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)

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. Indu...

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Published in:British journal of haematology 2012-01, Vol.156 (2), p.205-212
Main Authors: 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
Format: Article
Language:English
Subjects:
acute myeloid leukaemia
Adenine Nucleotides - administration & dosage
Adenine Nucleotides - adverse effects
Age Factors
Aged
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Arabinonucleosides - administration & dosage
Arabinonucleosides - adverse effects
Biological and medical sciences
clofarabine
Data processing
Disease-Free Survival
elderly patients
Female
Hematologic and hematopoietic diseases
Humans
Infection
Leukemia, Myeloid, Acute - drug therapy
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Male
mammalian target of rapamycin
Medical sciences
Middle Aged
Mortality
Neutropenia
Phosphorylation
Remission
Ribosomal proteins
Salvage Therapy - methods
Signal transduction
Sirolimus - administration & dosage
Sirolimus - adverse effects
Sirolimus - analogs & derivatives
Survival
temsirolimus
TOR protein
TOR Serine-Threonine Kinases - antagonists & inhibitors
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Summary: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/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 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.
ISSN:0007-1048
1365-2141
DOI:10.1111/j.1365-2141.2011.08940.x