRF-CLL4
LRG-MRC-LEUK-CLL4, EU-99030, MRC-LEUK-CLL4, NCT00004218, EUDRACT-58585610, ISRCTN58585610


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

Entry Criteria

Disease Characteristics:

  • 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/mm3)
    • 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


  • Stage II or III

Prior/Concurrent Therapy:

Biologic therapy

  • Not specified


  • Not specified

Endocrine therapy

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


  • Not specified


  • Not specified

Patient Characteristics:


  • 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

Expected Enrollment

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


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.

Published Results

Else M, Cocks K, Crofts S, et al.: Quality of life in chronic lymphocytic leukemia: 5-year results from the multicenter randomized LRF CLL4 trial. Leuk Lymphoma 53 (7): 1289-98, 2012.[PUBMED Abstract]

Gonzalez D, Martinez P, Wade R, et al.: Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol 29 (16): 2223-9, 2011.[PUBMED Abstract]

Wade R, Di Bernardo MC, Richards S, et al.: Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial. Haematologica 96 (10): 1496-503, 2011.[PUBMED Abstract]

Oscier D, Wade R, Davis Z, et al.: Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica 95 (10): 1705-12, 2010.[PUBMED Abstract]

Else M, Smith AG, Cocks K, et al.: Patients' experience of chronic lymphocytic leukaemia: baseline health-related quality of life results from the LRF CLL4 trial. Br J Haematol 143 (5): 690-7, 2008.[PUBMED Abstract]

Catovsky D, Richards S, Matutes E, et al.: Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 370 (9583): 230-9, 2007.[PUBMED Abstract]

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.

Trial Contact Information

Trial Lead Organizations

Leukemia Research Fund

Daniel Catovsky, MD, Protocol chair
Ph: 44-20-7808-2880 ext.2875

Medical Research Council's Working Party on Leukemia in Adults and Children

Daniel Catovsky, MD, Protocol chair
Ph: 44-20-7808-2880 ext.2875

Registry Information
Official Title Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide
Trial Start Date 1999-10-09
Registered in NCT00004218
Date Submitted to PDQ 1999-12-03
Information Last Verified 2006-01-23

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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