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Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia

This study has been completed.
Medical Research Council
Information provided by:
National Cancer Institute (NCI) Identifier:
First received: January 28, 2000
Last updated: December 17, 2013
Last verified: January 2006

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 Intervention Phase
Drug: chlorambucil
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Drug: fludarabine phosphate
Drug: prednisolone
Drug: vincristine sulfate
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Primary Purpose: Treatment
Official Title: Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Study Start Date: October 1999
Study Completion Date: July 2007
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.


Ages Eligible for Study:   Child, Adult, Senior
Genders Eligible for Study:   Both
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00004218

  Show 86 Study Locations
Sponsors and Collaborators
Leukemia Research Fund
Medical Research Council
Study Chair: Daniel Catovsky, MD Royal Marsden NHS Foundation Trust
  More Information

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): Identifier: NCT00004218     History of Changes
Obsolete Identifiers: NCT00222599
Other Study ID Numbers: CDR0000067454  LRF-CLL4  LRG-MRC-LEUK-CLL4  EU-99030  MRC-LEUK-CLL4  EUDRACT-58585610  ISRCTN58585610 
Study First Received: January 28, 2000
Last Updated: December 17, 2013
Health Authority: United States: Federal Government

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:
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
Antimetabolites, Antineoplastic
Antineoplastic Agents, Phytogenic processed this record on October 26, 2016