Purine antagonists for chronic lymphocytic leukaemia

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.

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.

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

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 We included full-text and abstract publications as well as unpublished data.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 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.

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 0.78-1.01], 4 trials, n=1638). However, the relative risk for achieving an overall response (RR 1.22 [95% CI 1.13-1.31], 5 trials, n=1751) and complete remission (RR 1.94 [95% CI 1.65-2.28], 5 trials, n=1751) was significantly higher, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61-0.82], 4 trials, n=1638). Incidence of grade III/IV infections was significantly higher in patients receiving treatment with purine antagonists (RR 1.83 [95% 1.30-2.58], 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 0.45-1.95]). Overall incidence of hemolytic anemia was low, but significantly increased in the purine antagonist group (RR 3.36 [95% CI 1.27-8.91], 3 trials, n=1258).

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 hemolytic anemia.