The evidence supporting this protocol is provided by a phase 3 multicentre international randomised trial involving 813 patients
Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square metre by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square metre (411 patients) or at an escalated dose of 90 mg per square metre (402 patients). The primary end point was event-free survival.
Eligible patients were randomly assigned to receive daunorubicin at a dose of 45 mg per square metre (conventional-dose group) (411 patients) or at a dose of 90 mg per square metre (escalated-dose group) (402 patients) — both administered intravenously over the course of 3 hours on days 1 to 3 of the first cycle of induction treatment plus cytarabine at a dose of 200 mg per square metre, administered by continuous infusion for 7 days. In the second cycle of treatment, both groups received cytarabine at a dose of 1000 mg per square metre twice daily, given intravenously over the course of 6 hours on days 1 through 6.r
In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects.
In this study, it is apparent that the subgroup of patients who were 60 to 65 years of age benefited the most from intensified doses of daunorubicin. In this subgroup, the rate of complete remission among patients who received the escalated dose, as compared with those who received the conventional dose, was 73% versus 51%; this subgroup, as compared with all other cytogenetic subgroups, also had the highest rates of overall survival.
From October 27, 2000, through June 9, 2006, a total of 813 eligible patients who could be evaluated were randomly assigned to a treatment group — 411 to the conventional-dose group and 402 to the escalated-dose group. The median follow-up period for patients who were still alive at the date of last contact (148 patients) was 40 months.
The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%).
© NEJM 2009
Exploratory post hoc analyses showed that patients who were 60 to 65 years of age had the greatest benefit from an escalated dose of daunorubicin with respect to the complete remission rate (51% in the conventional-dose group vs. 73% in the escalated-dose group), the 2-year rate of event-free survival (14% vs. 29%), and the 2-year rate of overall survival (23% vs. 38%). Tests for an interaction between age and treatment were significant with respect to complete remission, event-free survival, and overall survival. Tests for an interaction between cytogenetic risk category and treatment were not significant except with respect to disease-free survival, but in the subgroup with abnormalities in core-binding factors, the escalated dose was associated with an increased rate of complete remission and with reduced hazard ratios for disease progression or death. None of the tests for interaction with respect to the other factors were significant.
© NEJM 2009
There were no significant differences between the two groups in 30-day mortality (12% in the conventional-dose group and 11% in the escalated-dose group), the number of nights spent in the hospital, and the time to recovery of neutrophil or platelet counts. There were also no significant differences with respect to the rate of death during induction or the incidence of serious adverse events after the first two cycles overall. In the escalated-dose group, as compared with the conventional-dose group, there were more infections of grade 2 to 4, slightly more platelet transfusions were given, and the time to the beginning of the second cycle was, on average, 3 days longer. The difference in the time to the second cycle probably reflects the higher rate of complete remission after the first cycle in the escalated-dose group; among patients with no response, the second cycle was frequently started as soon as possible because hematologic recovery was not expected. There was no significant difference in the rate of grade 2 to 4 (i.e., moderate, severe, or life-threatening) side effects between the two groups (74% in the conventional-dose group and 80% in the escalated-dose group, P = 0.08).
© NEJM 2009