A randomised evaluation of low‐dose cytosine arabinoside (ara‐C) plus tosedostat versus low‐dose ara‐C in older patients with acute myeloid leukaemia: results of the LI‐1 trial. (7th May 2021)

• Record Type: Journal Article
• Authors: Dennis, Mike; Burnett, Alan; Hills, Robert; Thomas, Ian; Ariti, Cono; Severinsen, Marianne T.; Hemmaway, Claire; Greaves, Paul; Clark, Richard E.; Copland, Mhairi; Russell, Nigel
• Other Names: Kallenbach Maria investigator.; Culligan Dominic investigator.; Duncan Caroline investigator.; Krishnamurthy Pramila investigator.; Cuthbert Ann investigator.; Patalappa Chetan investigator.; Spanoudakis Michail investigator.; Galvani David investigator.; Berkahn I. investigator.; Patton N. investigator.; Pemberton Lucy investigator.; Virchis Andres investigator.; Jasani Parag investigator.; Parker Anne investigator.; Arnold Claire investigator.; Cuthbert Robert investigator.; Finnega Damien investigator.; Nikolousis Manos investigator.; Pratt Guy investigator.; Cahalin Paul investigator.; Ackroyd Sam investigator.; Mehta Priyanka investigator.; Protheroe Rachel investigator.; Weinkove Robert investigator.; Ali Sara investigator.; Welch Emma investigator.; Smith Mark investigator.; Spearing Ruth investigator.; Vyas Paresh investigator.; Campbell Gavin investigator.; Hamblin Mike investigator.; Wood Marion investigator.; Gupta Sunil investigator.; Westonsmith Simon investigator.; Pillai Arvind investigator.; Hunter Hannah investigator.; Rule Simon investigator.; Neilson Roderick investigator.; Lush Richard investigator.; Rothwell Kate investigator.; Swe Wunna investigator.; Chalmers Isobel investigator.; Prahladan Mahesh investigator.; Kwan Mark investigator.; Lyttleton Matthew investigator.; Hunter Ann investigator.; Martin Alexander M. investigator.; Saravanamuttu Kandeepan investigator.; Saif Muhammad investigator.; Tholouli Eleni investigator.; Andrews Vivienne investigator.; Jackson Sharon investigator.; Rajagopal Rajeev investigator.; Morrison Anne investigator.; Gordon William investigator.; Mitchell Lindsay investigator.; Bowen Angela investigator.; McGrann Alistair investigator.; Mittal Sajjan investigator.; Panoskaltsis Nicki investigator.; Byrne Jenny investigator.; Das‐Gupta Emma investigator.; Radia Rohini investigator.; Baker Bart investigator.; Kilfoyle Allanah investigator.; Knottenbelt Elayne investigator.; Rinaldi Ciro investigator.; Moreton Paul investigator.; Furby Darshyani investigator.; Jack Fergus investigator.; Alderman Charles investigator.; Belsham Edward investigator.; Corser Robert investigator.; Cranfield Tanya investigator.; Dignum Helen investigator.; James Christopher investigator.; Gudgin Emma investigator.; Mohan Mahalakshmi investigator.; Kampman Peter investigator.; Kjeldsen Lars investigator.; Mourek Jindrich investigator.; Nielsen Ove J. investigator.; Niemann Carsten U. investigator.; Grech Henri investigator.; Khan Asif investigator.; Sampson Rebecca investigator.; Creagh Desmond investigator.; Szabo Ferenc investigator.; Coppell J investigator.; Veale D investigator.; Kottaridis Panagiotis investigator.; Fernandes Savio investigator.; Cullis Jonathan investigator.; Grand Effie investigator.; Wandroo Farooq investigator.; Mohite Unmesh investigator.; O'Brien David investigator.; Nicholson Toby investigator.; Janes Sarah investigator.; Aitchison Robin investigator.; Galloway Mike investigator.; Mathew Susanna investigator.; Blesing Norbert investigator.; Green Sarah investigator.; Mamadigi Rajesh investigator.; Plews Diane investigator.; Chacko Joseph investigator.; Salim Rahuman investigator.; Allameddine Allameddine investigator.; Greenfield Hayley investigator.; Osborne David investigator.; Hodges Georgina investigator.; Lai Hock C. investigator.; Carrington Patrick investigator.; Sadik Walid investigator.; Yung Lynny investigator.; Lokare Anand investigator.; Alvares Caroline investigator.; Knapper Steve investigator.; Goodman Hugh investigator.; Islam Shahid investigator.; Aitchison Robin investigator.; Pattinson Jonathan investigator.; Pushkaran Beena investigator.; Heartin Earnest investigator.; Edwards David investigator.; Seale Jim investigator.;
• Is Part Of: British journal of haematology. Volume 194:Number 2(2021)
• Page Start: 298
• Page End: 308
• Publication Date: 2021-05-07
• Subjects: AML -- acute leukaemia -- chemotherapy -- elderly; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.17501
• Languages: English
• ISSNs: 0007-1048

Abstract

Summary: Older patients with acute myeloid leukaemia (AML) account for nearly half of those with the disease. Because they are perceived to be unfit for, unwilling to receive, or unlikely to benefit from conventional chemotherapy they represent an important unmet need. Tosedostat is a selective oral aminopeptidase inhibitor, which in phase I/II trials showed acceptable toxicity and encouraging efficacy. We report the only randomised study of low‐dose cytosine arabinoside (LDAC) combined with tosedostat (LDAC‐T) versus LDAC in untreated older patients not suitable for intensive treatment. A total of 243 patients were randomised 1:1 as part of the 'Pick‐a‐Winner' LI‐1 trial. There was a statistically non‐significant increase in the complete remission (CR) rate with the addition of tosedostat, LDAC‐T 19% versus LDAC 12% [odds ratio (OR) 0·61, 95% confidence interval (CI) 0·30–1·23; P = 0·17]. For overall response (CR+CR with incomplete recovery of counts), there was little evidence of a benefit to the addition of tosedostat (25% vs. 18%; OR 0·68, 95% CI 0·37–1·27; P = 0·22). However, overall survival (OS) showed no difference (2‐year OS 16% vs. 12%, hazard ratio 0·97, 95% CI 0·73–1·28; P = 0·8). Exploratory analyses failed to identify any subgroup benefitting from tosedostat. Despite promising pre‐clinical, early non‐randomised clinical data with acceptable toxicity and an improvement in response, we did not find evidence that the addition of tosedostat to LDAC produced a survival benefit in this group of patients with AML. International Standard Randomised Controlled Trial Number: ISRCTN40571019