HIGH DOSE DAUNORUBICIN FOR AML

September 24, 2009 — High-dose daunorubicin produced a higher rate of remission than the standard dose in patients with acute myeloid leukemia (AML), according to results from 2 large trials published in the September 24 issue of the New England Journal of Medicine.

The higher dose did not significantly increase adverse events or delay delivery of consolidation therapy in either study.

The results establish a new standard of care for AML — for some patients, says an accompanying editorial.

Different Ages in the 2 Trials

The patient population in the 2 trials differed widely in age. In the American trial, the median age was 48 years, and in the European trial (conducted in the Netherlands, Belgium, Germany, and Switzerland), the median age was 67 years.

In the American trial, the high-dose induction therapy (daunorubicin 90 mg/m² of body surface) resulted in improved overall survival, compared with the standard therapy of 45 mg/m² (23.7 vs 15.7 months; P =.003).

However, the beneficiaries of improved survival are younger patients (under age 50) and those who do not have adverse cytogenetic profiles, note the authors, led by Hugo F. Fernandez, MD, from the Moffitt Cancer Center and Research Institute in Tampa, Florida.

"The lack of an increase in toxic effects and the benefit in overall survival strongly argue for incorporating high-dose daunorubicin into the initial treatment of younger patients with AML, at least those with favorable- and intermediate-risk cytogenetic profiles," write the editorialists, Hervé Dombret, MD, and Claude Gardin, MD, from Université Paris in France.

The American authors agreed. "In younger patients, a dose of daunorubicin that exceeds the standard 45 mg/m² dose for induction should be considered the new standard of care," they write.

The European researchers did not have such strong words to offer because they did not find a survival benefit in their planned analyses. In post hoc analyses, they did find a survival benefit of high-dose daunorubicin in patients 60 to 65 years old, although they caution that this finding could be due to chance.

As a result, the European authors, headed by Bob Löwenberg, MD, from the Erasmus University Medical Center in Rotterdam, the Netherlands, conclude that the high-dose daunorubicin strategy could be "an alternative therapy" to high-dose cytarabine, which is effective in younger patients but "far too toxic" in those 60 years and older.

Not the First High-Dose Study

For more than 20 years, the standard induction therapy for attaining complete remission in AML has been an anthracycline — daunorubicin mostly — at a daily dose of 45 to 60 mg/m² of body surface area for 3 days, in combination with cytarabine for 7 days, the editorialists explain. Neither adding other drugs during the induction phase nor increasing the dose of cytarabine has led to improved survival, they add.

Previous studies have shown that various high doses of daunorubicin (70 to 95 mg/m² of body surface) improve the rate of remission, compared with the standard dose (45 mg/m²), but none have "definitively" shown an improvement in overall survival with the higher doses, write the American investigators.

In the new studies, this standard induction dose of daunorubicin was doubled. In the American trial, 657 patients with either primary or therapy-related AML were followed for a median of 25.2 months; all patients were 60 years of age or younger. Patients in complete remission continued with a consolidation phase that included either autologous or allogeneic stem cell transplantation.

In the trial conducted by the European collaborative, 813 patients with AML, including some with secondary AML or a high-risk myelodysplastic syndrome, were followed for a median of 40 months. All patients were 60 years of age or older, and a course of cytarabine followed for all those who survived the induction therapy.

Remission, Survival, and an Adverse Cytogenetic Profile

Significantly higher rates of remission were achieved with the higher dose than with the standard dose of daunorubicin in both studies (71% vs 57%, respectively, in American study and 64% vs 54% in the European study).

The rate of complete remission in the American trial was not as high as in some other trials because, the authors explain, the patients included those with an antecedent hematologic disorder (within previous 6 months) and those with multilineage dysplasia.

In addition, in the American study, the high-dose strategy did not significantly improve overall survival among patients with either the FLT3-ITD or MLL-PTD mutation. Other aspects of an unfavorable or adverse cytogenetic profile included MDR1 gene overexpression.

In the European trial, the 2-year rate of overall survival among those 60 to 65 years of age was 38% for the high-dose of group and 23% for the standard-dose group.

In the high-dose groups in both studies, there was no increase in early death rates, no delay in hematologic recovery, no affect on planned postremission therapies, and no increase in cardiac toxicities, observe the editorialists. The latter was "a relief," they suggest.

"On the basis of previous trials, a possible concern of dose intensification was an increase in cardiac toxic effects, which was not seen in either trial," they note.

However, it is still not entirely clear what the best dose of daunorubicin is, note the American authors.

"Whether standard-dose cytarabine with 90 mg of daunorubicin per square meter of body surface area is better than cytarabine with a 60 mg dose of daunorubicin (or idarubicin or mitoxantrone at equivalent doses) remains to be studied in future trials," write the study authors.