Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia
Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia
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DOI：
10.1182/blood-2013-11-535047
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发表时间：
2014-05-29
期刊：
影响因子：
20.3
通讯作者：
Furman, Richard R.
中科院分区：
文献类型：
--
作者：
Brown, Jennifer R.;Byrd, John C.;Furman, Richard R.
在一项1期试验中，选择性脂质激酶PI3K δ抑制剂GS-1101，CAL-101，在54例复发/难治性慢性淋巴细胞白血病（CLL）患者中进行了评价，这些患者的不良特征包括巨大淋巴结病（80%），广泛的既往治疗（中位5 [范围2 - 14]既往治疗方案）、治疗难治性疾病（70%）、未突变IGHV（91%）和del17 p和/或TP 53突变（24%）。患者以6个剂量水平的口服艾代拉里斯（范围为50 - 350 mg，每日一次或两次）进行治疗，并在获得临床益处的同时保持连续治疗。Idelalisib介导的PI3K δ抑制导致患者CLL细胞中Akt磷酸化的消除，并显著降低CLL相关趋化因子的血清水平。最常见的≥ 3级不良事件为肺炎（20%）、贫血性发热（11%）和腹泻（6%）。Idelalisib治疗导致81%的患者出现淋巴结反应。总体缓解率为72%，39%的患者符合IWCLL 2008的部分缓解标准，33%的患者符合最近更新的PR伴治疗诱导的淋巴细胞增多标准。（1，2）所有患者的中位无进展生存期为15.8个月。该研究证明了用艾代拉里斯抑制PI3Kd途径的临床效用。我们的研究结果支持Idelalisib在CLL患者中的进一步开发。这些试验在www.example.com上注册为#NCT 00710528和#NCT 01090414。
In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3K delta, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3K delta led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade >= 3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.(1,2) The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kd pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414.