Genetic Mutations May Be Used as Biomarkers for Relapsing CLL

Mutations in the BTK and PLCG2 genes have the potential to be used as a biomarker for relapse of chronic lymphocytic leukemia (CLL) after treatment with ibrutinib, according to a retrospective review published in the Journal of Clinical Oncology (published online February 13, 2017; doi:10.1200/JCO.2016.70.2282).
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Relapse of CLL after treatment with ibrutinib is an issue of increasing clinical significance. Previous studies have shown that relapse on ibrutinib can be a result of acquired mutations in BTK at the binding site of ibrutinib or in PLCG2, a nearby protein to BTK. Although such studies have suggested association between these mutations and ibrutinib resistance, the true scope of relapse on ibrutinib and the association with resistance mutations is not fully understood.

Jennifer A Woyach, MD, Ohio State University in Columbus, and colleagues reviewed 308 patients with relapsed or refractory CLL enrolled in sequential clinical trials of ibrutinib – 237 of whom received single-agent ibrutinib and 71 of whom received ibrutinib in combination with ofatumumab. All of the patients exhibited CLL associated with high-risk genetic features.

Results of the analysis showed that after a median follow-up time of 3.4 years, 158 patients discontinued ibrutinib – 83 did so because of disease progression in the form of transformation (n = 27), prolymphocytic leukemia (n = 1), and progressive CLL (N = 55). Of the 55 patients with progressive CLL, sequencing samples showed that 40 of them had mutations in BTK, PLCG2, or both at relapse.

Among patients who had CLL relapse, acquired mutations in BTK and PLCG2 occurred in 85% of cases. The mutations arose a median of 9.3 months prior to overt disease relapse, according to Dr. Woyach.

Of a group of 112 patients examined prospectively, 8 patients had experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional 8 patients who had not met criteria for clinical relapse.

Implications of such findings include monitoring mutations in the BTK and PLCG2 genes after treatment with ibrutinib and using these mutations as a potential biomarker before relapse occurs, suggesting an opportunity for intervention. – Zachary Bessette