1. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis
- Author
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Emilio Usala, Paola Guglielmelli, Elisabetta Gattoni, Giovanni Barosi, Tiziano Barbui, Alberto Bosi, Niccolò Bartalucci, Arianna Masciulli, Alessandro Pancrazzi, Maria Chiara Susini, Alessandro M. Vannucchi, Alberto Grossi, Roberto Marchioli, Ubaldo Occhini, Alessandro Rambaldi, Elisa Malevolti, Flavia Biamonte, Lisa Pieri, Elisabetta Antonioli, Lorenzo Tozzi, Simona Paratore, Guido Finazzi, Silvia Caglio, and Maria Letizia Lupo
- Subjects
Adult ,Male ,medicine.medical_specialty ,Clinical Trials and Observations ,Immunology ,Biochemistry ,Gastroenterology ,Polycythemia vera ,Internal medicine ,Medicine ,Humans ,Cyclin D1 ,Leukocytosis ,Everolimus ,RNA, Messenger ,Myelofibrosis ,WT1 Proteins ,Polycythemia Vera ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Myeloproliferative neoplasm ,Aged ,Sirolimus ,Thrombocytosis ,business.industry ,TOR Serine-Threonine Kinases ,Cell Biology ,Hematology ,Janus Kinase 2 ,Middle Aged ,medicine.disease ,Treatment Outcome ,Primary Myelofibrosis ,Mutation ,Female ,medicine.symptom ,business ,Receptors, Thrombopoietin ,medicine.drug ,Signal Transduction ,Thrombocythemia, Essential - Abstract
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.
- Published
- 2011