Classic Hairy Cell Leukemia With MAP2K1 Mutation: Diagnosis and Targeted Therapy

Hairy cell leukemia (HCL) is caused by the kinase-activating BRAF-V600E mutation in > 95% of patients, making this disease sensitive to oral BRAF inhibitors [1-3]. Rare HCL cases lacking BRAF-V600E have been recently described that respond suboptimally to standard chemotherapy with purine analogs and harbor alternative, potentially targetable, kinase-activating short deletions of BRAF or missense mutations of MAP2K1/MEK1, the kinase phosphorylated by BRAF within the RAF → MEK → ERK signaling pathway [4, 5]. Here, we describe a 60-year-old male with HCL who had received multiple treatments over the previous 23 years, that is splenectomy and six subsequent lines of chemo-immunotherapy, with refractoriness to the last one (pentostatin plus rituximab) resulting in persistent cytopenias (hemoglobin 5.7 g/dL, platelets 27 000/mm3; neutrophils 1190/mm3). This case had clinico-pathological features typical of classic HCL, including "fried-egg" histological pattern (Figure 1A) with marked reticulin fibrosis (not shown), as well as circulating leukemic cells with circumferential hairy projections and inconspicuous nucleoli (Figure 1B). However, leukemic cells lacked BRAF-V600E (Figure 1C), yet showed prominent ERK phosphorylation (Figure 1D) that was due to a clonal activating Q56P mutation of MAP2K1/MEK1 identified upon next-generation sequencing. Indeed, in vitro treatment of patients' leukemic cells with the MEK inhibitor cobimetinib strongly dephosphorylated ERK and elicited marked apoptosis (not shown). Because the patient had exhausted all standard therapeutic options, before the genetic and functional characterization of the patient's leukemia was complete, he was empirically started on the BRAF inhibitor vemurafenib (960 mg twice daily for 8 days) plus rituximab 375 mg/sqm (for 1 dose), but was then quickly switched to oral cobimetinib (60 mg daily) for 4 cycles (each comprising 21 days of dosing followed by 7 days of rest), with resolution of cytopenias and achievement of a complete remission immunohistochemically confirmed through a bone marrow biopsy. Since recurrent grade-2 cutaneous rash due to cobimetinib precluded long-term continuous treatment with the drug, this response was consolidated with an additional two cycles of cobimetinib (mostly at a reduced dose of 40 mg daily) combined with rituximab (375 mg/sqm intravenously) for eight doses (3 during cobimetinib therapy and 5 thereafter). A complete remission was re-confirmed at the end of such treatment, including clearing of the MAP2K1/MEK1 mutation, and progression-free survival was 15 months from the start of treatment. MAP2K1 mutations were first identified in HCL-variant [6], a distinct disease that has a worse prognosis than classic HCL [7], and in a patient with relapsed HCL-variant harboring mutant MAP2K1 (K57N) treatment with the MEK inhibitor trametinib was only modestly active (stable disease after 6 cycles) [8]. The current case highlights the importance of correctly diagnosing classic HCL even in the absence of its hallmark BRAF-V600E mutation and of searching for alternative, targetable kinase mutations to optimally guide patient management. Supported by grants from Associazione Italiana per la Ricerca sul Cancro ("Metastasis 5-per-mille" grant number, 21198, to Dr. Enrico Tiacci) and the Hairy Cell Leukemia Foundation–Leukemia and Lymphoma Society (HCL2025 Initiative–Translational Research grant number, HCL8029-22, to Dr. Enrico Tiacci). Open access publishing facilitated by Universita degli Studi di Perugia, as part of the Wiley - CRUI-CARE agreement. This report was prepared in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patient. All identifying details have been omitted or anonymized to protect patient confidentiality. The authors declare no conflicts of interest.