Intermediate-Dose Cytarabine/Mitoxantrone versus Standard-Dose Cytarabine/Daunorubicin Induction Therapy in AML Patients >60 Years: Results from the SAL 60+ Trial
Intensive induction chemotherapy consisting of daunorubicin plus cytarabine (DA) is the standard of care for patients with acute myeloid leukemia (AML); however, elderly patients experience high treatment-related morbidities and lower remission rates than younger patients, underscoring the need for active and tolerable induction regimens in this setting.1 A randomized controlled Study Alliance Leukemia (SAL) study previously showed that an intermediate-dose cytarabine plus mitoxantrone (IMA) regimen resulted in high complete response (CR) rates and acceptable toxicity in elderly (?60 years) patients with AML compared with the standard DA regimen; Röllig and colleagues reported the results of this trial at the 2015 ASH meeting.2
In this trial, the IMA regimen consisted of intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 on days 1-3). Patients in CR after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment; patients in CR after IMA received standard-dose cytarabine plus mitoxantrone. A total of 485 patients were randomized to receive DA (n = 241) or IMA (n = 244); the median age of the study population was 69 years and most baseline characteristics were well-balanced except for a higher proportion of patients with poor-risk cytogenetics in the control arm (27% vs 19%). A significantly higher proportion of patients treated with IMA achieved a CR compared with the standard regimen (55% vs 39%; P = .001). Subgroup analyses showed that the CR benefit extended to all subgroups by age, cytogenetics, de novo AML, and NPM1 and FLT3-ITD mutations. In both treatment groups, 6-week mortality was 14%. At a median follow-up of 66 months, relapse-free survival (RFS) was similar between the IMA and DA arms (median RFS, 10 months vs 11 months), but a separation in RFS curves was observed at longer follow-up; consequently, 3-year RFS rates were significantly higher with DA induction (29% vs 14; P = .042). The median overall survival (OS), 1-year OS, and 3-year OS rates were similar between the 2 arms. The 3-year cumulative incidence of relapse was higher in the IMA arm (76% vs 61%; P = .13), with no differences in 3-year nonrelapse mortality between the 2 treatment arms. Nonhematologic toxicities were similar between the 2 arms except for a higher incidence of liver toxicity (odds ratio [OR], 0.52; P = .001) and gastrointestinal symptoms (OR, 0.62; P = .041) with DA induction therapy. Based on these study results, the use of intermediate-dose cytarabine in induction therapy resulted in significantly higher CR rates and showed similar toxicity profiles compared with the standard regimen in elderly patients with AML, which did not translate to a survival advantage.