Most patients with follicular lymphoma (FL) experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of several B-cell malignancies, showed promising activity in FL in a phase 1 study. We report the results of a phase 2 trial evaluating ibrutinib in recurrent FL. Forty patients with recurrent FL were treated with ibrutinib 560 mg/d until progression or intolerance. The primary end point was overall response rate (ORR). Exploratory analyses included correlations of outcome with recurrent mutations identified in a cancer gene panel that used next-generation sequencing in pretreatment biopsies from 31 patients and results of early interim positron emission tomography/computed tomography scans in 20 patients. ORR was 37.5% with a complete response rate of 12.5%, median progression-free survival (PFS) of 14 months, and 2-year PFS of 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared with those who were rituximab refractory (16.7%) (P = .04). CARD11 mutations were present in 16% of patients (5 of 31) and predicted resistance to ibrutinib with only wild-type patients responding (P = .002). Maximum standardized uptake value at cycle 1 day 8 correlated with response and PFS. Ibrutinib was well-tolerated with a toxicity profile similar to labeled indications. Ibrutinib is a well-tolerated treatment with modest activity in relapsed FL. Evaluation of BTK inhibitors in earlier lines of therapy may be warranted on the basis of improved response rates in rituximab-sensitive disease. Somatic mutations such as CARD11 may have an impact on response to ibrutinib, may inform clinical decisions, and should be evaluated in larger data sets. This trial was registered at www.clinicaltrials.gov as #NCT01849263.

中文翻译：

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单药依鲁替尼治疗复发性或难治性滤泡性淋巴瘤：2 期联合试验


大多数滤泡性淋巴瘤 (FL) 患者会经历多次复发，需要后续治疗。依鲁替尼 (Ibrutinib) 是一种布鲁顿酪氨酸激酶 (BTK) 抑制剂，被批准用于治疗多种 B 细胞恶性肿瘤，在一项 1 期研究中显示出对 FL 有希望的活性。我们报告了一项评估依鲁替尼治疗复发性 FL 的 2 期试验的结果。 40 名复发性 FL 患者接受依鲁替尼 560 mg/d 治疗，直至出现进展或不耐受。主要终点是总体缓解率（ORR）。探索性分析包括结果与癌症基因组中发现的复发性突变的相关性，该组在 31 名患者的治疗前活检中使用下一代测序，以及 20 名患者的早期中期正电子发射断层扫描/计算机断层扫描结果。 ORR 为 37.5%，完全缓解率为 12.5%，中位无进展生存期 (PFS) 为 14 个月，2 年 PFS 为 20.4%。与利妥昔单抗难治性患者 (16.7%) 相比，疾病对利妥昔单抗敏感的患者 (52.6%) 的缓解率显着较高 (P = .04)。 16% 的患者（31 名患者中有 5 名）存在 CARD11 突变，并预测对依鲁替尼产生耐药性，只有野生型患者有反应 (P = .002)。第 1 周期第 8 天的最大标准化摄取值与反应和 PFS 相关。依鲁替尼具有良好的耐受性，其毒性特征与标签适应症相似。依鲁替尼是一种耐受性良好的治疗方法，对复发性 FL 具有中等活性。基于利妥昔单抗敏感疾病缓解率的提高，可能有必要对早期治疗中的 BTK 抑制剂进行评估。 CARD11 等体细胞突变可能会影响依鲁替尼的反应，可能为临床决策提供信息，并且应该在更大的数据集中进行评估。该试验在 www.clinicaltrials.gov 上注册为#NCT01849263。