BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia
BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia
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DOI：
10.1200/jco.2016.70.2282
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发表时间：
2017-05-01
影响因子：
45.3
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
Woyach, Jennifer A.;Ruppert, Amy S.;Byrd, John C.
目的慢性淋巴细胞性白血病中以布鲁顿酪氨酸激酶（BTK）为靶点的伊曲替尼治疗导致了治疗模式的转变，目前的随访中复发并不常见。获得性突变BTK和PLCG2可能会导致复发，但有关这些突变的患病率和自然史的数据是limited.Patients and MethodsPatients累计到四个连续的研究伊鲁替尼被列入这些分析。BTK和PLCG2的深度测序进行回顾性的复发和前瞻性的筛选population.ResultsWith中位随访时间为3.4年的患者，估计在4年的进展的累积发病率为19%（95%CI，14%至24%）。基线核型复杂性、存在del（17）（p13.1）和年龄小于65岁是进展的风险因素。在经历复发的患者中，在85%（95%CI，71%至94%）中发现BTK或PLCG 2的获得性突变，并且在复发前估计的中位时间9.3个月（95%CI，7.6至11.7个月）检测到这些突变。在一组前瞻性检查的112名患者中，8名患者经历了复发，所有这些患者在复发前都获得了耐药突变。在另外8例尚未达到临床复发标准的患者中检测到耐药突变。我们发现，BTK和PLCG 2的突变出现较早，有可能用作未来复发的生物标志物，这表明有机会进行干预。(C)2017年美国临床肿瘤学会
PurposeTherapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited.Patients and MethodsPatients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population.ResultsWith a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse.ConclusionRelapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention. (C) 2017 by American Society of Clinical Oncology