Intermediate versus High Dose of Cytarabine for Acute Myeloid Leukemia

For >30 years, acute myeloid leukemia (AML) has been treated with cytarabine. Initially, the drug was used in remission-induction therapy at a dose of 100 to 200 mg per square meter of body surface area. High-dose therapy was evaluated beginning in 1975; cytarabine was given at a dose of 3000 mg/m2 twice daily for 6 days. At the higher dose, patients with relapse had high response rates; there were promising results for newly diagnosed patients as well. A 1995 study showed that 4 cycles of cytarabine at a dose of 3000 mg/m2 administered twice a day on days 1, 3, and 5 and again after complete remission was superior to cytarabine at a dose of 100 or 400 mg/m2 relative to overall survival and relapse-free survival in patients <60 years of age. Currently, high-dose cytarabine is used for both induction therapy and consolidation therapy. Noting that high-dose cytarabine has not been compared with intermediate-dose cytarabine, researchers recently conducted a study to compare outcomes for patients given cytarabine at a dose of 2000 to 3000 mg/m2 to those for patients given the drug at an intermediate dose (approximately one third the total high dose). They reported study results in the New England Journal of Medicine [2011;364(11):1027-1036]. Patients with newly diagnosed AML were randomly assigned to remission-induction regimens with either intermediate-dose cytarabine (n=431) or high-dose cytarabine (n=429). The intermediate dose included idarubicin at a dose of 12 mg/m2 administered as a 3-hour infusion on days 5, 6, and 7 and cytarabine at a dose of 200 mg/m2 administered as a continuous infusion on days 1 through 7. Cycle 1 for the high-dose group was the same regimen with the exception that cytarabine was administered in a 3-hour infusion at a dose of 1000 mg/m2 every 12 hours on days 1 through 5. For the intermediate-dose group, cycle 2 consisted of amsacrine in a 1-hour infusion at a dose of 120 mg/m2 on days 3, 5, and 7 plus cytarabine at a dose of 1000 mg/m2 given intravenously for 3 hours twice daily on days 1 through 6. For the high-dose group, cycle 2 was the same regimen with the exception that cytarabine was administered intravenously at a dose of 2000 mg/m2 for 6 hours twice daily on days 1, 2, 4, and 6. Patients with a complete response did not receive additional cytarabine but received consolidation therapy in a third cycle of chemotherapy (mitoxantrone-etoposide) or underwent autologous or allogeneic stem cell transplantation. Outcome measures included complete remission rates, survival rates, and toxic effects in each group. During the study period, 858 patients received cycle 1 induction therapy and 748 received induction therapy cycle 2; distribution was similar between the intermediate-dose group and the high-dose group. During the final part of the study, patients were also randomly assigned to either granulocyte colony-stimulating factor priming or to no priming. At a median follow-up of 5 years, complete remission rates were similar for the intermediate-dose group and the high-dose group (80% and 82%, respectively); there was no significant difference between the groups in the rate of event-free survival (34% and 35%, respectively) or overall survival (40% and 42%, respectively). The cumulative 5-year probabilities for the competing risks of failure were also similar in the 2 groups: 39% and 37%, respectively, for relapse and 7% and 11% for death during the first complete remission. In the high-dose group, more patients had grade 3 to 4 adverse effects after cycle 1 compared with patients in the intermediate-dose group (61% vs 51%, respectively; P=.005). There were no significant differences between the 2 groups in 30-day mortality; however, the number of deaths in the first 3 months was greater in the high-dose group compared with the intermediate-dose group (72 vs 52, respectively; hazard ratio, 1.41; P=.057). In summary, the researchers said that “induction therapy with cytarabine at the lower dose already produced maximal antileukemic effects for all response end points, suggesting a plateau in the dose-response relationship about this dose level. High-dose cytarabine results in excessive toxic effects without therapeutic benefit.”