Stone Richard M, Mandrekar Sumithra J, Sanford Ben L, Laumann Kristina, Geyer Susan, Bloomfield Clara D, Thiede Christian, Prior Thomas W, Döhner Konstanze, Marcucci Guido, Lo-Coco Francesco, Klisovic Rebecca B, Wei Andrew, Sierra Jorge, Sanz Miguel A, Brandwein Joseph M, de Witte Theo, Niederwieser Dietger, Appelbaum Frederick R, Medeiros Bruno C, Tallman Martin S, Krauter Jürgen, Schlenk Richard F, Ganser Arnold, Serve Hubert, Ehninger Gerhard, Amadori Sergio, Larson Richard A, Döhner Hartmut
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.).
N Engl J Med. 2017 Aug 3;377(5):454-464. doi: 10.1056/NEJMoa1614359. Epub 2017 Jun 23.
Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population.
We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival.
A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups.
The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).
患有急性髓系白血病（AML）且存在FLT3突变的患者预后较差。我们开展了一项3期试验，以确定在标准化疗基础上加用米哚妥林（一种对FLT3突变患者有效的口服多靶点激酶抑制剂）是否能延长该人群的总生存期。
我们对3277例年龄在18至59岁、新诊断为AML的患者进行FLT3突变筛查。患者被随机分配接受标准化疗（柔红霉素和阿糖胞苷诱导治疗以及大剂量阿糖胞苷巩固治疗）加米哚妥林或安慰剂；巩固治疗后缓解的患者进入维持阶段，在此阶段接受米哚妥林或安慰剂治疗。随机分组根据FLT3突变亚型进行分层：酪氨酸激酶结构域（TKD）点突变或内部串联重复（ITD）突变，突变与野生型等位基因的比例分别为高比例（>0.7）或低比例（0.05至0.7）（分别为ITD[高]和ITD[低]）。允许进行异基因移植。主要终点是总生存期。
共有717例患者进行了随机分组；360例被分配到米哚妥林组，357例被分配到安慰剂组。FLT3亚型为ITD（高）的患者有214例，ITD（低）的患者有341例，TKD的患者有162例。治疗组在年龄、种族、FLT3亚型、细胞遗传学风险和血细胞计数方面均衡良好，但在性别方面不均衡（米哚妥林组女性占51.7%，安慰剂组女性占59.四岁，P=0.0四）。米哚妥林组的总生存期显著长于安慰剂组（死亡风险比为0.78；单侧P=0.009），无事件生存期也是如此（事件或死亡风险比为0.78；单侧P=0.002）。在主要分析以及对接受移植患者的数据进行审查的分析中，米哚妥林在所有FLT3亚型中的益处都是一致的。两组严重不良事件的发生率相似。
在标准化疗基础上加用多靶点激酶抑制剂米哚妥林可显著延长AML且存在FLT3突变患者的总生存期和无事件生存期。（由美国国立癌症研究所和诺华公司资助；ClinicalTrials.gov编号，NCT00651261。）
