Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia

被引：298

作者：

Ahn, Inhye E. ^{[1
]}

Underbayev, Chingiz ^{[2
]}

Albitar, Adam ^{[3
]}

Herman, Sarah E. M. ^{[2
]}

Tian, Xin ^{[4
]}

Maric, Irina ^{[5
]}

Arthur, Diane C. ^{[6
]}

Wake, Laura ^{[6
]}

Pittaluga, Stefania ^{[6
]}

Yuan, Constance M. ^{[6
]}

Stetler-Stevenson, Maryalice ^{[6
]}

Soto, Susan ^{[2
]}

Valdez, Janet ^{[2
]}

Nierman, Pia ^{[2
]}

Lotter, Jennifer ^{[2
]}

Xi, Liqiang ^{[6
]}

Raffeld, Mark ^{[6
]}

Farooqui, Mohammed ^{[2
]}

Albitar, Maher ^{[3
]}

Wiestner, Adrian ^{[2
]}

机构：

[1] Med Oncol Serv, Natl Canc Inst, Bethesda, MD 20892 USA

[2] Natl Heart & Blood Inst, Natl Lung & Blood Inst, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA

[3] NeoGen Labs, Irvine, CA USA

[4] Off Biostat Res, Natl Heart & Blood Inst, Natl Lung & Blood Inst, Bethesda, MD USA

[5] Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA

[6] Pathol Lab, Natl Canc Inst, Natl Inst Hlth, Bethesda, MD 20892 USA

来源：

BLOOD | 2017年 / 129卷 / 11期

基金：

美国国家卫生研究院;

关键词：

TYROSINE KINASE INHIBITOR; PHASE-II; TUMOR PROLIFERATION; INITIAL THERAPY; OPEN-LABEL; IN-VIVO; CLL; TRIAL; MUTATIONS; LYMPHOMA;

D O I：

10.1182/blood-2016-06-719294

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations in BTK and PLCG2. 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, TP53 aberration, advanced Rai stage, and high beta-2 microglobulin were independently associated with inferior progression-free survival (P<.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 BTK (Cys481) and/or PLCG2 (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 highsensitivity testing (detection limit similar to 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.

引用

页码：1469 / 1479

页数：11

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