靶向复发性或难治性毛细胞白血病中的突变型BRAF
Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.
作者信息
Tiacci Enrico, Park Jae H, De Carolis Luca, Chung Stephen S, Broccoli Alessandro, Scott Sasinya, Zaja Francesco, Devlin Sean, Pulsoni Alessandro, Chung Young R, Cimminiello Michele, Kim Eunhee, Rossi Davide, Stone Richard M, Motta Giovanna, Saven Alan, Varettoni Marzia, Altman Jessica K, Anastasia Antonella, Grever Michael R, Ambrosetti Achille, Rai Kanti R, Fraticelli Vincenzo, Lacouture Mario E, Carella Angelo M, Levine Ross L, Leoni Pietro, Rambaldi Alessandro, Falzetti Franca, Ascani Stefano, Capponi Monia, Martelli Maria P, Park Christopher Y, Pileri Stefano A, Rosen Neal, Foà Robin, Berger Michael F, Zinzani Pier L, Abdel-Wahab Omar, Falini Brunangelo, Tallman Martin S
机构信息
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
出版信息
N Engl J Med. 2015 Oct 29;373(18):1733-47. doi: 10.1056/NEJMoa1506583. Epub 2015 Sep 9.
BACKGROUND
BRAF 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.
METHODS
We 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.
RESULTS
The 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.
CONCLUSIONS
A 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.).
背景
BRAF V600E 是毛细胞白血病潜在的基因损伤。我们评估了口服BRAF抑制剂维莫非尼对嘌呤类似物治疗后复发或对嘌呤类似物难治的毛细胞白血病患者的安全性和活性。
方法
我们开展了两项维莫非尼（剂量为960 mg，每日两次）的2期单组多中心研究，一项在意大利进行，另一项在美国进行。在意大利的研究中，治疗的中位时间为16周，在美国的研究中为18周。主要终点为完全缓解率（意大利试验）和总缓解率（美国试验）。意大利试验于2013年4月完成入组（28例患者），美国试验仍在入组（计划入组36例患者，已入组26例）。
结果
在意大利研究中，中位8周后总缓解率为96%（26例可评估患者中的25例），在美国研究中，中位12周后总缓解率为100%（24例患者中的24例）。两项试验中的完全缓解率分别为35%（26例患者中的9例）和42%（24例患者中的10例）。在意大利试验中，中位随访23个月后，完全缓解患者的中位无复发生存期为19个月，部分缓解患者为6个月；中位无治疗生存期分别为25个月和18个月。在美国试验中，1年时无进展生存率为73%，总生存率为91%。与药物相关的不良事件通常为1级或2级，最常导致剂量减少的事件为皮疹和关节痛或关节炎。50例患者中有7例出现继发性皮肤肿瘤（采用简单切除治疗）。治疗结束时骨髓中磷酸化ERK阳性白血病细胞频繁持续存在，提示MEK和ERK旁路重新激活是一种耐药机制。
结论
维莫非尼短期口服疗程对复发或难治性毛细胞白血病患者高度有效。（由意大利癌症研究协会等资助；欧洲临床试验注册号，2011 - 005487 - 13；ClinicalTrials.gov编号NCT01711632。）
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