Purine Antagonists for Chronic Lymphocytic Leukaemia

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Abstract
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 to 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 We included full‐text and abstract publications as well as unpublished data.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 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). 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. 嘌呤拮抗劑(Purine Antagonists)治療慢性淋巴細胞白血病(Chronic Lymphocytic Leukaemia) 最近的試驗發現在治療B細胞之慢性淋巴白血病上, 使用嘌呤拮抗劑比烷基化劑藥物為基礎的化學治療(alkylatorbased regimens)又更好的治療反應率. 然而, 沒有研究顯示在存活時間上有幫助. 以確定在治療新診斷的B細胞之慢性淋巴細胞白血病上, 使用的嘌呤拮抗劑比上烷基化劑(單獨或合併使用) 是否有任何好處. 收集醫學資料庫(Cochrane Library, MEDLINE, EMBASE), 利用電子和/或手工搜查會議記錄和於網路上有註冊的試驗(包含1990年到2003年). 所有的引用文獻均確認過其試驗資訊. 我們還聯繫在該領域的專家和製藥公司 在未治療過的的B細胞之慢性淋巴細胞白血病的患者中,比較單用嘌呤拮抗劑或以烷基化劑藥物為基礎的化學治療的隨機對照試驗皆被納入. 我們選擇包括全文和摘要以及未發表的數據. 數據搜集和質量評價由兩個獨立的檢閱者重覆進行. 如有遺失的資料將從原作者處取得. 其研究的終點包括總存活期, 總有反應率, 完全緩解的比率, 無疾病進展存活期, 治療相關的併發症和死亡率. 五份隨機研究, 包含1838位隨機患者被包含進來. 有一些證據顯示對於使用的嘌呤拮抗劑比上烷基化劑, 能提高整體治療後總存活期, 但在統計學上沒有達到統計上的意義(HR: 0.89 [95％CI 0.78 – 1.01]，4個研究中，共1638位病患). 然而, 總反應率的相對危險度(RR: 1.22 [95％CI 1.13 – 1.31]，5個研究，共 1751位病患)和完全緩解的比率(RR: 1.94 [95％CI 1.65 – 2.28]，5個研究，共1751病患)則明顯較高, 且有較長的無疾病進展存活期(HR: 0.70 [95％CI 0.61 – 0.82]，4個研究，共1638位病患). 在接受嘌呤拮抗劑治療的患者, 發生第三級或第四級感染顯著較高(RR: 1.83 [95％ 1.30 – 2.58]，4個研究，共1620位病患). 至於第三級或第四級中性球細胞低下的相對危險度則無顯著差異(RR: 1.14 [95％CI 0.98 – 1.34]，4個研究，共1620位病患), 和治療相關的死亡率亦無顯著差異(RR: 0.94 [95％CI 0.45 – 1.95]). 總體的溶血性貧血發病率是低的, 但在嘌呤拮抗劑組還是有顯著增加(RR: 3.36 [95％CI 1.27 – 8.91]，3個研究，共1258位病患). 儘管在B細胞之慢性淋巴白血病的第一線治療上, 單獨使用嘌呤拮抗劑和烷基化劑為主的化學治療比較可顯著增加總反應率, 完全緩解率, 及無疾病進展存活期, 我們仍無法發現總存活期有顯著改善. 此外, 使用嘌呤拮抗劑也增加了第三級或第四級感染和溶血性貧血的機率. 本摘要由慈濟醫院吳懿峰翻譯。 此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。 儘管越來越多對於腫瘤生物學的認識, B細胞之慢性淋巴白血病仍是ㄧ不可治癒的疾病. 到目前為止, 化學治療使用烷基化劑, 如苯丁酸氮芥(chlorambucil), 一直是B細胞之慢性淋巴白血病的主要治療, 然而, 嘌呤拮抗劑,...