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Temsirolimus, an mTOR inhibitor, in combination with lowerdose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107)

Amadori, Sergio and Stasi, Roberto and Martelli, Alberto Maria and Venditti, Adriano and Meloni, Giovanna and Pane, Fabrizio and Martinelli, Giovanni and Lunghi, Monia and Pagano, Livio and Cilloni, Daniela and Rossetti, Elena and Di Raimondo, Francesco and Fozza, Claudio and Annino, Luciana and Chiarini, Francesca and Ricci, Francesca and Ammatuna, Emanuele and La Sala, Edoardo and Fazi, Paola and Vignetti, Marco (2012) Temsirolimus, an mTOR inhibitor, in combination with lowerdose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107). British Journal of Haematology, Vol. 156 (2), p. 205-212. eISSN 1365-2141. Article.

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DOI: 10.1111/j.1365-2141.2011.08940.x

Abstract

The mammalian target of rapamycin (mTOR) signalling pathway has emerged as an important therapeutic target for acute myeloid leukaemia (AML). This study assessed the combination of temsirolimus, an mTOR inhibitor, and lower-dose clofarabine as salvage therapy in older patients with AML. Induction consisted of clofarabine 20 mg/m2 on days 1–5 and temsirolimus 25 mg (flat dose) on days 1, 8 and 15. Patients achieving complete remission with (CR) or without (CRi) full haematological recovery could receive monthly temsirolimus maintenance. In 53 evaluable patients, the overall remission rate (ORR) was 21% (8% CR, 13% CRi). Median disease-free survival was 3Æ5 months, and median overall survival was 4 months (9Æ1 months for responders). The most common nonhaematological severe adverse events included infection (48%), febrile neutropenia (34%) and transaminitis (11%). The 30-d all-cause induction mortality was 13%. Laboratory data from 25 patients demonstrated that a >50% in vivo inhibition of S6 ribosomal protein phosphorylation was highly correlated with response rate (75% with inhibition versus 0% without inhibition; P = 0Æ0001), suggesting that targeting the mTOR pathway is clinically relevant. The acceptable safety profile and the predictive value of target inhibition encourage further investigation of this novel regimen.

Item Type:Article
ID Code:6918
Status:Published
Refereed:Yes
Uncontrolled Keywords:Acute myeloid leukaemia, mammalian target of rapamycin, temsirolimus, clofarabine, elderly patients
Subjects:Area 06 - Scienze mediche > MED/15 Malattie del sangue
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Scienze Biomediche
Publisher:Blackwell / Wiley
eISSN:1365-2141
Deposited On:02 Jan 2012 14:20

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