title: BRAF inhibition in hairy cell leukemia with low-dose vemurafenib.
abstract: The activating mutation of the BRAF serine/threonine protein kinase (BRAF V600E) is the key driver mutation in hairy cell leukemia (HCL), suggesting opportunities for therapeutic targeting. We analyzed the course of 21 HCL patients treated with vemurafenib outside of trials with individual dosing regimens (240-1920 mg/d; median treatment duration, 90 days). Vemurafenib treatment improved blood counts in all patients, with platelets, neutrophils, and hemoglobin recovering within 28, 43, and 55 days (median), respectively. Complete remission was achieved in 40% (6/15 of evaluable patients) and median event-free survival was 17 months. Response rate and kinetics of response were independent of vemurafenib dosing. Retreatment with vemurafenib led to similar response patterns (n = 6). Pharmacodynamic analysis of BRAF V600E downstream targets showed that vemurafenib (480 mg/d) completely abrogated extracellular signal-regulated kinase phosphorylation of hairy cells in vivo. Typical side effects also occurred at low dosing regimens. We observed the development of acute myeloid lymphoma (AML) subtype M6 in 1 patient, and the course suggested disease acceleration triggered by vemurafenib. The phosphatidylinositol 3-kinase hotspot mutation (E545K) was identified in the AML clone, providing a potential novel mechanism for paradoxical BRAF activation. These data provide proof of dependence of HCL on active BRAF signaling. We provide evidence that antitumor and side effects are observed with 480 mg vemurafenib, suggesting that dosing regimens in BRAF-driven cancers could warrant reassessment in trials with implications for cost of cancer care.
authors.affiliation: Department of Medicine V, University of Heidelberg, Heidelberg, Germany; Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany;
authors.forename: Sascha
authors.initials: S
authors.lastname: Dietrich
authors.affiliation: Division of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria;
authors.forename: Andreas
authors.initials: A
authors.lastname: Pircher
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany;
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.affiliation: Centre Antoine Lacassagne, Nice, France;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Peyrade
authors.affiliation: Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases, and Tropical Medicine, Hospital Munich-Schwabing, Munich, Germany;
authors.forename: Clemens-Martin
authors.initials: CM
authors.lastname: Wendtner
authors.affiliation: Department of Hematology, Addenbrookes Hospital, Cambridge, United Kingdom;
authors.forename: George A
authors.initials: GA
authors.lastname: Follows
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hüllein
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Jethwa
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany;
authors.forename: Elena
authors.initials: E
authors.lastname: Ellert
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Tatjana
authors.initials: T
authors.lastname: Walther
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Xiyang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom;
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology, Cluster of Excellence-Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Elter
authors.affiliation: Institute of Molecular Medicine and Cell Research and Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany;
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.affiliation: Department of Hematology/Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany;
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.affiliation: Department of Hematology and Oncology, Helios Kliniken Erfurt, Erfurt, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hermann
authors.affiliation: Department of Hematology and Oncology, Helios Kliniken Erfurt, Erfurt, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Herold
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany;
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: The Royal Marsden Hospital, London, United Kingdom;
authors.forename: Claire
authors.initials: C
authors.lastname: Dearden
authors.affiliation: Munich Leukemia Laboratory, Munich, Germany;
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Division of Genetics, German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Martina
authors.initials: M
authors.lastname: Seiffert
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology, Cluster of Excellence-Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.affiliation: Department of Medicine V, University of Heidelberg, Heidelberg, Germany;
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Department of Hematology, Lucerne Cantonal Hospital, Lucerne, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Gaehler
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany;
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Andrulis
authors.affiliation: Division of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria;
authors.forename: Michael
authors.initials: M
authors.lastname: Steurer
authors.affiliation: Department of Medicine V, University of Heidelberg, Heidelberg, Germany; Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany;
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D007943:Leukemia, Hairy Cell / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D012008:Recurrence; D019233:Retreatment; D012189:Retrospective Studies; D000069283:Rituximab / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D000069283:Rituximab; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf