Purine Antagonists for Chronic Lymphocytic Leukaemia

Despite increasing insight into its tumour biology B-CLL remains an incurable disease. So far, chemotherapy with alkylating agents such as chlorambucil has been the mainstay of treatment in B-CLL. However, purine antagonists such as fludarabine are increasingly being used, as it has been suggested that these novel drugs are more effective. This review confirms the greater response rates achievable by using purine antagonists but at the cost of greater toxicity, mainly infections. There is inconclusive evidence whether treatment with purine antagonists improves survival. None of the studies included quality of life data. More research is needed to fully explore the role of purine antagonists in the treatment of B-CLL and their potential impact on survival.

Authors' conclusions: 

Despite significantly increased overall response and complete remission rates and longer progression-free survival with first-line treatment of B-CLL patients with single-agent purine antagonists, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine antagonists also augments the risk for grade III/IV infections and haemolytic anaemia.

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Background: 

Recent trials suggest improved response rates for purine antagonists compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage.

Objectives: 

To determine if there is any advantage of purine antagonists compared to alkylating agents (alone or in combination) in the treatment of patients with previously untreated B-CLL.

Search strategy: 

Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and internet-based trial registers were searched electronically and/or by hand (1990 to 2003). All references were checked for further trial information. We also contacted experts in the field and pharmaceutical companies.

Selection criteria: 

Randomised controlled trials comparing purine antagonists as single agents with alkylator-based regimens in patients with previously untreated B-CLL were included. We included full-text and abstract publications as well as unpublished data.

Data collection and analysis: 

Data extraction and quality assessment were done in duplicate by two independent reviewers. Missing data were obtained from original authors. Endpoints included overall survival, overall response rate, rate of complete remissions, progression-free survival, treatment-related morbidity and mortality.

Main results: 

Five trials with 1838 randomised patients were included. There is some evidence for improved overall survival after treatment with purine antagonists compared to alkylators, but statistical significance was not reached (HR 0.89 [95% CI 0.78 to 1.01], 4 trials, N = 1638). However, the relative risk for achieving an overall response (RR 1.22 [95% CI 1.13 to 1.31], 5 trials, N = 1751) and complete remission (RR 1.94 [95% CI 1.65 to 2.28], 5 trials, N = 1751) was significantly higher, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61 to 0.82], 4 trials, N = 1638). Incidence of grade III/IV infections was significantly higher in patients receiving treatment with purine antagonists (RR 1.83 [95% 1.30 to 2.58], 4 trials, N = 1620). There was no significant difference concerning the relative risk for grade III/IV neutropenia (RR 1.14 [95% CI 0.98-1.34], 4 trials, N = 1620) and therapy-related mortality (RR 0.94 [95% CI 0.45 to 1.95]). Overall incidence of haemolytic anaemia was low, but significantly increased in the purine antagonist group (RR 3.36 [95% CI 1.27 to 8.91], 3 trials, N = 1258).

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