Induction Therapy with Intermediate-Dose of Cytarabine Just as Effective in AML

Lowering the induction dose of cytarabine to 200-mg/m² in patients with acute myeloid leukemia (AML) reduced the rate of treatment-related toxicities but was no less effective than an induction dose >1000 mg/ m² according to a report in the New England Journal of Medicine. Investigators for the phase III multinational study recruited ~860 patients and randomized them 1:1 to an intermediate- or high-dose induction regimen of cytarabine. After median follow-up of 66 months, rates of remission, relapse, and 5-year overall survival (OS) were nearly identical between the groups. The study authors said, "Increasing the dose of cytarabine to more than 1000 mg/ m² provides no greater antileukemic activity than does the intermediate dose."

 

All patients in the study had untreated AML and ranged in age from 18 to 60 years. The first cycle of treatment for the intermediate-dose group (n = 431) consisted of 12 mg/ m²of idarubicin infused over 3 hours on days 5-7 plus 200-mg/m² of cytarabine administered continuously on days 1-7. Cycle 2 comprised 120-mg/m² of amsacrine infused over 1 hour on days 3, 5, and 7; with 1000 mg/m² of cytarabine administered as a 3-hour infusion twice daily on days 1-6.

 

Cycle 1 for patients in the high-dose group (n = 429) included the same regimen of idarubicin, but cytarabine was increased to 1000 mg/m² and given as a 3-hour infusion every 12 hours on days 1-5. They received the same dose of amsacrine in cycle 2 as the intermediate group, but the cytarabine dose was increased to 2000 mg/m² and administered as a 6-hour infusion twice daily on days 1, 2, 4, and 6.

 

Most patients in the study completed cycle 1 and ~85% completed cycle 2. The 694 patients who demonstrated complete response (CR) following the second cycle received a third consolidation cycle of chemotherapy or underwent stem-cell transplantation.

 

Investigators recorded 170 relapses and 260 deaths in the intermediate-dose group compared with 157 relapses and 251 deaths in the high-dose group. The 5-year rate of event-free survival (EFS) was 34% in the intermediate-dose arm versus 35% in the high-dose arm. OS was also comparable between the groups, with 40% of patients in the intermediate-dose group and 42% of patients in the high-dose group alive at 5 years.

 

While the intensity of the induction dose did not appear to affect outcomes, certain cytogenetic features proved prognostic. Patients with monosomal karotype had the lowest rates of remission, event-free survival, and OS. Patients with abnormalities of core-binding factor had the highest rate of CR and the highest rates of EFS and OS. Patients aged >50 years and those with secondary AML had statistically significant worse 5-year outcomes.

Following cycle 1, 61% of patients in the high-dose group experienced grade 3/4 adverse events compared with 51% of patients in the intermediate dose group (P = .005). The most common toxicities affected the skin, gastrointestinal tract, and eyes.

 

At 30-days post-induction, 10% of patients in each arm had died. At 3 months, 72 patients had died in the high-dose group compared with 52 in the intermediate-dose group (hazard ratio, 1.41; P = .057). Patients in the high-dose group also had delayed neutrophil and platelet recovery compared with patients in the low-dose group. Patients treated with the higher dose of cytarabine spent more nights in the hospital and required more platelet transfusions. The authors said the myelosuppressive effects of high-dose cytarabine appeared cumulative and persisted into postremission chemotherapy.