title: Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis.
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.
authors: Department of Medical and Surgical Care, Section of Hematology, University of Florence, Florence, Italy.
authors: Paola
authors: P
authors: Guglielmelli
authors: Giovanni
authors: G
authors: Barosi
authors: Alessandro
authors: A
authors: Rambaldi
authors: Roberto
authors: R
authors: Marchioli
authors: Arianna
authors: A
authors: Masciulli
authors: Lorenzo
authors: L
authors: Tozzi
authors: Flavia
authors: F
authors: Biamonte
authors: Niccolò
authors: N
authors: Bartalucci
authors: Elisabetta
authors: E
authors: Gattoni
authors: Maria Letizia
authors: ML
authors: Lupo
authors: Guido
authors: G
authors: Finazzi
authors: Alessandro
authors: A
authors: Pancrazzi
authors: Elisabetta
authors: E
authors: Antonioli
authors: Maria Chiara
authors: MC
authors: Susini
authors: Lisa
authors: L
authors: Pieri
authors: Elisa
authors: E
authors: Malevolti
authors: Emilio
authors: E
authors: Usala
authors: Ubaldo
authors: U
authors: Occhini
authors: Alberto
authors: A
authors: Grossi
authors: Silvia
authors: S
authors: Caglio
authors: Simona
authors: S
authors: Paratore
authors: Alberto
authors: A
authors: Bosi
authors: Tiziano
authors: T
authors: Barbui
authors: Alessandro M
authors: AM
authors: Vannucchi
mesh_terms: D000328:Adult; D000368:Aged; D019938:Cyclin D1 / Q000235:genetics; D000068338:Everolimus; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011087:Polycythemia Vera / Q000150:complications; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013920:Thrombocythemia, Essential / Q000150:complications; D016896:Treatment Outcome; D025721:WT1 Proteins / Q000235:genetics
chemical_list: C530104:CCND1 protein, human; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D053628:Receptors, Thrombopoietin; D025721:WT1 Proteins; D019938:Cyclin D1; C082218:MPL protein, human; D000068338:Everolimus; C546842:MTOR protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus