Enrico Tiacci1, Luca De Carolis1, Edoardo Simonetti1, Monia Capponi1, Achille Ambrosetti1, Eugenio Lucia1, Agostino Antolino1, Alessandro Pulsoni1, Samantha Ferrari1, Pier L Zinzani1, Stefano Ascani1, Vincenzo M Perriello1, Luigi Rigacci1, Gianluca Gaidano1, Roberta Della Seta1, Natalia Frattarelli1, Paolo Falcucci1, Robin Foà1, Giuseppe Visani1, Francesco Zaja1, Brunangelo Falini1. 1. From the Institute of Hematology, Ospedale S. Maria della Misericordia, and the Department of Medicine, University of Perugia, Perugia (E.T., L.D.C., E.S., M.C., S.A., V.M.P., B.F.), the Department of Medicine, Section of Hematology, University of Verona, Verona (A. Ambrosetti), the Hematology Unit, Ospedale di Cosenza, Cosenza (E.L.), the Hematology Unit, Department of Transfusional Medicine-SIMMT, Maria Paternò-Arezzo Hospital, Ragusa (A. Antolino), the Hematology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome (A.P., R.F.), and the Hematology and Stem Cell Transplant Unit, A.O. San Camillo Forlanini (L.R.), Rome, the Department of Hematology, Spedali Civili di Brescia, Brescia (S.F.), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna (P.L.Z.), the Department of Translational Medicine, Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara (G.G.), the Hematology Unit, Ospedale di Carrara, Carrara (R.D.S.), the Hematology Unit, Ospedale di Frosinone, Frosinone (N.F.), the Hematology Unit, Ospedale di Ronciglione, Viterbo (P.F.), the Hematology Unit, Ospedale di Pesaro, Pesaro (G.V.), and the Hematology Unit, Azienda Sanitaria Universitaria Integrata-Ospedale Maggiore, Trieste (F.Z.) - all in Italy.
Abstract
BACKGROUND: Hairy-cell leukemia (HCL) is a CD20+ indolent B-cell cancer in which a BRAF V600E kinase-activating mutation plays a pathogenetic role. In clinical trials involving patients with refractory or relapsed HCL, the targeting of BRAF V600E with the oral BRAF inhibitor vemurafenib led to a response in 91% of the patients; 35% of the patients had a complete response. However, the median relapse-free survival was only 9 months after treatment was stopped. METHODS: In a phase 2, single-center, academic trial involving patients with refractory or relapsed HCL, we assessed the safety and efficacy of vemurafenib (960 mg, administered twice daily for 8 weeks) plus concurrent and sequential rituximab (375 mg per square meter of body-surface area, administered for 8 doses over a period of 18 weeks). The primary end point was a complete response at the end of planned treatment. RESULTS: Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents. CONCLUSIONS: In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL. (Funded by the European Research Council and others; HCL-PG03 EudraCT number, 2014-003046-27.).
BACKGROUND:Hairy-cell leukemia (HCL) is a CD20+ indolent B-cell cancer in which a BRAF V600E kinase-activating mutation plays a pathogenetic role. In clinical trials involving patients with refractory or relapsed HCL, the targeting of BRAF V600E with the oral BRAF inhibitor vemurafenib led to a response in 91% of the patients; 35% of the patients had a complete response. However, the median relapse-free survival was only 9 months after treatment was stopped. METHODS: In a phase 2, single-center, academic trial involving patients with refractory or relapsed HCL, we assessed the safety and efficacy of vemurafenib (960 mg, administered twice daily for 8 weeks) plus concurrent and sequential rituximab (375 mg per square meter of body-surface area, administered for 8 doses over a period of 18 weeks). The primary end point was a complete response at the end of planned treatment. RESULTS: Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents. CONCLUSIONS: In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL. (Funded by the European Research Council and others; HCL-PG03 EudraCT number, 2014-003046-27.).
Authors: Hagop M Kantarjian; Nitin Jain; Guillermo Garcia-Manero; Mary Alma Welch; Farhad Ravandi; William G Wierda; Elias J Jabbour Journal: Cancer Date: 2021-10-06 Impact factor: 6.860