Single-agent Purine Analogues for the Treatment of Chronic Lymphocytic Leukaemia: A Systematic Review and Meta-Analysis

Cancer Treat Rev. 2006 Aug;32(5):377-89. doi: 10.1016/j.ctrv.2006.05.002. Epub 2006 Jun 21.

Abstract

Background: Recent 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.

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 We included full-text and abstract publications as well as unpublished data.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

Findings: Five 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.

Interpretation: Despite 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.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Anemia, Hemolytic / chemically induced
  • Antineoplastic Agents / therapeutic use*
  • Cladribine / therapeutic use
  • Disease-Free Survival
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Pentostatin / therapeutic use
  • Randomized Controlled Trials as Topic
  • Survival Analysis
  • Treatment Outcome
  • Vidarabine / analogs & derivatives
  • Vidarabine / therapeutic use

Substances

  • Antineoplastic Agents
  • Pentostatin
  • Cladribine
  • Vidarabine
  • fludarabine