The combination of cytosine arabinoside (Ara-C) and an anthracycline has held its ground as the standard induction therapy for acute myeloid leukemia (AML) for more than 30 years, with a variety of modifications yielding no differences in outcomes. While doubling the dose of the anthracycline daunorubicin (from the standard of 45 mg/m2 up to 90 mg/m2) has led to improved overall survival in younger adults (<60 years) adults, is it possible to gain the same survival advantage with less?
Investigators from the United Kingdom, led by Alan K. Burnett, MD, of Cardiff University in Wales, believe they have found an optimal dose of daunorubicin to provide the greatest benefit with a lower risk of adverse effects: 60 mg/m2. According to the results of a prospective, randomized trial of more than 1,000 AML patients, the lower dose performed favorably compared with the higher dose – 90 mg/m2.
"Fairly recently, three randomized trials showed that a 90 mg/m2 dose was better than 45 mg/m2," Dr. Burnett told ASH Clinical News. "Although open to criticism, this provided evidence that the 45 mg/m2 should not continue. However, many clinicians use a 60 mg/m2 dose, and it has never been prospectively compared in randomized trials."
The current UK NCRI AML 17 Trial enrolled 1,206 adults (median age = 53 years) with untreated AML or high-risk myelodysplastic syndromes. Patients received two rounds of induction chemotherapy: In the first round, they were randomized to 90 mg/m2 or 60 mg/m2 of daunorubicin and cytosine arabinoside on days 1, 3, and 5; in the second round of induction, all patients received another daunorubicin-containing course (50 mg/m2 on days 1, 3, and 5). So, patients received either a total daunorubicin dose of 420 mg/m2 (in the 90 mg/m2 arm) or 330 mg/m2 (in the 60 mg/m2 arm).
Ultimately, the authors found very little difference between the two doses of daunorubicin, with respect to both complete remission rates, induction death, and overall survival (TABLE).
The causes of death at 60 days included infection, hemorrhage, and resistant disease – all of which occurred more often in the 90 mg/m2 group. In terms of toxicity, there were more high-grade cases of nausea and diarrhea in the higher-dose arm during the first treatment course, but not during the second therapy course, the authors pointed out.
In an exploratory subgroup analysis, Dr. Burnett and investigators found only one factor that had a significant association with worse outcome: the presence of a FLT3-ITD mutation. The 462 FLT3-ITD wild-type patients who received the 90 mg/m2 dose experienced significantly worse outcomes than non-FLT3-ITD patients (HR=1.30 [1.02-1.66]; p=0.03). There was, however, a non-significant trend for benefit beyond 12 months in FLT3-ITD mutant patients who received the 90 mg/m2 dose (HR=0.74 [0.47-1.17]; p=0.2).
"Taken altogether, the mean survival, truncated at 24 months, was 16.5 months [for the 90 mg/m2 dose] and 16.0 months [for the 60 mg/m2 dose]," the authors wrote. "There was no evidence of benefit for the 90 mg/m2 arm in any cytogenic subgroup, and there was no significant difference between the arms in survival 12 months after relapse."
The overall take-home message from this trial? "There is no need to go to 90 mg/m2 dose," Dr. Burnett said. "A 60 mg/m2 dose is fine, but if you use 45 mg/m2, change to 60 mg/m2."
However, that message may carry less weight in the United States, according to Harry Erba, MD, PhD, of the University of Alabama at Birmingham and chair of the Southwest Oncology Group (SWOG) Leukemia Committee. The design of the trial has a lot to do with that.
The U.S. standard of practice – based largely on results from the Eastern Cooperative Oncology Group E1900 trial – for younger AML patients is to give one round of induction therapy containing daunorubicin at 60 mg/m2. In the E1900 trial, a second round was given only to patients with persistent disease at day 14, but most of the participants opted out of the second round of daunorubicin.
"With the U.K. trial results, we are looking at the long-term outcomes in terms of survival of a cumulative dose of daunorubicin during two rounds of induction, not just that first cycle," Dr. Erba told ASH Clinical News. "It is possible that there really was a benefit with the 90 mg/m2 dose, but, because all patients received a second round of an anthracycline-containing regimen, it is difficult to know for certain that the 60 mg/m2 is as effective as the higher dose."
Burnett AK, Russell NH, Hills RK, et al. A randomised comparison of daunorubicin 90mg/m2 vs 60mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood. 2015 April 1. [Epub ahead of print]
|TABLE. Trial Outcomes and Results of Dose Comparisons|
60 mg/m2 dose
|90 mg/m2 dose||Odds ratio or hazard ratio (95% CI)||
|2-year overall survival||
|2-year relapse-free survival||
|2-year cumulative incidence of relapse||