Areas covered: Herein the authors review the role of BRAF V600E and RAF-MEK-ERK signaling in the pathogenesis ofHCL, 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.
Identification of the BRAF-V600E kinase mutation as the genetic cause of HCL has opened the way, in the relapsed/refractory experimental setting, to targeted and non-myelotoxic effective strategies that are based on inhibition of BRAF with vemurafenib, co-inhibition of BRAF and its target MEK with dabrafenib and trametinib, and BRAF inhibition with vemurafenib combined with anti-CD20 immunotherapy.
Hairy cell leukemia (HCL) is a rare, low-grade mature B-cell neoplasm with a characteristic clinical, morphological, immunophenotypic, and more recently described molecular (BRAF p.V600E mutation) profile.
Many such genetic events have already demonstrated clinical utility, such as BRAF V600E that confers sensitivity to vemurafenib in patients with hairy cell leukemia.
Diagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11C, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral medullary infiltration and the presence of BRAF V600E somatic mutation.
Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition.
Accompanying mutationsof the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF-V600E in HCL pathogenesis.
The recent surge in next generation sequencing (NGS) technology has shed more light on the genetic landscape of SBCLs through characterization of numerous driver mutations including SF3B1 and NOTCH1 in CLL, ATM and CCND1 in MCL, KMT2D and EPHA7 in FL, MYD88 (L265P) in LPL, KLF2 and NOTCH2 in splenic MZL (SMZL) and BRAF (V600E) in HCL.
Sensitive molecular assays for detecting BRAF V600E allow HCL (highly responsive to purine analogs) to be better distinguished from HCL-like disorders, which are treated differently.
This report presents a patient with HCL and malignant melanoma with the BRAF p.V600E mutation, and discusses the successful treatment of both cancers with the BRAF inhibitor dabrafenib.
The discovery of the BRAF V600E mutation in most cases of classical hairy cell leukemia opens up unique opportunities for tumor specific treatment of HCL targeting the MEK/ERK signaling pathway.
The detection of BRAF V600E by IHC is useful in the distinction of HCLs from other splenic-based lymphomas, although the identification of at least rare SMZLs containing this abnormality illustrates the continuing need for a multiparameter approach to diagnosis.
In this issue of Blood, Pettirossi et al, including Drs Tiacci and Falini, who led the effort in 2011 defining the BRAF-V600E driving mutation in hairy cell leukemia (HCL),provide extensive laboratory studies showing that inhibitors of BRAF-V600E and/or mitogen-activated protein kinase kinase (MEK) reach their targets and cause HCL cell death
Two V600E-negative HCL contained novel, potentially functionally relevant mutations in exon 11 (F468C and D449E), while one other HCL was BRAF wild-type in exons 2-17.