title: 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).
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 20mg/m(2) on days 1-5 and temsirolimus 25mg (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 3·5months, and median overall survival was 4months (9·1months 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.
authors.affiliation: Department of Haematology, Tor Vergata University Hospital, Roma, Italy Department of Haematology, St. George's Hospital, London, UK. sergio.amadori@ptvonline.it
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Roberto
authors.initials: R
authors.lastname: Stasi
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.forename: Adriano
authors.initials: A
authors.lastname: Venditti
authors.forename: Giovanna
authors.initials: G
authors.lastname: Meloni
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Monia
authors.initials: M
authors.lastname: Lunghi
authors.forename: Livio
authors.initials: L
authors.lastname: Pagano
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.forename: Elena
authors.initials: E
authors.lastname: Rossetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
authors.forename: Claudio
authors.initials: C
authors.lastname: Fozza
authors.forename: Luciana
authors.initials: L
authors.lastname: Annino
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiarini
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.forename: Emanuele
authors.initials: E
authors.lastname: Ammatuna
authors.forename: Edoardo
authors.initials: E
authors.lastname: La Sala
authors.forename: Paola
authors.initials: P
authors.lastname: Fazi
authors.forename: Marco
authors.initials: M
authors.lastname: Vignetti
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage / Q000009:adverse effects; D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000009:adverse effects; D000077866:Clofarabine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016879:Salvage Therapy / Q000379:methods*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; C401859:temsirolimus; D000077866:Clofarabine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus