Targeting the Mutational Landscape of Bystander Cells: Drug-Promoted Blood Cancer From High-Prevalence Pre-neoplasias in Patients on BRAF Inhibitors.

Drug-promoted cancers are increasingly recognized as a serious clinical problem in patients receiving BRAF inhibitory treatment. Here we report on a patient withBRAFmutant hairy cell leukemia and monoclonal B-cell lymphocytosis (MBL), who responded durably to BRAF/MEK inhibitors (BRAFi/MEKi) but experienced transformation of aRASmutant MBL to chronic lymphocytic leukemia (CLL) with accelerated nodal progression. Hypothesizing that BRAFi triggered excessive MEK-ERK signaling in the MBL/CLL clone via the CRAF/RAS complex as previously described for BRAFi-induced cancers, BRAFi was discontinued inducing a rapid remission of the CLL on MEKi alone. Liquid biopsy monitoring showed a continuous increase of the MBL/CLL clone from the start of BRAFi/MEKi treatment followed by a rapid decline upon BRAFi withdrawal. Next-generation sequencing of a cohort of patients with MBL and monoclonal gammopathy of unclear significance (MGUS) revealed that almost one third of these cases harboredRASmutations. In view of the population frequency of lymphatic pre-malignant conditions and the prevalence ofRASmutations in such cases, vigilant surveillance remains critical in patients treated with BRAF inhibitors.