Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Results regarding daunorubicin escalation in induction for patients with acute myeloid leukemia (AML) have varied among different studies.

And a 90 mg/m² dose has been shown to be more effective than 45. Now, results of the UK NCRI AML17 trial have added yet another dimension to the discussion—the use of 60 mg/m² compared to 90.

Alan K. Burnett, MD, of Cardiff University in the UK, presented the data as abstract 7 at the 2014 ASH Annual Meeting.

He explained that ECOG E1900 had demonstrated superior remission and overall survival for a 90-mg dose of daunorubicin compared to a 45-mg dose in adults younger than 60.

The HOVON trial showed superior remission but no difference in overall survival for the higher dose of daunorubicin in patients older than 60.

The Korean trial demonstrated superior remission and survival rates for the 90-mg dose in patients younger than 60.

And in the GOELAMS trial, investigators found no difference between a 90-mg and a 60-mg dose level.

So the UK AML Study Group undertook to clarify the issue by comparing 90 mg to 60 mg in induction.

The investigators randomized 1206 patients younger than 60 with de novo or secondary AML or high-risk myelodysplastic syndromes (MDS) to receive 90 or 60 mg of daunorubicin on days 1, 3, and 5 of their first induction course, followed by 50 mg/m² on days 1, 3, and 5 in course 2.

All patients received ara-C during courses 1 and 2. Patients had to have LVEF of 45% or greater to be included in the trial.

The median follow-up was 29 months. Patient characteristics were comparable between the 2 groups.

The median age was 53 in both groups (range, 16-72 years), and slightly more than half of patients were male. Eighty-five percent and 84% had de novo AML in the 60-mg and 90-mg arms, respectively. Ten percent in each group had secondary AML. And 5% and 6%, respectively, had high-risk MDS.

Eleven percent in the 60-mg arm had favorable cytogenetics, compared with 9% in the 90-mg arm. Eighteen percent in each arm had mutant FLT3-ITD, and 40% in each arm were poor risk.

The investigators found no significant difference in response between the two arms—84% in the 60-mg arm and 81% in the 90-mg arm.

However, they observed a trend for increased 30-day mortality in the 90-mg arm and a significant difference in the 60-day mortality rate, which was 5% in the 60-mg arm and 10% in the 90-mg arm (P=0.001).

Twenty-nine people died by day 60 in the 60-mg arm compared with 58 in the 90-mg arm.

The main reasons for 60-day mortality in the 60-mg and 90-mg dose groups, respectively, included infection (11 vs 25 deaths), hemorrhage (3 vs 5 deaths), infection plus hemorrhage (3 vs 1 death), and resistant disease (2 vs 14 deaths), among other causes.

At 24 months, overall survival between the 2 groups was comparable, at 60% in the 60-mg arm and 59% in the 90-mg arm.

The cumulative incidence of relapse at 24 months from complete response was 41% in the 60-mg arm and 37% in the 90-mg arm.

One hundred ninety-seven patients in the 60-mg arm and 169 patients in the 90-mg arm went on to receive a stem cell transplant.

When survival was censored at transplant, there was also no difference between the arms, at 60% for the 90-mg group and 61% for the 60-mg group.

The investigators conducted subgroup analyses and found no significant benefit for 90 mg/m² in any subgroup. Dr Burnett noted, however, that there could be a potential late benefit for FLT3-ITD mutated patients who receive a 90-mg dose.

FLT3 mutated patients had a non-significant survival benefit (HR 0.74 [0.47-1.17] P=0.2) with a 90-mg dose. However, survival was significantly worse for FLT3 wild type patients receiving 90 mg (HR 1.31 [1.03-1.67] P=0.03).

Otherwise, the group found that there is no evidence to suggest that 90 mg is superior to 60 mg.

More isn’t always better with daunorubicin induction in AML