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

To evaluate the survival benefit of chemotherapy intensification in older patients with AML who have not achieved a measurable residual disease (MRD)-negative remission. 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). Overall survival (OS) was not improved in the intensification arms (DAC <i>v</i> DA: hazard ratio [HR], 0.74 [95% CI, 0.55 to 1.01]; <i>P</i> = .054; FLAG-Ida <i>v</i> DA: HR, 0.86 [95% CI, 0.66 to 1.12]; <i>P</i> = .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 <i>v</i> 4% after DA or DAC; <i>P</i> = .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]; <i>P</i> = .018) and FLAG-Ida (HR, 0.72 [95% CI, 0.53 to 0.98]; <i>P</i> = .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 <i>v</i> DA: HR, 0.66 [95% CI, 0.45 to 0.98]; <i>P</i> = .039; FLAG-Ida <i>v</i> DA: HR, 0.70 [95% CI, 0.49 to 0.99]; <i>P</i> = .042). DAC benefit was maintained when survival was censored for transplant (<i>P</i> = .042). 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.