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 chlorambucilregimen is more effective in treating advanced chronic lymphocytic leukemia.

PURPOSE: Randomizedphase III trial to determine the effectiveness of different regimens of chlorambucil in treating patients who have advanced chronic lymphocytic leukemia.

Condition	Treatment or Intervention	Phase
stage III chronic lymphocytic leukemia stage IV chronic lymphocytic leukemia B-cell Chronic Lymphocytic Leukemia	Drug: chlorambucil  Drug: cyclophosphamide  Drug: fludarabine  Procedure: chemotherapy  Procedure: high-dose chemotherapy	Phase III

Further Study Details: 

OBJECTIVES:

• Compare overall and disease-related survival of patients with B-cell chronic lymphocytic leukemia treated with high-dose chlorambucil induction therapy with or without low-dose chlorambucil maintenance therapy.
• Compare the time to salvage treatment in these patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Compare the treatment-related mortality of these patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, time to complete response (before 12 weeks vs after 12 weeks vs partial response), and cytopenia at diagnosis (Binet stage A+B vs C).

All patients receive induction therapy comprising high-dose oral chlorambucil daily. Treatment continues until achievement of complete response or a maximum of 24 weeks in the absence of disease progression or unacceptable toxicity.

Patients who respond to induction therapy are randomized to 1 of 2 treatment arms for maintenance therapy.

• Arm I: Patients receive low-dose oral chlorambucil twice a week. Therapy continues for up to 5 years in the absence of disease progression or unacceptable toxicity. If disease progression occurs, then patients may proceed to salvage therapy.
• Arm II: Patients receive no maintenance therapy. If disease progresses, patients receive induction therapy again. If disease does not respond to re-induction therapy, then patients may proceed to salvage therapy.
• Salvage therapy: Patients with progressive disease during maintenance therapy receive fludarabine IV daily and cyclophosphamide IV daily on days 1-3. Treatment repeats every 4 weeks for 3-6 courses. Patients are followed monthly for 3 months, every 2 months for 6 months, and then every 3 months thereafter.

PROJECTED ACCRUAL: Approximately 470 patients will be accrued for this study within 4.7 years.

Ages Eligible for Study:  18 Years   -   75 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of B-cell chronic lymphocytic leukemia
• Co-expression of CD5/CD19 or CD5/CD20 positivity, dim sIg, and CD23 positivity
• Previously untreated advanced disease defined as presence of at least 1 of the following:
• Total tumor mass (TTM) score greater than 9
• TTM doubling time less than 12 months
• Bone marrow failure (platelet count less than 100,000/mm^3 and/or hemoglobin less than 10 g/dL)

PATIENT CHARACTERISTICS: Age:

• 18 to 75

Performance status:

• WHO 0-2

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin less than 3 times upper limit of normal (ULN)
• Hepatitis B negative
• No active hepatitis C

Renal:

• Creatinine less than 3 times ULN OR
• Creatinine clearance greater than 0.5 times normal

Cardiovascular:

• No severe cardiovascular disease
• No arrhythmia requiring chronic treatment
• No New York Heart Association class III or IV congestive heart failure
• No symptomatic ischemic heart disease

Other:

• No uncontrolled systemic infection
• HIV negative
• No prior or concurrent uncontrolled malignancy
• No prior or concurrent central nervous system or psychiatric disorders requiring hospitalization
• No psychological, familial, sociological, or geographical condition that would preclude study participation

PRIOR CONCURRENT THERAPY: Biologic therapy:

• No prior biologic therapy

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Prior steroid therapy for less than 2 weeks allowed

Radiotherapy:

• No prior radiotherapy

Surgery:

• Not specified

Belgium
      Cliniques Universitaires Saint-Luc, Brussels,  1200,  Belgium
      Hopital de Jolimont, Haine-Saint-Paul,  7100,  Belgium
      Hopital Universitaire Erasme, Brussels,  1070,  Belgium
Czech Republic
      University Hospital - Olomouc, Olomouc,  775 20,  Czech Republic
Hungary
      County Hospital, Kaposvar,  H-7400,  Hungary
Italy
      Azienda Ospedaliera Papardo, Messina,  Italy
      Ospedale Sant' Eugenio, Rome,  00144,  Italy
Macedonia, The Former Yugoslav Republic of
      Clinical Center Skopje, Skopje,  91000,  Macedonia, The Former Yugoslav Republic of
Netherlands
      Leiden University Medical Center, Leiden,  2300 CA,  Netherlands
      Leyenburg Ziekenhuis, 's-Gravenhage,  2545 CH,  Netherlands
      Onze Lieve Vrouwe Gasthuis, Amsterdam,  1091 HA,  Netherlands
      University Medical Center Nijmegen, Nijmegen,  NL-6500 HB,  Netherlands
Portugal
      Hospital Escolar San Joao, Porto,  4200,  Portugal

Study chairs or principal investigators

Branimir Jaksic, MD, PhD,  University of Zagreb Medical School   

Study ID Numbers:  CDR0000068650; EORTC-06992-CLL-3
Record last reviewed:  July 2004
Last Updated:  October 13, 2004
Record first received:  June 6, 2001
ClinicalTrials.gov Identifier:  NCT00017108
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08