ArticlesAddition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial
Introduction
Chronic lymphocytic leukaemia is the most common adult lymphoid malignant disease in western countries, affecting about five in 100 000 of the population per year.1, 2 Its clinical course is highly variable and can be predicted by use of various criteria,3 including clinical staging,4, 5 chromosomal abnormalities,6 or mutations of the immunoglobulin heavy variable chain (IGHV) gene.7, 8
For more than 40 years, chronic lymphocytic leukaemia has been treated with various chemotherapies. Chlorambucil, an alkylating drug, was the main drug for three decades.9, 10 Combinations of alkylating drugs with vinca alkaloids or anthracycline drugs did not improve outcomes.11 In the 1990s, purine analogues were a new class of drugs that were active against chronic lymphocytic leukaemia.12, 13 In the past decade, the combination of purine analogues with alkylating drugs, particularly fludarabine and cyclophosphamide, improved the rates of clinical response, complete remission, and progression-free survival (PFS).14, 15, 16 Until now, however, none of these drug combinations have shown an improvement in overall survival in clinical studies.
Chemoimmunotherapy—the addition of monoclonal antibodies to chemotherapy—was created for the treatment of indolent and aggressive lymphoma. Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen,17 became the standard drug for use with chemotherapy for various B-cell lymphomas.18, 19 In chronic lymphocytic leukaemia, however, the low expression of the CD20 antigen on leukaemic cells,20, 21 and poor response rates with standard-dose rituximab led to the initial expectation that rituximab might not generate sufficient clinical benefit in this disease.22 However, higher doses of rituximab used alone improved response rates.23 Moreover, the results of phase 2 trials suggested that rituximab in combination with chemotherapy might have additive or synergistic effects in pretreated and treatment-naive patients.24, 25, 26, 27, 28 In these trials, the standard dose of rituximab (375 mg/m2 per day) was increased to 500 mg/m2 per day.24 In a study of 300 treatment-naive patients, the combination of fludarabine, cyclophosphamide, and rituximab resulted in an overall response rate of 95%, with 72% of patients achieving a complete response.24, 28 These response rates were among the highest reported so far for first-line treatments in patients with chronic lymphocytic leukaemia. On the basis of these promising results, the German Chronic Lymphocytic Leukaemia Study Group initiated a phase 3 study to compare the efficacy and safety of fludarabine and cyclophosphamide with fludarabine, cyclophosphamide, and rituximab as first-line treatment in patients with advanced, symptomatic chronic lymphocytic leukaemia.
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Study design and patients
A prospective, randomised, open-label, phase 3 study was done in 190 centres in 11 countries. Treatment-naive patients (aged 30–81 years) diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia in Binet stage C,4 or with confirmed active disease in Binet stages A or B29 were enrolled (webappendix p 1). Additional inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and a low comorbidity, which was defined as a cumulative illness
Results
Previously untreated patients with chronic lymphocytic leukaemia were enrolled between July, 2003, and March, 2006. Figure 1 shows the trial profile. Patients were randomly assigned to receive chemotherapy with fludarabine and cyclophosphamide, or chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. Both groups were well balanced with respect to age, sex, disease stage, physical fitness (cumulative illness rating scale, ECOG), creatinine clearance, serum concentrations of β2
Discussion
The combination of fludarabine, cyclophosphamide, and rituximab substantially increased the proportions of patients achieving a complete remission and remaining free of progression for 3 years. Most importantly, this treatment also increased the likelihood of patients surviving 3 years or more after randomisation (table 4) and was an independent prognostic factor for overall survival in the multivariate analysis. This result is unexpected, because treatment of an indolent disease of recurrent
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