Fludarabine, Cyclophosphamide, and Rituximab in Treating Patients With Chronic Lymphocytic Leukemia

• Complete remission rate by NCI response criteria and minimal residual disease (MRD) analysis [ Time Frame: A formal assessment of response by NCI Criteria (Appendix 3) with the addition of assessment of minimal residual disease in the marrow and if relevant assessment of bulky disease by CT scanning will be made after 4 +/-6 courses of therapy. ] [ Designated as safety issue: No ]
  

• Time to treatment failure (TFF) [ Time Frame: A clinical assessment of response will be made after 4 courses of therapy, Patients with evidence of progressive disease will stop therapy and will be deemed to have failed treatment. ] [ Designated as safety issue: No ]
  
• Overall survival [ Time Frame: at 10 years ] [ Designated as safety issue: No ]
  
• Predictive value of immunophenotype, FISH, and hypermutation analysis in determining TTF and OS [ Time Frame: See description ] [ Designated as safety issue: No ]

  Timing and type of response assessment

  During chemotherapy. A clinical assessment of response will be made after 4 courses of therapy. Patients with evidence of progressive disease will stop therapy and will be deemed to have failed treatment. A formal assessment of response by NCI Criteria (Appendix 3) with the addition of assessment of minimal residual disease in the marrow and if relevant assessment of bulky disease by CT scanning will be made after 4 +/-6 courses of therapy.

  Following chemotherapy. Disease assessment after the end of therapy will involve a history(recording B-symptoms), complete physical examination, full blood count and blood MRD analysis every 6 months for 5 years and then annually for 5 years or until disease progression.

  
  
• Acute and chronic toxicity as assessed by NCI criteria [ Time Frame: A formal assessment of response by NCI Criteria (Appendix 3) with the addition of assessment of minimal residual disease in the marrow and if relevant assessment of bulky disease by CT scanning will be made after 4 +/-6 courses of therapy. ] [ Designated as safety issue: Yes ]
  

OBJECTIVES:

Primary

• Evaluate the efficacy, in terms of complete remission rate, of fludarabine phosphate, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia.

Secondary

• Determine the time to treatment failure (TTF) in these patients.
• Determine the overall survival of these patients at 10 years.
• Assess the predictive value of immunophenotype, hypermutation analysis, and FISH in determining TTF and OS in these patients.
• Determine the safety profile of this regimen.

OUTLINE: This is a multicenter study.

Patients receive fludarabine IV over 30 minutes or orally and cyclophosphamide IV or orally on days 1-3 and pegfilgrastim subcutaneously on day 4. Starting on course 2, patients receive rituximab IV on day 1. Treatment repeats every 28 days for up to 6* courses in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients achieving negative minimal residual disease receive 4 courses of treatment.

Blood samples are collected periodically for biomarker analysis. Samples are analyzed for protein expression (i.e., CD38, CD20, and ZAP70) by flow cytometry; quantitative immunoglobulins, β2-microglobulin, and T-cell subsets by electrophoresis; IgVH mutation status; and cytogenetics (i.e., +12, del 13q, del 11q, and del 17p) by FISH.

After completion of study therapy, patients are followed every 6 months for 5 years and then annually for 5 years.