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米哚妥林联合化疗治疗FLT3基因突变急性髓系白血病的研究
Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation


Richard M. Stone ... 肿瘤 • 2017.08.03
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摘要



背景

携带FLT3基因突变的急性髓系白血病(AML)患者结局不良。米哚妥林(midostaurin)是一种口服的多靶点激酶抑制剂,在携带FLT3基因突变的患者中有治疗活性。我们开展了一项3期试验,以判断米哚妥林联合标准化疗能否延长这一患者群体的总生存期。

 

方法

我们筛选了3,277例患者,这些患者的年龄在18~59岁,新近确诊AML,并且携带FLT3基因突变。患者被随机分组,接受标准化疗(诱导治疗采用柔红霉素和阿糖胞苷,巩固治疗采用大剂量阿糖胞苷)加用米哚妥林或安慰剂治疗;巩固治疗后获得缓解的患者进入维持治疗阶段,并接受米哚妥林或安慰剂治疗。我们根据FLT3突变亚型对随机化进行分层:酪氨酸激酶结构域(TKD)的点突变或内部串联重复(ITD)突变;对于ITD,又根据突变与野生型等位基因比值分为高比值(>0.7;ITD[高])或低比值(0.05~0.7;ITD[低])。允许患者接受同种异体移植治疗。主要终点为总生存期。

 

结果

共717例患者接受随机化;360例分配至米哚妥林组,357例分配至安慰剂组。214例患者属于ITD(高)FLT3亚型,341例属于ITD(低)亚型,162例属于TKD亚型。两组在下列方面平衡:年龄、人种、FLT3亚型、细胞遗传学风险以及血细胞计数。但性别一项除外(米哚妥林组有51.7%的患者为女性,安慰剂组为59.4%; P=0.04)。与安慰剂组相比,米哚妥林组的总生存期显著延长(死亡风险比,0.78;单侧P=0.009),无事件生存期亦如此(事件或死亡风险比,0.78;单侧P=0.002)。无论是主要分析,还是将接受移植的患者数据截尾后再进行分析,在所有FLT3亚型中,米哚妥林的获益是一致的。两组的重度不良事件发生率相似。

 

结论

在患有AML并携带FLT3突变的患者中,标准化疗加用多靶点激酶抑制剂米哚妥林能够显著延长患者的总生存期和无事件生存期(由美国国立癌症研究院和诺华公司资助;在ClinicalTrials.gov注册号为NCT00651261)。





作者信息

Richard M. Stone, M.D., Sumithra J. Mandrekar, Ph.D., Ben L. Sanford, M.S., Kristina Laumann, B.A., Susan Geyer, Ph.D., Clara D. Bloomfield, M.D., Christian Thiede, M.D., Thomas W. Prior, Ph.D., Konstanze Döhner, M.D., Guido Marcucci, M.D., Francesco Lo-Coco, M.D., Rebecca B. Klisovic, M.D., Andrew Wei, M.B., B.S., Ph.D., Jorge Sierra, M.D., Ph.D., Miguel A. Sanz, M.D., Ph.D., Joseph M. Brandwein, M.D., Theo de Witte, M.D., Dietger Niederwieser, M.D., Frederick R. Appelbaum, M.D., Bruno C. Medeiros, M.D., Martin S. Tallman, M.D., Jürgen Krauter, M.D., Richard F. Schlenk, M.D., Arnold Ganser, M.D., Hubert Serve, M.D., Gerhard Ehninger, M.D., Sergio Amadori, M.D., Richard A. Larson, M.D., and Hartmut Döhner, M.D.
From the Department of Medical Oncology, Dana–Farber Cancer Institute, Boston (R.M.S.); the Division of Biomedical Statistics and Informatics (S.J.M., K.L.) and the Alliance Statistics and Data Center (S.J.M., K.L., S.G.), Mayo Clinic, Rochester, MN; the Alliance Statistics and Data Center, Duke University, Durham, NC (B.L.S.); the Ohio State University Comprehensive Cancer Center, Columbus (S.G., C.D.B., T.W.P., G.M., R.B.K.); Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden (C.T., G.E.), Department of Internal Medicine III, University Hospital of Ulm, Ulm (K.D., R.F.S., H.D.), Hematology and Oncology, University of Leipzig, Leipzig (D.N.), Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover (J.K., A.G.), and Department of Medicine II, Hematology–Oncology, Goethe University Hospital Frankfurt, Frankfurt am Main (H.S.) — all in Germany; the Department of Biomedicine and Prevention, University Tor Vergata, Rome (F.L.-C., S.A.); the Department of Clinical Haematology, Alfred Hospital and Monash University, Melbourne, VIC, Australia (A.W.); Hospital de la Santa Creu i Sant Pau, Hematology Department, Autonomous University of Barcelona, Barcelona (J.S.), and Hospital Universitario la Fe, Hematology Department, Department of Medicine, University of Valencia, Valencia (M.A.S.) — both in Spain; the Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto (J.M.B.); Radboud Institute Molecular Studies, Radboud University Medical Center, Nijmegen, the Netherlands (T.W.); the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle (F.R.A.); the Division of Hematology–Oncology, Stanford Comprehensive Cancer Center, Stanford University, Stanford, CA (B.C.M.); the Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (M.S.T.); and the Department of Medicine, University of Chicago, Chicago (R.A.L.). Address reprint requests to Dr. Stone at the Dana–Farber Cancer Institute, 450 Brookline Ave., D-2053, Boston, MA 02115, or at richard_stone@dfci.harvard.edu.

 

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