From the Abramson Cancer Center, University of Pennsylvania (A.E.P.), and Thomas Jefferson University (M.K.) - both in Philadelphia; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Meldola (G.M.), L. and A. Seràgnoli Institute of Hematology, Bologna University Medical School, Bologna (S.P.), Ospedali Riuniti Villa Sofia-Cervello, Palermo (F.F.), and IRCCS San Raffaele Scientific Institute, Milan (F.C.) - all in Italy; University of Texas M.D. Anderson Cancer Center, Houston (J.E.C.); Universitätsklinikum Giessen und Marburg, Marburg, Germany (A.N.); Memorial Sloan Kettering Cancer Center, New York (E. Berman); Hospital Universitari i Politècnic La Fe, Valencia, and Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto Carlos III, Madrid - both in Spain (P.M.); University of Maryland Greenebaum Comprehensive Cancer Center (M.R.B.) and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University (M.J.L.) - both in Baltimore; University of Chicago, Chicago (R.A.L.), and Astellas Pharma, Northbrook (C.L., N. Hasabou, X.L., E. Bahceci) - both in Illinois; University of Minnesota, Minneapolis (C.U.); University of Alabama at Birmingham, Birmingham (H.P.E., A.D.S.); Hollings Cancer Center, Medical University of South Carolina, Charleston (R.S.); University of California, San Francisco, San Francisco (R.O.); National Taiwan University, Taipei City, Taiwan (W.-C.C.); Yale University School of Medicine, New Haven, CT (N.P.); Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, France (C.R.); Sendai Medical Center, National Hospital Organization, Sendai (H.Y.), and University of Fukui, Fukui (N. Hosono) - both in Japan; Seoul National University (S.-S.Y.) and Asan Medical Center, University of Ulsan College of Medicine (J.-H.L.) - both in Seoul, South Korea; Wake Forest Baptist Medical Center, Winston-Salem, NC (T.P.); and Massachusetts General Hospital, Harvard Medical School, Boston (A.T.F.).
N Engl J Med. 2019 Oct 31;381(18):1728-1740. doi: 10.1056/NEJMoa1902688.
Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene () infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory -mutated AML.
In a phase 3 trial, we randomly assigned adults with relapsed or refractory -mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission.
Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).
Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory -mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).
FMS 样酪氨酸激酶 3 基因（）突变的复发性或难治性急性髓系白血病（AML）患者对挽救性化疗反应不佳。吉瑞替尼是一种口服、强效、选择性 FLT3 抑制剂，在复发性或难治性 -突变的 AML 中有单药活性。
在一项 3 期临床试验中，我们将复发性或难治性 -突变的 AML 成人患者以 2:1 的比例随机分配，接受吉瑞替尼（每天 120 毫克）或挽救性化疗。两个主要终点是总生存期和完全缓解（完全或部分血液学恢复）的患者比例。次要终点包括无事件生存期（无治疗失败[即复发或无缓解]或死亡）和完全缓解的患者比例。
在 371 名合格患者中，247 名被随机分配至吉瑞替尼组，124 名至挽救化疗组。吉瑞替尼组的中位总生存期明显长于化疗组（9.3 个月比 5.6 个月；死亡风险比，0.64；95%置信区间[CI]，0.49 至 0.83；P<0.001）。吉瑞替尼组的无事件生存期为 2.8 个月，化疗组为 0.7 个月（治疗失败或死亡的风险比，0.79；95%CI，0.58 至 1.09）。完全缓解（完全或部分血液学恢复）的患者比例，吉瑞替尼组为 34.0%，化疗组为 15.3%（风险差异，18.6 个百分点；95%CI，9.8 至 27.4）；完全缓解率分别为 21.1%和 10.5%（风险差异，10.6 个百分点；95%CI，2.8 至 18.4）。在调整治疗持续时间的分析中，吉瑞替尼组的 3 级或更高级别的不良事件和严重不良事件发生率低于化疗组；吉瑞替尼组最常见的 3 级或更高级别的不良事件为发热性中性粒细胞减少症（45.9%）、贫血（40.7%）和血小板减少症（22.8%）。
在复发性或难治性 -突变的 AML 患者中，与挽救性化疗相比，吉瑞替尼可显著延长生存期，并提高缓解率。（由安斯泰来制药公司资助；ADMIRAL 临床试验.gov 编号，NCT02421939。）
