Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: A systematic review and meta-analysis

SummaryBackgroundRecent trials suggest improved response rates for purine analogues compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage. Thus, a systematic Cochrane review may be able to further define the role of purine analogues in the first-line treatment of B-CLL.MethodsRandomized controlled trials comparing single-agent purine analogues with alkylator-based regimens were included. Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and trial registers were searched. We included full-text and abstract publications as well as unpublished data. Relative risks (RR) and hazard ratios (HR) were calculated under a fixed-effects model, clinical and statistical heterogeneity was examined with sensitivity analyses and meta-regression. If applicable, numbers needed to treat or harm (NNT, NNH) were also determined.FindingsFive trials with 1838 randomized patients were included. Importantly, four trials had a cross-over design. There was a trend for improved overall survival for patients receiving purine analogues as initial therapy but statistical significance was just not reached (HR 0.89 [95% CI 0.78–1.01]). The RR for achieving an overall (RR 1.22 [95% CI 1.13–1.31]; NNT 8 [95% CI 6–13]) and complete response (RR 1.94 [95% CI 1.65–2.28]; NNT 6 [5–8]) was significantly improved, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61–0.82]). Incidence of grade III/IV infections (RR 1.83 [95% CI 1.30–2.58]; NNH 20 [95% CI 12.5–50]) and haemolytic anaemia (RR 3.36 [95% CI 1.27–8.91]; NNH 21 [95% CI 6–185]) was significantly higher in patients receiving purine analogues.InterpretationDespite significantly increased response rates and longer progression-free survival with purine analogues as first-line therapy, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine analogues augments the risk for grade III/IV infections and haemolytic anaemia.