Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis.

摘要: 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 phase 1/2 study everolimus, an mTOR inhibitor, 39 high- or intermediate-risk primary postpolycythemia vera/postessential thrombocythemia myelofibrosis subjects. Responses were evaluated 30 patients 2. No dose-limiting toxicity was observed 1 up 10 mg/d. When this dose used 2, grade ≥ 3 toxicities infrequent; commonest 1-2 stomatitis. Rapid and sustained splenomegaly reduction > 50% 30% occurred 20% 44% subjects, respectively. A total 69% 80% experienced complete resolution systemic symptoms pruritus. Response leukocytosis, anemia, thrombocytosis 15%-25%. Clinical responses not associated reduced JAK2V617F burden, circulating CD34(+) cells, cytokine levels, whereas CCDN1 mRNA phospho-p70S6K level, known targets mTOR, WT1 identified as possible biomarkers response. rate 60% when European Network for Myelofibrosis criteria (8 major, 7 moderate, minor responses) 23% IWG-MRT (1 partial response, 6 clinical improvements) used. These results provide proof-of-concept that targeting may be clinically relevant.