Certain mutations in relapsed chronic lymphocytic leukemia (CLL) after targeted therapy have the potential to be used as a biomarker for relapse, according to research published in the Journal of Clinical Oncology (May 2017;35[13]:1437-1443).
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The Bruton tyrosine kinase (BTK)-inhibitor ibrutinib has revolutionized the treatment paradigm for CLL. While most patients exhibit durable remissions after ibrutinib, some patients experience relapse. Previous trials have shown that relapse on ibrutinib can be a result of acquired mutations in BTK at the binding site of ibrutinib or in PLCG2, the protein immediately downstream of BTK. However, data regarding the true scope of relapse on ibrutinib and the association with resistance mutations are limited.
Jennifer A Woyach, MD, Ohio State University, and colleagues sought to analyze the natural history of ibrutinib-resistant CLL in regards to outcomes and mechanisms for relapse as well as suggest strategies for monitoring resistance mutations. Researchers sampled patients from 4 studies involving ibrutinib in their analysis. Researchers performed deep sequencing for BTK and PLCG2 retrospectively on patients who experienced relapse and prospectively on a screening population.
After a median follow-up of 3.4 years, the estimated cumulative incidence of progression at 4 years was 19% (95% CI, 14%-24%). Identified risk factors for progression included baseline karyotypic complexity, presence of del (17) (p13.1), and age younger than 65 years.
Among the retrospectively-analyzed patient cohort who experienced relapse, acquired mutations of BTK and PLCG2 were found in 85% (95% CI, 71%-94%). These mutations were detected a median of 9.3 months (95% CI, 7.6-11.7 months) before relapse.
Among the prospectively-analyzed patient cohort (n = 112), 8 patients had experienced relapse, all of whom had acquired the mutations before relapse. Resistance mutations were identified in an additional 8 patients who had not met criteria for clinical relapse.
Researchers concluded that the large cohort of patients demonstrate definitively that BTK and PLCG2 mutations are the predominant mechanism from which CLL becomes resistant to ibrutinib.
Additionally, researchers acknowledge that clinical resistance is preceded by a period of asymptomatic clonal expansion, which suggests a biomarker for relapse and an impetus for targeting these cells with alternative therapies before relapse occurs.
Further research into intervention strategies are needed for patients who exhibit resistance to ibrutinib, the authors write. — Zachary Bessette
