Fernandez et al on behalf of the SWOG group (ECOG1900 trial) studied adults aged 17 to 60 (median age 48), combining cytarabine 100 mg/m2 by short IV infusion with daunorubicin on day 1 to 3 either at 45 mg/m2 or 90 mg/m2. Notably, a second induction at standard dose was given if residual blasts were detected in the bone marrow on day 12 to 14. Both CR (70.6 vs 57.3%) and OS (23.7 vs 15.7 months) were superior in the HD group at a follow-up of 25 months. The greatest difference in survival was observed in patients under the age of 50 years and those with intermediate risk cytogenetics. This group has subsequently published an updated analysis of this cohort showing a significant reduction in death (HR 0.74, P= 0.002) for patients who received daunorubicin at 90 mg/m2 vs 45 mg/m2 at a median follow up of 80 months. Furthermore, significant survival benefit continued to be seen in patients under 50 years and intermediate cytogenetic risk but also extended across all cytogenetic and molecular risk groups, especially NPM1 and DNMT3A mutations.r
Kaplan-Meier Estimates of Overall Survival
© NEJM 2009
Lee et al followed a similar schema for a lower total cohort of patients, the only variance being cytarabine 200 mg/m2 by continuous infusion. Again, CR rates (82.5 vs 72%) and OS (46.8 vs 34.6%) were superior in the higher dose arm but at a follow up of 52 months. In this study, which featured a longer follow-up than the ECOG study, also confirmed that the survival benefit of HD daunorubicin was most evident in the intermediate cytogenetic risk group.r
Survival differences between the standard-dose(SD-DN) and high-dose (HD-DN) arms.
© Blood 2011
Lowenberg et al studied a large group of patients with AML aged 60 to 83 (median age 67), with randomisation as described above. In this study patients could receive a second induction following (“7+3”) which consisted of cytarabine at 1 g/m2. CR rates were 52% vs 35% after the first induction, in favour of higher dose daunorubicin. OS did not differ for the group as a whole, but in the age group 60 to 65 was 38% vs 23% in favour of HD daunorubicin. An OS was also pronounced for patients with core binding factor abnormalities.r
Effect of Remission-Induction Chemotherapy with an Escalated Dose of Daunorubicin versus a Conventional Dose on Event-free Survival and Overall Survival in Patients 60 years of Age or Older with Acute Myeloid Leukaemia.
© NEJM 2009
Rollig et al compared 60mg/m2 versus 90mg/m2 of daunorubcin in the randomized SAL-DAUNODUBLE trial, given 60mg/m2 is the standard of care in many countries. In this study, presented in abstract form, response rates after induction were comparable between 60 and 90 (42.7% v 47.8%, p=0.29). No clear difference in toxicity was seen. Survival analyses were not presented.r
Several studies have compared HD daunorubicin with idarubcin. Lee et alr randomly assigned 299 patients to idarubicin 12mg/m2 (IDA) versus daunorubicin 90mg/m2 (HDD), both given in combination with cytarabine 200mg/m2. CR rates were no different between the two groups (80.5% v 74.7%, p=0224), and at a median follow-up of nearly 3 years, no difference in relapse rates or survival were demonstrated in the whole cohort. However, significant improvement on overall survival with HDD (15.5 months v NR, p=0.030) was seen in patients with FLT3-ITD mutations. Trifilio et alr retrospectively compared HDD and IDA, finding no difference in CR rates after the induction. Interestingly, patients over 55 years of age and those with adverse cytogenetics had a higher CR rate in the IDA arm. Choi et alr retrospectively examined the outcomes of patients treated with IDA 12mg/m2 or daunorubcin at 45mg/m2 (LDD) or 90mg/m2 (HDD). In this analysis, higher complete response rates were seen with HDD versus LDD. Furthermore, overall survival was higher in the HDD group compared with LDD, and a non-significant trend was seen favouring HDD v IDA.
A metanalysis reviewing the outcomes of HDD and IDA, including the aforementioned studies, concluded that CR rates were higher with idarubicin, with comparable toxicity.r