Blood. 2011 Jul 1. [Epub ahead of print]
Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis.
Guglielmelli P, Barosi G, Rambaldi A, Marchioli R, Masciulli A, Tozzi L, Biamonte F, Bartalucci N, Gattoni E, Lupo ML, Finazzi G, Pancrazzi A, Antonioli E, Susini MC, Pieri L, Malevolti E, Usala E, Occhini U, Grossi A, Caglio S, Paratore S, Bosi A, Barbui T, Vannucchi AM.
Department of Medical and Surgical Care, Section of Hematology, University of Florence and Istituto Toscano Tumori, Florence, Italy;
In addition to dysregulated JAK/STAT signaling, activation of AKT/mTOR pathway occurs in myelofibrosis, a myeloproliferative neoplasm with no approved therapies. We conducted a phase 1/2 study with everolimus, a mTOR inhibitor, in 39 high- or intermediate-risk primary or post-polycythemia vera/post-essential 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/day. Using this dose in phase 2, grade >3 toxicities were infrequent; commonest toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of >50% and >30% occurred in 20% and 44% of subjects, respectively. Sixty-nine and eighty per cent experienced complete resolution of systemic symptoms and pruritus. Response in leukocytosis, anemia and thrombocytosis occurred in 15% to 25%. Clinical responses were not associated with reduced JAK2V617F burden, circulating CD34(+) cells or cytokine levels, while 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% using EUMNET criteria (8 major, 7 moderate, 3 minor responses) or 23% using IWG-MRT criteria (one partial response and six clinical improvements). These results provide proof-of concept that targeting mTOR pathway in myelofibrosis may be clinically relevant. The study was registered at ANZCTR (http://www.anzctr.org.au) number 12608000614392. |
