Shifting ecologies of malignant and nonmalignant cells following BRAF inhibition

Clinical vignette: A 49-year-old man with stage IV BRAF^V600E-driven melanoma was initiated on twice-daily 960 mg of vemurafenib for treatment of progressive and recurrent subcutaneous metastatic disease of the left lower extremity. The patient’s melanoma responded well to targeted BRAF inhibition. At treatment onset, hematologic parameters were all within normal limits; however, within three months of initiating therapy, wbc were found to be elevated (to 20 K) with sustained lymphocytosis of mature phenotype. Immunophenotypic analysis was consistent with chronic lymphocytic leukemia (CLL), and FISH results revealed presence of the CLL-associated deletion in chromosome 13q14 as well as in 2p33. Vemurafenib was withdrawn after approximately one year of therapy, and subsequently, his peripheral lymphocytosis resolved and CLL regressed. Nevertheless, a monoclonal B cell population persisted even 732 days after discontinuation of vemurafenib.In this issue, Yaktapour et al. describe a patient with metastatic melanoma harboring the BRAF^V600E mutation who, upon treatment with the BRAF inhibitor vemurafenib, developed a sustained lymphocytosis that was ultimately diagnosed as del13q14 chronic lymphocytic leukemia (CLL) without mutations in IGHV. Notably, Yaktapour and colleagues demonstrate that SYK-mediated B cell receptor (BCR) signaling in CLL in the presence of drug-bound BRAF is a putative driver of the paradoxical MEK/ERK activation that has been occasionally observed in response to BRAF inhibition (1).