• Enrico Tiacci, Jae H Park, Luca De Carolis, Stephen S Chung, Alessandro Broccoli, Sasinya Scott, Francesco Zaja, Sean Devlin, Alessandro Pulsoni, Young R Chung, Michele Cimminiello, Eunhee Kim, Davide Rossi, Richard M Stone, Giovanna Motta, Alan Saven, Marzia Varettoni, Jessica K Altman, Antonella Anastasia, Michael R Grever, Achille Ambrosetti, Kanti R Rai, Vincenzo Fraticelli, Mario E Lacouture, Angelo M Carella, Ross L Levine, Pietro Leoni, Alessandro Rambaldi, Franca Falzetti, Stefano Ascani, Monia Capponi, Maria P Martelli, Christopher Y Park, Stefano A Pileri, Neal Rosen, Robin Foà, Michael F Berger, Pier L Zinzani, Omar Abdel-Wahab, Brunangelo Falini, and Martin S Tallman.
• From the Institute of Hematology, Department of Medicine, and Centro di Ricerca Emato-Oncologico (CREO), University of Perugia, and Ospedale Santa Maria della Misericordia, Perugia (E.T., L.D.C., F.F., S.A., M.C., M.P.M., B.F.), the Department of Experimental, Diagnostic, and Specialty Medicine, Units of Hematology and Hematopathology, Bologna University School of Medicine, Bologna (A.B., S.A.P., P.L.Z.), Hematology Unit, Centro Trapianti e Terapie Cellulari Carlo Melzi, Dipartimento di Science Mediche Sperimentali e Cliniche, Azienda Ospedaliero Universitaria, Udine (F.Z.), the Department of Cellular Biotechnologies and Hematology, Division of Hematology, Sapienza University, Rome (A.P., R.F.), the Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Regionale San Carlo, Potenza (M.C.), the Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara (D.R.), Hematology Unit, Ospedale Ferrarotto, Catania (G.M.), the Department of Onco-Hematology, Fondazione IRCCS, Policlinico San Matteo, Pavia (M.V.), Hematology Unit, Spedali Civili, Brescia (A. Anastasia), the Department of Medicine, Section of Hematology, University of Verona, Verona (A. Ambrosetti), Onco-Hematology Unit, Fondazione di Ricerca e Cura S.S. Giovanni Paolo II, Campobasso (V.F.), Institute of Hematology 1, IRCCS, Azienda Ospedaliero Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa (A.M.C.), the Department of Hematology, Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona (P.L.), and the Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy; Leukemia Service (J.H.P., S.S.C., R.L.L., O.A-W., M.S.T.,) and Dermatology Service (M.E.L.), the Department of Medicine, Human Oncology and Pathogenesis Program (S.S., Y.R.C., E.K., R.L.L., C.Y.P., M.F.B., O.A-W.), the Departments of Epidemiology and Biostatistics (S.D.), Pathology (C.Y.P.), and Pharmaco
• N. Engl. J. Med. 2015 Oct 29; 373 (18): 1733-47.

BackgroundBRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.MethodsWe conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial.ResultsThe overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism.ConclusionsA short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).

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