Efficacy
Escalation of the daunorubicin to 90 mg/m2/day has been shown to improve OS and remission rates when compared to daunorubicin dose of 45 mg/m2/day, which had previously been the conventional dose for induction therapy in AML. This has been demonstrated in three randomised trials, two enrolling younger patients (<60 years) and the other patients over 60.
The first study treated 813 patients >60 years (range 60-83) with daunorubicin 90 mg/m2 or 45 mg/m2 for 3 days in addition to cytarabine 200 mg/m2 continuous intravenous infusion for 7 days.r A higher response rate was reported in the 90 mg/m2 group when compared to the 45 mg/m2 group with CR rates 64% vs. 54% (p= 0.002), without additional toxicity. However, there was no significant difference in OS between the two groups except in patients 60-65 years.
In the second trial, 657 enrolled patients, escalation of the daunorubicin dose to 90 mg/m2/day for 3 days in combination with cytarabine 100 mg/m2/day continuous infusion for 7 days resulted in increased complete response (CR) rates (70.6% vs 57.3%, p<0.001) and median OS compared to 45 mg/m2/day (23.7 vs 15.7 months, p=0.003).r There was no major increase in toxicity- in particular, the rate of death during induction was 5.5% and 4.5% for the high-dose and standard-dose daunorubicin groups, respectively (p=0.60). Initial analysis appeared to limit the benefit of high-dose daunorubicin to younger (age <50 years) and those with favourable or intermediate risk cytogenetics. Longer follow up indicates the benefit of the higher anthracycline dose to potentially extend to patients with unfavourable cytogenetics (adjusted hazard ratio 0.66, p=0.04) and those with FLT3-ITD (HR 0.61, p=0.009).r Superior outcomes in younger patients using high-dose daunorubicin has been confirmed in a contemporaneous randomised trial of 383 patients from Korea.r
Although doses of daunorubicin higher than 45 mg/m2 improve outcomes, particularly in younger patients with AML, it is unknown whether a dose of 90 mg/m2 daunorubicin is required or, alternatively if 60 mg/m2 may provide the same benefit. The UK NCRI AML17 trial was a randomised trial comparing daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction.r 1206 patients (mostly under 60 years) were randomised to receive daunorubicin on days 1, 3, and 5 at a dose of 90 mg/m2 or 60 mg/m2 with cytarabine 100 mg/m2 every 12 hours on days 1 to 10 inclusive. A second course was given to patients with favourable or intermediate-risk disease, consisting of daunorubicin 50 mg/m2 on days 1, 3 and 5 with cytarabine 100 mg/m2 every 12 hours on days 1 to 8 inclusive. High-risk patients were randomised to receive either FLAG-Ida or clofarabine with 3 doses of daunorubicin 50 mg/m2.
No difference was seen in achievement of CR according to daunorubicin dose, with rates of 75% and 73% in the 60 mg/m2 and 90 mg/m2 groups, respectively (p=0.6). Day 30 mortality was similar in the two dose groups, but at day 60, there were increased deaths in the 90 mg/m2 group (10% vs 5%, p=0.001). Grade 3 or 4 gastrointestinal toxicity was also higher in the 90 mg/m2 cohort. Time to count recovery (neutrophils and platelets) and cardiac toxicity were not different between dose groups. Two-year OS was 60% in the 60 mg/m2 group compared to 59% in the 90 mg/m2 group (p=0.15), relapse-free survival (RFS) was also similar (48% vs 51%). Exploratory analysis did not reveal any subgroups benefiting from the higher dose of daunorubicin.
A subsequent re-analysis after extended follow up (median 28 months) now indicates that patients with FLT-3 ITD mutations experience improved RFS (45% vs 33%, p=0.02) and OS (54% vs 34%, p=0.03) if they receive 90 mg/m2 daunorubicin in induction rather than 60 mg/m2.r This appears to be independent of NPM1 mutation status. Outcomes remain unchanged for all other subgroups.
Figure 1: Effect of daunorubicin dose on survival according to cytogenetic riskr
© Blood 2015
Figure 2: Effect of daunorubicin dose according to FLT-3 ITD status r
© Blood 2016