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Temsirolimus, an mTOR inhibitor, in combination with lower‐dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML‐1107)
Author(s) -
Amadori Sergio,
Stasi Roberto,
Martelli Alberto M.,
Venditti Adriano,
Meloni Giovanna,
Pane Fabrizio,
Martinelli Giovanni,
Lunghi Monia,
Pagano Livio,
Cilloni Daniela,
Rossetti Elena,
Di Raimondo Francesco,
Fozza Claudio,
Annino Luciana,
Chiarini Francesca,
Ricci Francesca,
Ammatuna Emanuele,
La Sala Edoardo,
Fazi Paola,
Vignetti Marco
Publication year - 2012
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2011.08940.x
Subject(s) - clofarabine , medicine , temsirolimus , discovery and development of mtor inhibitors , salvage therapy , myeloid leukaemia , oncology , myeloid leukemia , chemotherapy , pi3k/akt/mtor pathway , cytarabine , apoptosis , biochemistry , chemistry
Summary 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/m 2 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 3·5 months, and median overall survival was 4 months (9·1 months for responders). The most common non‐haematological 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 = 0·0001), 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.