Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.
Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.
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DOI：
10.1056/nejmoa1315226
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发表时间：
2014-03-13
期刊：
影响因子：
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通讯作者：
O'Brien SM
中科院分区：
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作者：
Furman RR;Sharman JP;Coutre SE;Cheson BD;Pagel JM;Hillmen P;Barrientos JC;Zelenetz AD;Kipps TJ;Flinn I;Ghia P;Eradat H;Ervin T;Lamanna N;Coiffier B;Pettitt AR;Ma S;Stilgenbauer S;Cramer P;Aiello M;Johnson DM;Miller LL;Li D;Jahn TM;Dansey RD;Hallek M;O'Brien SM
患有具有临床意义的共存疾病的复发性慢性淋巴细胞白血病（CLL）患者接受标准化疗的能力较差。该患者人群需要具有可接受副作用特征的有效治疗。在这项多中心、随机、双盲、安慰剂对照、III期研究中，我们评估了艾代拉里斯（一种磷脂酰肌醇3-激酶δ亚型的口服抑制剂）与利妥昔单抗联合治疗与利妥昔单抗联合安慰剂治疗的疗效和安全性。我们将220例肾功能下降、既往治疗引起的骨髓抑制或主要并存疾病的患者随机分配接受利妥昔单抗和艾代拉里斯（剂量为150 mg）或安慰剂，每日两次。主要终点是无进展生存期。在第一次预先规定的中期分析中，由于压倒性的疗效，根据数据和安全性监测委员会的建议，该研究提前停止。安慰剂组的中位无进展生存期为5.5个月，而艾代拉里斯组未达到（艾代拉里斯组进展或死亡的风险比为0.15; P<0.001）。与接受安慰剂的患者相比，接受艾代拉里斯的患者的总体缓解率（81% vs. 13%;比值比，29.92; P<0.001）和12个月时的总生存率（92% vs. 80%;死亡风险比，0.28; P = 0.02）有所改善。40%接受艾代拉里斯和利妥昔单抗治疗的患者发生严重不良事件，35%接受安慰剂和利妥昔单抗治疗的患者发生严重不良事件。与安慰剂和利妥昔单抗相比，艾代拉里斯和利妥昔单抗的组合显著改善了不太能够接受化疗的复发性CLL患者的无进展生存期、应答率和总生存期。（由吉利德资助; ClinicalTrials.gov编号，NCT 01539512。）
Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemo-therapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta iso-form of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemo-therapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.)