Comparison of idarubicin and high-dose daunorubicin in the induction chemotherapy for AML – a phase III study

In an article published in the Journal of Clinical Oncology on 20^th June 2017, Je-Hwan Lee and colleagues from the Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, discussed results from their prospective randomized phase III study (NCT01145846), which aimed to compare the effectiveness of two induction regimens, cytarabine plus idarubicin (AI) versus cytarabine plus high-dose daunorubicin in young adults with newly diagnosed Acute Myeloid Leukemia (AML). The study was conducted by the Cooperative Study Group A for Hematology.

In total, 299 young adult AML patients (median age = 49 years) were randomly assigned to receive either AI (idarubicin 12 mg/m²/d for three consecutive days plus cytarabine 200 mg/m²/d for 7 days [n = 149]) or AD (daunorubicin 90 mg/m²/d for three consecutive days plus cytarabine 200 mg/m²/d for 7 days [n = 150]). The primary endpoint of the study was Complete Remission (CR) rate.

The key results of the study were:

• CR rates in patients in the AI and AD arms; 80.5% vs 74.7%, P = 0.224
• 4-year Overall Survival (OS) in patients in the AI and AD arm; 51.1% vs 54.7%, P = 0.756
• 4-year Event Free Survival (EFS) in patients in the AI and AD arm; 45.5% vs 50.8%, P = 0.772
• 4-year Cumulative Incidence of Relapse (CIR) in patients in the AI and AD arm; 35.2% vs 25.1%, P = 0.194
• Fms Like Tyrosine Kinase 3 – Internal Tandem Duplication (FLT3-ITD) mutated patients in the AD arm (n = 17) had a higher median OS and EFS rate compared to patients in the AI arm (n = 27); not reached vs 15.5 months, P = 0.030 and not reached vs 11.9 months, P = 0.028 respectively

In summary, there were no significant differences in CR rate and survival when comparing idarubicin to high-dose daunorubicin in newly diagnosed young adult AML patients. However, “high-dose daunorubicin was more effective than idarubicin in patients with FLT3-ITD mutation”.

Abstract

Purpose

We compared two induction regimens, idarubicin (12 mg/m2/d for 3 days) versus high-dose daunorubicin (90 mg/m2/d for 3 days), in young adults with newly diagnosed acute myeloid leukemia (AML).

Patients and Methods

A total of 299 patients (149 randomly assigned to cytarabine plus idarubicin [AI] and 150 assigned to cytarabine plus high-dose daunorubicin [AD]) were analyzed. All patients received cytarabine (200 mg/m2/d for 7 days).

Results

Complete remission (CR) was induced in 232 patients (77.6%), with no difference in CR rates between the AI and AD arms (80.5% v 74.7%, respectively; P = .224). At a median follow-up time of 34.9 months, survival and relapse rates did not differ between the AI and AD arms (4-year overall survival, 51.1% v 54.7%, respectively; P = .756; cumulative incidence of relapse, 35.2% v 25.1%, respectively; P = .194; event-free survival, 45.5% v 50.8%, respectively; P = .772). Toxicity profiles were also similar in the two arms. Interestingly, overall and event-free survival times of patients with FLT3 internal tandem duplication (ITD) mutation were significantly different (AI v AD: median overall survival, 15.5 months v not reached, respectively; P = .030; event-free survival, 11.9 months v not reached, respectively; P = .028).

Conclusion

This phase III trial comparing idarubicin with high-dose daunorubicin did not find significant differences in CR rates, relapse, and survival. Significant interaction between the treatment arm and the FLT3-ITD mutation was found, and high-dose daunorubicin was more effective than idarubicin in patients with FLT3-ITD mutation.