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.
Mike DennisAlan BurnettRobert K HillsIan ThomasCono AritiMarianne Tang SeverinsenClaire HemmawayPaul GreavesRichard E ClarkMhairi CoplandNigel Russellnull nullPublished in: British journal of haematology (2021)
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.
Keyphrases
- low dose
- study protocol
- clinical trial
- open label
- phase iii
- acute myeloid leukemia
- double blind
- phase ii
- placebo controlled
- randomized controlled trial
- high dose
- end stage renal disease
- physical activity
- ejection fraction
- bone marrow
- oxidative stress
- community dwelling
- peritoneal dialysis
- middle aged
- chronic kidney disease
- allogeneic hematopoietic stem cell transplantation
- depressive symptoms
- squamous cell carcinoma
- mental health
- prognostic factors
- immune response
- big data
- patient reported outcomes
- free survival
- solid state
- electronic health record
- systemic lupus erythematosus
- disease activity
- ulcerative colitis
- combination therapy