Acquired mutations in BTK or PLCG2 were detected in patients with chronic lymphocytic leukemia (CLL) prior to relapse after treatment with ibrutinib and may be a marker of ibrutinib resistance, according to a retrospective study published in the Journal of Clinical Oncology.1

Ibrutinib is highly efficacious and results in durable responses among most patients with CLL, though some patients will relapse with progressive disease or Richter transformation.

Previous studies suggest that relapse during ibrutinib therapy may be caused by acquired mutations in BTK or PLCG2, whose protein product is downstream of BTK. The purpose of this study was to evaluate the natural course of ibrutinib-resistant CLL.

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Data from 4 sequential trials of ibrutinib in CLL were analyzed using deep sequencing for BTK and PLCG2 retrospectively in patients who experienced relapse and prospectively in a screening cohort. Sequencing was performed on samples from the screening cohort every 3 months.

At 4 years, the estimated cumulative incidence of disease progression in the retrospective cohort was 19% (95% CI, 14-24%). Among those who relapsed, 85% (95% CI, 71-94%) acquired BTK or PLCG2 mutations a median 9.3 months (95% CI, 7.6-11.7 months) prior to relapse.

In the prospective screening cohort, about 7% (8 of 112 patients, to date) experienced relapse, all of whom acquired the mutation resulting in the BTKC481S alteration prior to relapse.

RELATED: CLL: Long-term Outcomes After Ibrutinib Discontinuation

According to the authors, “we are likely just starting to see the first emergence of relapse in the community setting.” They concluded that understanding the molecular and clinical mechanisms of relapse “may allow for strategic alterations in monitoring and management that could change the natural history of ibrutinib resistance.”


  1. Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017 Feb 13. doi: 10.1200/JCO.2016.70.2282 [Epub ahead of print]