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 Caglio & 4 others Simona Paratore, Alberto Bosi, Tiziano Barbui, Alessandro M. Vannucchi

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

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
JournalBlood
Volume118
Issue number8
DOIs
Publication statusPublished - Aug 25 2011

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Primary Myelofibrosis
Toxicity
70-kDa Ribosomal Protein S6 Kinases
Safety
Thrombocytosis
Biomarkers
Chemical activation
Cytokines
Messenger RNA
Stomatitis
Splenomegaly
Leukocytosis
Pruritus
Anemia
Everolimus
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Guglielmelli, P., Barosi, G., Rambaldi, A., Marchioli, R., Masciulli, A., Tozzi, L., ... Vannucchi, A. M. (2011). Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood, 118(8), 2069-2076. https://doi.org/10.1182/blood-2011-01-330563

Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. / Guglielmelli, Paola; Barosi, Giovanni; Rambaldi, Alessandro; Marchioli, Roberto; Masciulli, Arianna; Tozzi, Lorenzo; Biamonte, Flavia; Bartalucci, Niccolò; Gattoni, Elisabetta; Lupo, Maria Letizia; Finazzi, Guido; Pancrazzi, Alessandro; Antonioli, Elisabetta; Susini, Maria Chiara; Pieri, Lisa; Malevolti, Elisa; Usala, Emilio; Occhini, Ubaldo; Grossi, Alberto; Caglio, Silvia; Paratore, Simona; Bosi, Alberto; Barbui, Tiziano; Vannucchi, Alessandro M.

In: Blood, Vol. 118, No. 8, 25.08.2011, p. 2069-2076.

Research output: Contribution to journalArticle

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 2011, 'Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis', Blood, vol. 118, no. 8, pp. 2069-2076. https://doi.org/10.1182/blood-2011-01-330563
Guglielmelli P, Barosi G, Rambaldi A, Marchioli R, Masciulli A, Tozzi L et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood. 2011 Aug 25;118(8):2069-2076. https://doi.org/10.1182/blood-2011-01-330563
Guglielmelli, Paola ; Barosi, Giovanni ; Rambaldi, Alessandro ; Marchioli, Roberto ; Masciulli, Arianna ; Tozzi, Lorenzo ; Biamonte, Flavia ; Bartalucci, Niccolò ; Gattoni, Elisabetta ; Lupo, Maria Letizia ; Finazzi, Guido ; Pancrazzi, Alessandro ; Antonioli, Elisabetta ; Susini, Maria Chiara ; Pieri, Lisa ; Malevolti, Elisa ; Usala, Emilio ; Occhini, Ubaldo ; Grossi, Alberto ; Caglio, Silvia ; Paratore, Simona ; Bosi, Alberto ; Barbui, Tiziano ; Vannucchi, Alessandro M. / Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. In: Blood. 2011 ; Vol. 118, No. 8. pp. 2069-2076.
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AU - Masciulli, Arianna

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AU - Grossi, Alberto

AU - Caglio, Silvia

AU - Paratore, Simona

AU - Bosi, Alberto

AU - Barbui, Tiziano

AU - Vannucchi, Alessandro M.

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