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Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide

Phase 3
Open (Enrolling)

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Trial Information

Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide


- 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

- 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.

Inclusion Criteria


- 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


Biologic therapy

- Not specified


- Not specified

Endocrine therapy

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


- Not specified


- Not specified

Type of Study:


Study Design:

Allocation: Randomized, Primary Purpose: Treatment

Principal Investigator

Daniel Catovsky, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Royal Marsden NHS Foundation Trust


United States: Federal Government

Study ID:




Start Date:

October 1999

Completion Date:

Related Keywords:

  • Leukemia
  • 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
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid