Mutations in CLL patients relapsing under ibrutinib
Over time, many CLL patients who are treated with ibrutinib discontinue treatment due to relapses. This represents a new unmet clinical need, explained Dr Lydia Scarfò (Università Vita-Salute San Raffaele, Milan, Italy), during the late breaking oral session. Mutations in BTK, the target for ibrutinib, and in PLCG2, a member of the BTK pathway, have been found in relapsed CLL. In an international, retrospective study Scarfò and colleagues determined the prevalence of BTK and PLCG2 mutations in 22 CLL patients relapsing on ibrutinib in a real-world setting. As a control, they also analyzed 32 CLL patients responding to ibrutinib.
Using targeted deep sequencing, with a variant allele frequency (VAF) cut-off of 1%, the investigators detected BTK mutations in approximately half (10/22) of the relapsed cases, and in two of the responding cases. In the relapsed cases all BTK mutations were found at C481 in the kinase domain, involved in binding to ibrutinib. PLCG2 mutations were only detected in three relapsed cases, which all carried BTK mutations. PCLG2 mutations were also present in three responding cases. Scarfò: “These results indicate the outgrowth of several resistant clones during ibrutinib treatment. The mechanism leading to resistance in cases without BTK/PCLG2 mutations remains to be established.”