Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial

Abstract

PURPOSE To evaluate the survival benefit of chemotherapy intensification in older patients with AML who have not achieved a measurable residual disease (MRD)–negative remission. METHODS Five hundred twenty-three patients with AML (median age, 67 years; range, 51-79) without a flow cytometric MRD-negative remission response after a first course of daunorubicin and AraC (DA; including 165 not in remission) were randomly assigned between up to two further courses of DA or intensified chemotherapy—either fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-Ida) or DA with cladribine (DAC). RESULTS Overall survival (OS) was not improved in the intensification arms (DAC v DA: hazard ratio [HR], 0.74 [95% CI, 0.55 to 1.01]; P = .054; FLAG-Ida v DA: HR, 0.86 [95% CI, 0.66 to 1.12]; P = .270); OS at 3 years was 34%, 46%, and 42% for DA, DAC, and FLAG-Ida, respectively. Early deaths and other adverse events were more frequent with FLAG-Ida (9% day 60 deaths v 4% after DA or DAC; P = .032). Of patients entering random assignment, 131 had MRD unknown status. In this subgroup of patients lacking evidence of residual leukemia by flow cytometry, there was no detectable survival advantage from intensification. A planned sensitivity analysis excluding these patients demonstrated a survival benefit for both DAC (HR, 0.66 [95% CI, 0.46 to 0.93]; P = .018) and FLAG-Ida (HR, 0.72 [95% CI, 0.53 to 0.98]; P = .035); OS at 3 years was 30%, 46%, and 46% for DA, DAC, and FLAG-Ida, respectively. There was a concordant reduction in relapse (DAC v DA: HR, 0.66 [95% CI, 0.45 to 0.98]; P = .039; FLAG-Ida v DA: HR, 0.70 [95% CI, 0.49 to 0.99]; P = .042). DAC benefit was maintained when survival was censored for transplant ( P = .042). CONCLUSION 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.