• Paola Guglielmelli, Giovanni Barosi, Alessandro Rambaldi, Roberto Marchioli, Arianna Masciulli, Lorenzo Tozzi, Flavia Biamonte, Niccolò Bartalucci, Elisabetta Gattoni, Maria Letizia Lupo, Guido Finazzi, Alessandro Pancrazzi, Elisabetta Antonioli, Maria Chiara Susini, Lisa Pieri, Elisa Malevolti, Emilio Usala, Ubaldo Occhini, Alberto Grossi, Silvia Caglio, Simona Paratore, Alberto Bosi, Tiziano Barbui, Alessandro M Vannucchi, and AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM) investigators.
• Department of Medical and Surgical Care, Section of Hematology, University of Florence, Florence, Italy.
• Blood. 2011 Aug 25;118(8):2069-76.

AbstractIn 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.

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