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

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 CaglioSimona Paratore, Alberto Bosi, Tiziano Barbui, Alessandro M. Vannucchi

Research output: Contribution to journalArticlepeer-review


In addition to dysregulated JAK/STATsignaling, 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 toxicitywasobserved 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.Atotal 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 CCDN1mRNAand 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-ofconcept that targeting mTOR pathway in myelofibrosis may be clinically relevant.

Original languageEnglish
Pages (from-to)2069-2076
Number of pages8
Issue number8
Publication statusPublished - Aug 25 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


Dive into the research topics of 'Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis'. Together they form a unique fingerprint.

Cite this