The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is inducing durable responses
in chronic lymphocytic leukemia (CLL) patients with refractory/relapsed disease or
with TP53 defect, with BTK and PLCG2 mutations representing the predominant mechanisms
conferring secondary ibrutinib resistance. To understand the landscape of genomic
changes and the dynamics of subclonal architecture associated with ibrutinib treatment,
an ultra-deep next-generation sequencing analysis of 30 recurrently mutated genes
was performed on sequential samples of 20 patients, collected before and during single-agent
ibrutinib treatment. Mutations in the SF3B1, MGA and BIRC3 genes were enriched during
ibrutinib treatment, while aberrations in the BTK, PLCG2, RIPK1, NFKBIE and XPO1 genes
were exclusively detected in post-treatment samples. Besides the canonical mutations,
four novel BTK mutations and three previously unreported PLCG2 variants were identified.
BTK and PLCG2 mutations were backtracked in five patients using digital droplet PCR
and were detectable on average 10.5 months before clinical relapse. With a median
follow-up time of 36.5 months, 7/9 patients harboring BTK mutations showed disease
progression based on clinical and/or laboratory features. In conclusion, subclonal
heterogeneity, dynamic clonal selection and various patterns of clonal variegation
were identified with novel resistance-associated BTK mutations in individual patients
treated with ibrutinib. This article is protected by copyright. All rights reserved.
