Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.

中文翻译：

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雷帕霉素抑制剂在系统性肥大细胞增多症中的哺乳动物靶点的功效和安全性：法国全国试点研究

系统性肥大细胞增多症（SM）是一种罕见且异质的疾病，其特征是非典型肥大细胞（MC）的积累。晚期肥大细胞增多症 (Adv-SM) 与较差的生存率相关；相反，非晚期 SM (non-Adv-SM) 患者通常预期寿命正常，但生活质量可能较差。尽管最近在包括酪氨酸激酶抑制剂在内的治疗方面取得了进展，但对于患有严重症状和 Adv-SM 的难治性和/或不耐受患者，仍需要新的治疗选择。在体外，携带KIT D816V 突变的患者的 MC 中 mTOR 通路被激活。此外，雷帕霉素选择性诱导KIT D816V MC凋亡。在这项全国性研究中，我们报告了法国国家肥大细胞增多症参考中心 (CEREMAST) 诊断为 SM 并接受哺乳动物雷帕霉素靶点抑制剂 (imTOR) 治疗的患者的结果。所有登记的患者均为复发、难治性或不适合其他细胞减灭治疗的患者。非 Adv-SM 患者接受 imTOR 作为单一疗法（雷帕霉素/依维莫司），Adv-SM 患者接受 imTOR 作为单一疗法或与阿糖胞苷联合治疗。非 Adv-SM 的客观缓解率 (ORR) 为 60%（部分缓解 40%，主要缓解 20%），包括皮肤受累、介质释放症状和血清类胰蛋白酶的减少。在 Adv-SM 组中，ORR 为 20%（包括一名主要缓解和一名部分缓解，均为携带KIT D816V 突变的患者），这使得一名患者成功过渡到同种异体干细胞移植。我们的结果表明，imTOR 治疗对携带KIT D816V 突变的 SM 患者具有潜在益处。