Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia

Inhye E. Ahn, Chingiz Underbayev, Adam Albitar, Sarah E. M. Herman, Xin Tian, Irina Maric, Diane C. Arthur, Laura Wake, Stefania Pittaluga, Constance M. Yuan, Maryalice Stetler-Stevenson, Susan Soto, Janet Valdez, Pia Nierman, Jennifer Lotter, Liqiang Xi, Mark Raffeld, Mohammed Farooqui, Maher Albitar and Adrian Wiestner

Key Points

  • Most cases of ibrutinib-resistant CLL were due to mutations in BTK and/or PLCG2 and often composed of multiple independent subclones.

  • High sensitivity testing identified resistance mutations up to 15 months before manifestation of clinical progression.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


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 β-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 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 as #NCT01500733.

  • Submitted June 7, 2016.
  • Accepted December 21, 2016.
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