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A 60-year-old man with long treatment history and persistent cytopenias showed classic clinico-pathological features and strong ERK phosphorylation without BRAF-V600E, linked to a clonal MAP2K1/MEK1 Q56P mutation. Cobimetinib produced rapid cytopenia resolution and complete remission, with progression-free survival of 15 months.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/classic-hairy-cell-leukemia-with-map2k1-mutation-diagnosis-and-targeted-therapy/439056/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/classic-hairy-cell-leukemia-with-map2k1-mutation-diagnosis-and-targeted-therapy/439056.png","ImageObject",300,407,{"name":92,"@type":93},"Aurelia","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is this case considered unusual in classic hairy cell leukemia?","Question",{"text":112,"@type":113},"The patient’s leukemia lacked the hallmark BRAF-V600E mutation found in more than 95% of classic HCL cases, yet showed typical clinical and histological features and strong ERK phosphorylation.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What genetic alteration explained the signaling activity in this patient?",{"text":117,"@type":113},"Next-generation sequencing identified a clonal activating MAP2K1/MEK1 Q56P mutation, which accounted for prominent ERK phosphorylation despite absence of BRAF-V600E.",{"name":119,"@type":110,"acceptedAnswer":120},"How did targeted therapy affect the patient’s cytopenias and remission status?",{"text":121,"@type":113},"After switching to the MEK inhibitor cobimetinib with rituximab, cytopenias resolved and complete remission was achieved and re-confirmed, including clearing of the MAP2K1/MEK1 mutation, with 15-month progression-free survival.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},439056,1791001232,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":14,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":24,"preview_page_count":4},1099514068365,"https://ap-avatar.wpscdn.com/avatar/10000253d8d9f28188e?_k=1776742907772140068","American Journal of Hematology  \n IMAGES IN HEMATOLOGY  OPEN ACCESS   \nClassic Hairy Cell Leukemia With MAP2K1 Mutation: Diagnosis and Targeted Therapy  \nAndrea Duminuco1  | Alessandra Venanzi2 | Alessia Santi2 | Alessandro Mancini2  | Alessandra Romano1  | Enrico Tiacci2   \n1Institute of Hematology, University and Hospital of Catania, Catania, Italy | 2Institute of Hematology and Center for Hemato-Oncology Research,  \nDepartment of Medicine and Surgery, University and Hospital of Perugia, Perugia, Italy Correspondence: Enrico Tiacci ([enrico.tiacci@unipg.it](enrico.tiacci@unipg.it))  \nReceived: 18 July 2025 | Accepted: 5 August 2025  \nFunding: This work was supported by Fondazione AIRC per la ricerca sul cancro ETS (21198), HCL Foundation and Leukemia/Lymphoma Society (HCL8029-22) .  \nKeywords: hairy cell leukemia | MAP2K1 mutation | neoplasia-lymphoid leukemias | neoplasia-pharmacotherapeutics | targeted therapy  \nHairy 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, kinaseactivating short deletions of BRAF or missense mutations of MAP2K1/MEK1, the kinase phosphorylated by BRAF within the RAF → MEK → ERK signaling pathway [4, 5] .  \nHere, we describe a 60-year-old male with HCL who had received multiple treatments over the previous 23 years, that issplenectomy 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  \nMEK inhibitor cobimetinib strongly dephosphorylated ERK and elicited marked apoptosis (not shown) .  \nBecause 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 ofcobimetinib (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.  \nMAP2K1 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  \n\n| Alessandra Romano and Enrico Tiacci contributed equally to this study. |\n| --- |\n| This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro","cbCaiffmAJMntNpt","https://ap.wps.com/l/cbCaiffmAJMntNpt","pdf",503752,"English","# Diagnosis and targeted therapy overview\n## Clinical course and treatment response\n## Pathology and molecular findings\n## Implications for patient management","[{\"question\":\"Why is this case considered unusual in classic hairy cell leukemia?\",\"answer\":\"The patient’s leukemia lacked the hallmark BRAF-V600E mutation found in more than 95% of classic HCL cases, yet showed typical clinical and histological features and strong ERK phosphorylation.\"},{\"question\":\"What genetic alteration explained the signaling activity in this patient?\",\"answer\":\"Next-generation sequencing identified a clonal activating MAP2K1/MEK1 Q56P mutation, which accounted for prominent ERK phosphorylation despite absence of BRAF-V600E.\"},{\"question\":\"How did targeted therapy affect the patient’s cytopenias and remission status?\",\"answer\":\"After switching to the MEK inhibitor cobimetinib with rituximab, cytopenias resolved and complete remission was achieved and re-confirmed, including clearing of the MAP2K1/MEK1 mutation, with 15-month progression-free survival.\"}]","Classic Hairy Cell Leukemia With MAP2K1 Mutation - Diagnosis and Targeted Therapy | PDF",1790687307]