Ahn Inhye E, Underbayev Chingiz, Albitar Adam, Herman Sarah E M, Tian Xin, Maric Irina, Arthur Diane C, Wake Laura, Pittaluga Stefania, Yuan Constance M, Stetler-Stevenson Maryalice, Soto Susan, Valdez Janet, Nierman Pia, Lotter Jennifer, Xi Liqiang, Raffeld Mark, Farooqui Mohammed, Albitar Maher, Wiestner Adrian
Medical Oncology Service, National Cancer Institute, and.
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
Blood. 2017 Mar 16;129(11):1469-1479. doi: 10.1182/blood-2016-06-719294. Epub 2017 Jan 3.
Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations in and The rate of resistance and clonal composition of PD are incompletely characterized. We report on CLL patients treated with single-agent ibrutinib on an investigator-initiated phase 2 trial. With median follow-up of 34 months, 15 of 84 evaluable patients (17.9%) progressed. Relapsed/refractory disease at study entry, aberration, advanced Rai stage, and high β-2 microglobulin were independently associated with inferior progression-free survival ( < .05 for all tests). Histologic transformation occurred in 5 patients (6.0%) and was limited to the first 15 months on ibrutinib. In contrast, progression due to CLL in 10 patients (11.9%) occurred later, diagnosed at a median 38 months on study. At progression, mutations in (Cys481) and/or (within the autoinhibitory domain) were found in 9 patients (10.7%), in 8 of 10 patients with progressive CLL, and in 1 patient with prolymphocytic transformation. Applying high-sensitivity testing (detection limit ∼1 in 1000 cells) to stored samples, we detected mutations up to 15 months before manifestation of clinical progression (range, 2.9-15.4 months). In 5 patients (6.0%), multiple subclones carrying different mutations arose independently, leading to subclonal heterogeneity of resistant disease. For a seamless transition to alternative targeted agents, patients progressing with CLL were continued on ibrutinib for up to 3 months, with 19.8 months median survival from the time of progression. This trial was registered at www.clinicaltrials.gov as #NCT01500733.
接受依鲁替尼治疗的慢性淋巴细胞白血病（CLL）患者的疾病进展归因于组织学转化或 和 中的获得性突变。对PD的耐药率和克隆组成尚未完全明确。我们报告了在一项研究者发起的2期试验中接受单药依鲁替尼治疗的CLL患者情况。中位随访34个月时，84例可评估患者中有15例（17.9%）病情进展。研究入组时的复发/难治性疾病、 畸变、晚期Rai分期和高β-2微球蛋白与无进展生存期较差独立相关（所有检验P<0.05）。5例患者（6.0%）发生组织学转化，且仅限于依鲁替尼治疗的前15个月。相比之下，10例患者（11.9%）因CLL导致的病情进展发生较晚，中位发病时间为研究开始后的38个月。病情进展时，9例患者（10.7%）检测到 （Cys481）和/或 （在自抑制域内）突变，其中10例病情进展的CLL患者中有8例，1例幼淋巴细胞转化患者检测到该突变。对储存样本应用高灵敏度检测（检测限约为千分之一细胞），我们在临床进展出现前15个月就检测到了突变（范围为2.9 - 15.4个月）。5例患者（6.0%）出现携带不同突变的多个亚克隆独立出现，导致耐药疾病的亚克隆异质性。为了无缝过渡到替代靶向药物，病情进展的CLL患者继续接受依鲁替尼治疗长达3个月，从病情进展时起的中位生存期为19.8个月。该试验在www.clinicaltrials.gov上注册，编号为#NCT01500733。
