Elsevier

The Lancet

Volume 376, Issue 9747, 2–8 October 2010, Pages 1164-1174
The Lancet

Articles
Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial

https://doi.org/10.1016/S0140-6736(10)61381-5Get rights and content

Summary

Background

On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia.

Methods

Treatment-naive, physically fit patients (aged 30–81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m2 per day) and cyclophosphamide (250 mg/m2 per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m2 on day 0 of first course, and 500 mg/m2 on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918.

Findings

408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46–0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48–0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group.

Interpretation

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia.

Funding

F Hoffmann-La Roche.

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.

Section snippets

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

References (41)

  • J Golay et al.

    CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59

    Blood

    (2001)
  • D Huhn et al.

    Rituximab therapy of patients with B-cell chronic lymphocytic leukemia

    Blood

    (2001)
  • H Schulz et al.

    Phase II study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia

    Blood

    (2002)
  • JC Byrd et al.

    Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011

    Blood

    (2005)
  • CS Tam et al.

    Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia

    Blood

    (2008)
  • BD Cheson et al.

    National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment

    Blood

    (1996)
  • V Kunzmann et al.

    Tumor cell agglutination and not solely cytokine release as mechanism of adverse reactions during anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) treatment

    Blood

    (2001)
  • U Winkler et al.

    Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8)

    Blood

    (1999)
  • H Döhner et al.

    p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias

    Blood

    (1995)
  • H Döhner et al.

    11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis

    Blood

    (1997)
  • Cited by (1633)

    • Frontline Therapy of CLL—Changing Treatment Paradigms

      2024, Current Hematologic Malignancy Reports
    View all citing articles on Scopus

    Contributed equally

    View full text