Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R
Innsbruck University Hospital, Division of Haematology & Oncology, Anichstrasse 35, A-6020 Innsbruck, Austria.
Cochrane Database Syst Rev. 2006 Jul 19;2006(3):CD004270. doi: 10.1002/14651858.CD004270.pub2.
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 We included full-text and abstract publications as well as unpublished data.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).
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 hemolytic anemia.
近期试验表明，在B细胞慢性淋巴细胞白血病（B-CLL）治疗中，与基于烷化剂的治疗方案相比，嘌呤拮抗剂的缓解率有所提高。然而，尚无试验能够显示出生存优势。
确定在治疗初治B-CLL患者时，与烷化剂（单独使用或联合使用）相比，嘌呤拮抗剂是否具有任何优势。
通过电子检索和/或手工检索医学数据库（Cochrane图书馆、MEDLINE、EMBASE）、会议论文集和基于互联网的试验注册库（1990 - 2003年）。检查所有参考文献以获取更多试验信息。我们还联系了该领域的专家和制药公司。
纳入比较嘌呤拮抗剂单药与基于烷化剂的治疗方案治疗初治B-CLL患者的随机对照试验。我们纳入了全文和摘要出版物以及未发表的数据。
由两名独立的审阅者重复进行数据提取和质量评估。缺失的数据从原始作者处获取。终点指标包括总生存期、总缓解率、完全缓解率、无进展生存期、治疗相关的发病率和死亡率。
纳入了5项试验，共1838例随机分组患者。有一些证据表明，与烷化剂相比，嘌呤拮抗剂治疗后的总生存期有所改善，但未达到统计学显著性（风险比0.89 [95%可信区间0.78 - 1.01]，4项试验，n = 1638）。然而，获得总缓解（相对风险1.22 [95%可信区间1.13 - 1.31]，5项试验，n = 1751）和完全缓解（相对风险1.94 [95%可信区间1.65 - 2.28]，5项试验，n = 1751）的相对风险显著更高，从而带来更长时间的无进展生存期（风险比0.70 [95%可信区间0.61 - 0.82]，4项试验，n = 1638）。接受嘌呤拮抗剂治疗的患者中III/IV级感染的发生率显著更高（相对风险1.83 [95% 1.30 - 2.58]，4项试验，n = 1620）。III/IV级中性粒细胞减少的相对风险（相对风险1.14 [95%可信区间0.98 - 1.34]，4项试验，n = 1620）和治疗相关死亡率（相对风险0.94 [95%可信区间0.45 - 1.95]）无显著差异。溶血性贫血的总体发生率较低，但在嘌呤拮抗剂组显著增加（相对风险3.36 [95%可信区间1.27 - 8.91]，3项试验，n = 1258）。
尽管单药嘌呤拮抗剂一线治疗B-CLL患者可显著提高总缓解率和完全缓解率，并延长无进展生存期，但与基于烷化剂的治疗方案相比，我们未能检测到总生存期有统计学显著性的改善。此外，使用嘌呤拮抗剂还会增加III/IV级感染和溶血性贫血的风险。
