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

 

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

1. Paola Guglielmelli1,
2. Giovanni Barosi2,
3. Alessandro Rambaldi3,
4. Roberto Marchioli4,
5. Arianna Masciulli4,
6. Lorenzo Tozzi1,
7. Flavia Biamonte1,
8. Niccolò Bartalucci1,
9. Elisabetta Gattoni2,
10. Maria Letizia Lupo2,
11. Guido Finazzi3,
12. Alessandro Pancrazzi1,
13. Elisabetta Antonioli1,
14. Maria Chiara Susini1,
15. Lisa Pieri1,
16. Elisa Malevolti1,
17. Emilio Usala5,
18. Ubaldo Occhini6,
19. Alberto Grossi7,
20. Silvia Caglio8,
21. Simona Paratore8,
22. Alberto Bosi1,
23. Tiziano Barbui3,
24. Alessandro M. Vannucchi1, and
25. on behalf of the AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM) investigators

+ Author Affiliations

1. ¹Department of Medical and Surgical Care, Section of Hematology, University of Florence and Istituto Toscano Tumori, Florence, Italy;
2. ²Unit of Clinical Epidemiology and Center for the Study of Myelofibrosis, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy;
3. ³Hematology Department, Ospedali Riuniti di Bergamo, Bergamo, Italy;
4. ⁴Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy;
5. ⁵Hematology and Bone Marrow Transplant Unit, Ospedale A. Businco, Cagliari, Italy;
6. ⁶UOC di Ematologia, Ospedale San Donato, Arezzo, Italy;
7. ⁷Oncology Unit, Ospedale di Prato, Prato, Italy; and
8. ⁸Novartis Farma SpA, Origgio, Varese, Italy

1. Presented in part at the annual meeting of the American Society of Hematology, Orlando, FL, December 6, 2010.

Next Section

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.

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