Two studies in the September 24, 2009 issue of the New England Journal of Medicine confirm the importance of daunorubicin dose intensity for optimal treatment of patients with acute myeloid leukemia (AML).

An anthracycline, usually daunorubicn, and cytarabine have been the main drugs for treating AML since the mid 1960s. During this period there has been significant progress in the treatment of patients with AML who are 60 years of age or younger. However, there has been very little progress in the treatment of patients over the age of 60 years.

The incidence of AML increases significantly after age 60; the median age at diagnosis is over 65 years.  Most studies of AML exclude older patients, making it difficult to know what impact chemotherapy has on elderly patients, especially those without significant co-morbidities. However, age appears to be an independent risk factor for survival.

Researchers from the United Kingdom affiliated with the National Cancer Research Institute AML14 randomized trial have reported that patients with AML over the age of 60 years do not benefit from increasing the dose of daunorubicin or cytarabine or increasing the number of treatment courses.

Researchers from several U.S. medical centers have reported that intensifying induction therapy with a “high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival.”[1] This study included 657 patients between the ages of 17 and 60 years who received three days of daunorubicin at a dose of 45 mg/m2 or 90 mg/m2. Daunorubicin was combined with cytarabine. Patients who achieved a complete remission (CR) were offered an allogeneic stem cell transplant or chemotherapy consolidation. The complete remission rate was 70.6% for patients receiving the higher dose of daunorubicin and 57.3% for those receiving the lower dose. Overall survival was improved from 15.7 months in the lower dose group to 23.7 months in the higher dose group. These authors reported that serious adverse events were similar between the two dose groups.

Researchers from Europe reported that increasing the dose of daunorubicin to 90 mg/m2 for three days in induction in patients with AML who were 60 years or older (median of 67 years and range up to 83 years) also increased the response rate without increasing the toxicity.[2] This study included 411 patients who received daunorubicin at a dose of 45 mg/m2 for three days and 402 patients who received 90 mg/m2 for three days. The CR rate was 64% for patients receiving the higher dose of daunorubicin and 54% for patients receiving the lower dose. Thirty-day mortality was 11% for the high-dose group and 12% for the low-dose group. There were more severe toxicities in the high-dose group, but this did not reach statistically significance (P=0.08). There was no effect of increasing dose of daunorubicin on overall survival for the entire group. However, patients aged 60-65 appeared to do the best. In this age group, the CR rate was 73% for the higher dose of daunorubicin versus 51% for the lower dose. Event-free survival was 29% for the higher dose group versus 14% for the lower dose group. Overall survival was 38% for the higher dose group and 23% for the lower dose group.

Comments: These data, taken together, suggest that patients up to the age of 65 years derive survival benefit from increasing the dose of daunorubicin in the induction regimen.

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