As reported in the Journal of Clinical Oncology by Russell et al, the NCRI AML18 trial has shown survival benefit with treatment intensification in fit older patients with measurable residual disease (MRD)-positive response after first induction for acute myeloid leukemia (AML).
Study Details
In the trial, 523 patients (median age = 67 years) from sites in the UK and Denmark without flow cytometric MRD-negative remission response after a first course of daunorubicin and cytarabine (DA; including 165 without remission) were randomly assigned to up to two further courses of DA (n = 193) or intensified chemotherapy with either fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-Ida; n = 191) or DA with cladribine (DAC; n = 106). The primary outcome measure was overall survival.
Key Findings
No significant overall survival benefit was observed with intensification among all patents. Hazard ratios (HRs) were 0.74 (95% confidence interval [CI] = 0.55–1.01, P = .054) for DAC vs DA and 0.86 (95% CI= 0.66-1.12, P = .270) for FLAG-IDA vs DA. Overall survival at 3 years was 34.6% with DA, 46% with DAC, and 42% with FLAG-Ida.
Among the 523 randomly assigned patients, 131 had MRD-unknown status; among these patients, no survival advantage from intensification was identified. In a planned sensitivity analysis excluding these patients, overall survival benefit vs DA was demonstrated for both DAC (HR = 0.66, 95% CI = 0.46–0.93, P = .018) and FLAG-Ida (HR = 0.72, 95% CI = 0.53–0.98, P = .035). In this analysis, overall survival at 3 years was 30% with DA, 46% with DAC, and 46% with FLAG-Ida. Risk of relapse was also significantly reduced vs DA with DAC (HR = 0.66, 95% CI = 0.45–0.98, P = .039) and FLAG-Ida (HR = 0.70, 95% CI = 0.49–0.99, P = .042).
Patients receiving FLAG-Ida had greater risk for 60-day mortality vs those receiving DAC (9% vs 4%), with a slight increase in death due to infection. Patients receiving FLAG-Ida had increased risk of grade ≥ 2 gastrointestinal and liver toxicity; grade ≥ 3 cardiac function adverse events were more common with DAC.
The investigators concluded: “In this study of older patients with AML considered fit and with evidence of residual disease after first induction, chemotherapy intensification improved survival. DAC intensification was better tolerated than FLAG-Ida.”
Sylvie D. Freeman, MD, DPhil, of University of Birmingham College of Medicine and Health, Birmingham, UK, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Cancer Research UK. For full disclosures of the study authors, visit ascopubs.org.
