Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis
Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis
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DOI：
10.1182/blood-2011-01-330563
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发表时间：
2011-08-25
期刊：
影响因子：
20.3
通讯作者：
Vannucchi, Alessandro M.
中科院分区：
文献类型：
--
作者：
Guglielmelli, Paola;Barosi, Giovanni;Vannucchi, Alessandro M.
除了JAK/STAT信号转导失调外，AKT/mTOR通路的激活还发生在骨髓纤维化中，骨髓纤维化是一种骨髓增生性肿瘤，没有批准的治疗方法。我们在39例高或中危原发性或真性红细胞增多症/血小板增多症后骨髓纤维化受试者中进行了一项mTOR抑制剂依维莫司的1/2期研究。在II期的30例患者中评价了缓解。在1期研究中，剂量高达10 mg/d时未观察到剂量限制性毒性。当该剂量用于2期时，≥ 3级毒性很少发生;最常见的毒性是1-2级口腔炎。分别有20%和44%的受试者出现快速和持续的脾肿大减少> 50%和> 30%。共有69%和80%的患者出现全身症状和瘙痒完全消退。白细胞增多、贫血和血小板增多的反应发生在15%-25%。临床缓解与JAK 2 V617 F负荷降低、循环CD 34（+）细胞或细胞因子水平无关，而CCDN 1 mRNA和磷酸化p70 S6 K水平（mTOR的已知靶点）和WT 1 mRNA被确定为可能与缓解相关的生物标志物。使用欧洲骨髓纤维化网络标准时的缓解率为60%（8例严重缓解，7例中度缓解，3例轻微缓解），或使用IWG-MRT标准时的缓解率为23%（1例部分缓解，6例临床改善）。这些结果提供了在骨髓纤维化中靶向mTOR通路可能具有临床相关性的概念验证。（血。2011;118（8）：2069-2076）
In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis, a myeloproliferative neoplasm with no approved therapies. We conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high- or intermediate-risk primary or postpolycythemia vera/postessential thrombocythemia myelofibrosis subjects. Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in phase 1 up to 10 mg/d. When this dose was used in phase 2, grade >= 3 toxicities were infrequent; the commonest toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of > 50% and > 30% occurred in 20% and 44% of subjects, respectively. A total of 69% and 80% experienced complete resolution of systemic symptoms and pruritus. Response in leukocytosis, anemia, and thrombocytosis occurred in 15%-25%. Clinical responses were not associated with reduced JAK2V617F burden, circulating CD34(+) cells, or cytokine levels, whereas CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA were identified as possible biomarkers associated with response. Response rate was 60% when European Network for Myelofibrosis criteria were used (8 major, 7 moderate, 3 minor responses) or 23% when IWG-MRT criteria (1 partial response, 6 clinical improvements) were used. These results provide proof-of-concept that targeting mTOR pathway in myelofibrosis may be clinically relevant. (Blood. 2011;118(8):2069-2076)