Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity
Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity
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DOI：
10.1182/blood-2016-03-707133
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发表时间：
2016-07-14
期刊：
影响因子：
20.3
通讯作者：
Brown, Jennifer R.
中科院分区：
文献类型：
--
作者：
Lampson, Benjamin L.;Kasar, Siddha N.;Brown, Jennifer R.
Idelalisib 是一种 PI3Kd 的小分子抑制剂，已被证明对治疗复发/难治性慢性淋巴细胞白血病 (CLL) 有效。为了评估 idelalisib 作为一线治疗的效果，我们在一项 2 期研究中招募了 24 名受试者，该研究包括 2 个月的 idelalisib 单药治疗，以及 6 个月的 idelalisib 和抗 CD20 抗体 ofatumumab 联合治疗。中位随访期为 14.7 个月后，发现肝毒性是一种常见且往往严重的不良事件。研究期间，共有 19 名受试者 (79%) 经历了 1 级 ALT 或 AST 升高，13 名受试者 (54%) 经历了 3 级以上转氨炎。发生转氨炎的中位时间为 28 天，发生在奥法木单抗引入之前。年龄较小和免疫球蛋白重链状态突变是发生肝毒性的重要危险因素。多种证据表明这种肝毒性是免疫介导的。从 2 名患有转氨炎的受试者身上采集的肝活检标本中发现淋巴细胞浸润，并且在经历肝毒性的受试者中，促炎细胞因子 CCL-3 和 CCL-4 的水平较高。所有转氨炎病例均通过停药、启动免疫抑制剂或两者兼而有之得到解决，并且在重新开始使用 idelalisib 时，服用类固醇的患者的复发性毒性发生率较低。在治疗中出现毒性的患者中发现外周血调节性 T 细胞减少，这与免疫介导的机制一致。这些结果表明，应谨慎行事，因为此类药物是针对 CLL 开发的，特别是对于先前未接受过疾病特异性治疗的年轻患者。这项研究在 www.clinicaltrials.gov 上注册为#NCT02135133。
Idelalisib is a small-molecule inhibitor of PI3Kd with demonstrated efficacy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as front-line therapy, we enrolled 24 subjects in a phase 2 study consisting of 2 months of idelalisib monotherapy followed by 6 months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up period of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. A total of 19 subjects (79%) experienced either grade >= 1 ALT or AST elevation during the study, and 13 subjects (54%) experienced grade >= 3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain status were significant risk factors for the development of hepatotoxicity. Multiple lines of evidence suggest that this hepatotoxicity was immune mediated. A lymphocytic infiltrate was seen on liver biopsy specimens taken from 2 subjects with transaminitis, and levels of the proinflammatory cytokines CCL-3 and CCL-4 were higher in subjects experiencing hepatotoxicity. All cases of transaminitis resolved either by holding the drug, initiating immunosuppressants, or both, and rates of recurrent toxicity were lower in patients taking steroids when idelalisib was reinitiated. A decrease in peripheral blood regulatory T cells was seen in patients experiencing toxicity on therapy, which is consistent with an immune-mediated mechanism. These results suggest that caution should be taken as drugs within this class are developed for CLL, particularly in younger patients who have not received prior disease-specific therapy. This study was registered at www.clinicaltrials.gov as #NCT02135133.