Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;; Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria;.
Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, USA.
Ann Oncol. 2017 Oct 1;28(10):2367-2376. doi: 10.1093/annonc/mdx290.
Clinically relevant features in patients with systemic mastocytosis (SM) include the cosmetic burden of lesional skin, mediator-related symptoms, and organ damage resulting from mast cell (MC) infiltration in advanced forms of SM. Regardless of the SM variant, expansion of neoplastic MC in the skin and other organs is triggered by mutant forms of KIT, the most prevalent being D816V. Activation of MC with subsequent release of chemical mediators is often caused by IgE-dependent mechanisms in these patients. Midostaurin, also known as PKC412, blocks the kinase activity of wild-type KIT and KIT D816V, counteracts KIT-dependent growth of neoplastic MC, and inhibits IgE-dependent mediator secretion. Based on this activity-profile, the drug has been used for treatment of patients with advanced SM. Indeed, encouraging results have been obtained with the drug in a recent multi-center phase II trial in patients with advanced SM, with an overall response rate of 60% and a substantial decrease in the burden of neoplastic MC in various organs. Moreover, midostaurin improved the overall survival and relapse-free survival in patients with advanced SM compared with historical controls. In addition, midostaurin was found to improve mediator-related symptoms and quality of life, suggesting that the drug may also be useful in patients with indolent SM suffering from mediator-related symptoms resistant to conventional therapies or those with MC activation syndromes. Ongoing and future studies will determine the actual value of midostaurin-induced MC depletion and MC deactivation in these additional indications.
系统肥大细胞增多症（SM）患者的临床相关特征包括皮损的美容负担、介质相关症状以及肥大细胞（MC）浸润导致的晚期 SM 形式的器官损伤。无论 SM 变异如何，皮肤和其他器官中肿瘤性 MC 的扩张都是由 KIT 的突变形式触发的，最常见的是 D816V。在这些患者中，MC 的激活以及随后的化学介质释放通常是由 IgE 依赖性机制引起的。米哚妥林，也称为 PKC412，可阻断野生型 KIT 和 KIT D816V 的激酶活性，拮抗 KIT 依赖性肿瘤性 MC 的生长，并抑制 IgE 依赖性介质的分泌。基于这种活性谱，该药物已用于治疗晚期 SM 患者。事实上，在最近一项针对晚期 SM 患者的多中心 II 期试验中，该药物取得了令人鼓舞的结果，总体缓解率为 60%，并在各种器官中实质性地减少了肿瘤性 MC 的负担。此外，与历史对照相比，米哚妥林改善了晚期 SM 患者的总生存期和无复发生存期。此外，米哚妥林还发现可改善与介质相关的症状和生活质量，这表明该药物对于患有介质相关症状且对常规治疗有抗性的惰性 SM 患者或患有 MC 激活综合征的患者也可能有用。正在进行和未来的研究将确定米哚妥林诱导的 MC 耗竭和 MC 失活在这些附加适应症中的实际价值。
