From the Hematology Division, Stanford University School of Medicine-Stanford Cancer Institute, Stanford, CA (J.G.); Faculty of Medical Sciences, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (H.C.K.-N.); Department of Pathology, University of New Mexico, Albuquerque (T.I.G.); Mastocytosis Center, Brigham and Women's Hospital, Boston (C.A.); Institute of Pathology, Ludwig-Maximilians-University Munich, Munich (K.S., H.-P.H.), Department of Dermatology and Venereology, University of Cologne, Cologne, and University of Luebeck, Luebeck (K.H.), and Department of Hematology and Oncology, University Hospital Mannheim of the University of Heidelberg, Mannheim (A.R.) - all in Germany; University of Paris Descartes, Institut Imagine INSERM Unité 1163 and Centre National de la Recherche Scientifique ERL8654, Centre de Reference des Mastocytoses, Paris (O.H.); Division of Hematology, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus (F.T.A.); Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia (E.H.); Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center, New York (M.J.M.); Novartis Pharmaceuticals, East Hanover, NJ (D.W.S., E.J.S.); Novartis Pharma, Basel, Switzerland (M.V., A.H.L.); and the Department of Internal Medicine I, Division of Hematology and Hemostaseology, and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna (P.V.).
N Engl J Med. 2016 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098.
Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis.
We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response.
The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias.
In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT00782067.).
高级系统性肥大细胞增多症包含罕见的血液学肿瘤，与预后不良相关，且缺乏有效治疗选择。多激酶抑制剂米哚妥林可抑制疾病发病机制的主要驱动因素 KIT D816V。
我们开展了一项开放标签研究，在 116 例患者中使用每日两次、每次 100 毫克的口服米哚妥林进行治疗，其中 89 例有肥大细胞相关器官损伤的患者符合主要疗效人群的纳入标准；16 例患者患有侵袭性系统性肥大细胞增多症，57 例患者患有伴有血液学肿瘤的系统性肥大细胞增多症，16 例患者患有肥大细胞白血病。主要终点是最佳总体缓解率。
总体缓解率为 60%（95%置信区间，49 至 70）；45%的患者有主要缓解，即至少一种肥大细胞相关器官损伤完全缓解。无论高级系统性肥大细胞增多症的亚型、KIT 突变状态或是否接受过既往治疗，缓解率均相似。骨髓肥大细胞负荷和血清类胰蛋白酶水平的最佳百分比变化中位数分别为-59%和-58%。中位总生存期为 28.7 个月，中位无进展生存期为 14.1 个月。在 16 例肥大细胞白血病患者中，中位总生存期为 9.4 个月（95%置信区间，7.5 至未估计）。因毒性作用而减少剂量的患者占 56%；在这些患者中，32%的患者可行重新开始起始剂量治疗。最常见的不良事件是低级别恶心、呕吐和腹泻。新发生或恶化的 3 级或 4 级中性粒细胞减少症、贫血和血小板减少症分别发生在 24%、41%和 29%的患者中，大多数患者存在预先存在的血细胞减少症。
在这项开放标签研究中，米哚妥林在高级系统性肥大细胞增多症患者中显示出疗效，包括致命性较高的肥大细胞白血病变异型。（由诺华制药公司等资助；临床试验.gov 编号，NCT00782067）。
