Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial
Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial
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DOI：
10.1182/blood-2017-09-804641
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发表时间：
2018-01-11
期刊：
影响因子：
20.3
通讯作者：
Fehniger, Todd A.
中科院分区：
文献类型：
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作者：
Bartlett, Nancy L.;Costello, Brian A.;Fehniger, Todd A.
大多数滤泡性淋巴瘤（FL）患者经历多次复发，需要后续治疗。伊马替尼是一种布鲁顿酪氨酸激酶（BTK）抑制剂，获批用于治疗多种B细胞恶性肿瘤，在1期研究中显示出对FL的良好活性。我们报告了一项评估伊克替尼治疗复发性FL的2期试验结果。40例复发性FL患者接受伊克替尼560 mg/d治疗，直至进展或不耐受。主要终点为总缓解率（ORR）。探索性分析包括结果与癌症基因组中确定的复发突变的相关性，该癌症基因组在31例患者的预治疗活检中使用下一代测序，并在20例患者中进行早期中期正电子发射断层扫描/计算机断层扫描。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%。利妥昔单抗敏感患者的缓解率（52.6%）显著高于利妥昔单抗难治患者（16.7%）（P = 0.04）。CARD 11突变存在于16%的患者中（31例中的5例），并预测对伊鲁替尼的耐药性，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缓解和PFS相关。伊布替尼耐受性良好，毒性特征与标签适应症相似。伊曲替尼是一种耐受性良好的治疗方法，在复发性FL中具有适度的活性。在利妥昔单抗敏感性疾病中，基于改善的应答率，可能有必要对BTK抑制剂在早期治疗中进行评估。CARD 11等体细胞突变可能会影响对伊鲁替尼的反应，可能会为临床决策提供信息，应在更大的数据集中进行评估。
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.