ABSTRACT
Introduction: Hairy cell leukemia (HCL) is a rare, chronic B-cell lymphoproliferative disorder characterized by distinctive morphologic features and an indolent clinical course. The discovery of a recurrent activating mutation in BRAF (BRAF V600E) as a disease-defining genetic event in HCL has substantial diagnostic and therapeutic implications.
Areas covered: Herein the authors review the role of BRAF V600E and RAF-MEK-ERK signaling in the pathogenesis of HCL, anecdotal clinical reports of BRAF inhibitor monotherapy in management of relapsed or refractory HCL, larger phase 2 trials investigating efficacy of BRAF inhibitor therapy for HCL, adverse effects commonly associated with BRAF inhibitor therapy, including cutaneous toxicity, and mechanisms of therapeutic resistance.
Expert opinion: Ongoing and planned studies will help to optimize the use of BRAF inhibitor therapy for HCL by determining the efficacy of BRAF inhibition in combination with other antigen targeted or molecularly targeted therapies, and more broadly, to determine how hematologists can best utilize and sequence emerging diagnostic and therapeutic modalities in the care of patients with newly diagnosed and relapsed or refractory HCL.
Article highlights
The discovery of recurrent somatic BRAF V600E mutations in the vast majority of patients with HCL has clear diagnostic and therapeutic implications.
Monotherapy with the BRAF inhibitor vemurafenib is associated with high rates of clinical response, even at doses lower than commonly utilized in the treatment of melanoma
Vemurafenib therapy is associated with high rates of cutaneous adverse events, which are generally manageable with supportive measures and dose interruption/reduction, though squamous cell carcinomas arising during therapy typically require excision
HCL can exploit multiple mechanisms of resistance to BRAF inhibitor monotherapy, including paradoxical activation of the MAPK pathway
Declaration of interest
MB Geyer has received grant support from: Lymphoma research foundation, the American Society of Hematology and the National Centre for Advancing Translational Sciences (UL1TR00457). MB Geyer also received an honorarium from Dava Oncology. MS Tallman has received research funding from AbbVie; ADC Therapeutics, Arog Pharmaceuticals, and Cellerant. MS Tallman also serves on advisory boards for Daiichi-Sankyo, Orsenix, and BioSight. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.