Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma: Results From the Open-Label, Multicenter, Phase II DAWN Study
Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma: Results From the Open-Label, Multicenter, Phase II DAWN Study
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DOI：
10.1200/jco.2017.76.8853
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发表时间：
2018-08-10
影响因子：
45.3
通讯作者：
Salles, Gilles
中科院分区：
文献类型：
--
作者：
Gopal, Ajay K.;Schuster, Stephen J.;Salles, Gilles
目的布鲁顿公司的酪氨酸激酶抑制剂伊曲替尼已在B细胞恶性肿瘤中显示出临床活性。DAWN研究评估的疗效和安全性的单剂伊鲁替尼在化学免疫治疗复发性/难治性滤泡性淋巴瘤（FL）patients.MethodsDAWN是一个开放标签，单臂，II期研究伊鲁替尼在FL患者有两个或两个以上的治疗前线。患者每日接受560 mg伊曲替尼治疗，直至疾病进展/出现不可接受的毒性。主要目的是独立审查委员会评估的总体缓解率（ORR;完全缓解加部分缓解）。探索性分析外周血T细胞亚群（基线/周期3）和细胞因子/趋化因子（基线/周期2）进行了可用samples.ResultsBetween 2013年3月和2016年5月，110例患者的中位数的三线治疗。中位随访27.7个月时，ORR为20.9%（95% CI，13.7%-29.7%，不符合主要终点的下限阈值18%）。12例患者达到完全缓解（11%; 95% CI，5.8%-18.3%）。中位缓解持续时间为19.4个月（范围：1 - 33个月），中位无进展生存期为4.6个月，30个月总生存期为61%（95% CI，0.51%-0.70%）。67%的淋巴瘤症状消退。32例发生初始放射学进展的患者中有7例在继续治疗后有反应（假进展）。最常见的不良事件是腹泻、疲劳、咳嗽和肌肉痉挛; 48.2%的患者报告了严重不良事件。在经历应答的患者中，调节性T细胞在C3 D1下调（P = 0.02），Th 1促进（抗肿瘤）细胞因子干扰素和白细胞介素-12增加结论伊曲替尼在复发/难治性FL患者的化学免疫治疗中未能达到其主要疗效终点，ORR为20.9%，尽管反应是持久的，并且与调节性T细胞的减少和促炎细胞因子的增加有关。
PurposeThe Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients.MethodsDAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee-assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples.ResultsBetween March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 (P = .02), and Th1-promoting (antitumor) cytokines interferon- and interleukin-12 increased (P .035).ConclusionWith an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.