Contributions
Abstract: S861
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 17:00 - 17:15
Location: Room A2
Background
Seven days of cytarabine plus three days of anthracycline, most commonly daunorubicin, remains the standard approach for curative treatment of acute myeloid leukemia (AML). Two randomized trials have shown a survival benefit for a daunorubicin dose of 90 mg/m2 versus 45 mg/m2 as part of a standard 7+3 schedule using seven days of continuous cytarabine (c.i.) and three subsequent days of daunorubicin. However, a daunorubicin dose of 60 mg/m2 rather than 45 mg/m2 has been an established standard in many countries, posing the question if 90 mg/m2 would still be a superior approach. The NRCI-AML 17 study explored 90 mg/m2 versus 60 mg/m2 in a 10+3 induction using cytarabine bolus infusion twice daily plus daunorubicin on days 1, 3, 5 followed by diverse induction and consolidation options, but showing no differences in complete remission (CR) rates, early death or survival.
Aims
In order to compare 90 mg/m2 versus 60 mg/m2 in a standard 7+3 induction regimen, we set up the randomized multicenter DaunoDouble trial.
Methods
Patients with newly diagnosed AML without previous anthracycline treatment, normal cardiac and organ function and 18-60 years of age were randomly assigned to receive induction treatment with seven days of cytarabine 100 mg/m2 c.i. plus daunorubicin infusion on days 3-5, either with 90 mg/m2 (Dauno90) or with 60 mg/m2 (Dauno60). Response assessment in bone marrow was done 15 days after commencement of chemotherapy. A blast count <5% was defined as good response. Responses were compared using Chi squared test and multivariable logistic regression analyses accounting for established prognostic factors. Incidence and grade of adverse events and early mortality were compared between Dauno90 and Dauno60. Patients with good response were eligible for a second randomization to proceed to a routinely administered second induction with 7+3 or to no further induction. This second part of the DaunoDouble trial is ongoing and results will be presented in the future.
Results
Between April 2014 and August 2017, 314 patients were randomized, 157 in each arm. The median age was 48 years, 87% had de novo AML, NPM1 mutation was present in 41% of patients, FLT3-ITD in 20%, CEBPA double mutation in 5%; favorable, intermediate and adverse risk (ELN 2017) was present in 7%, 73% and 20% of patients, respectively. No significant imbalances were observed between the two treatment arms. Response rates after 7+3 induction with 90 mg/m2 daunorubicin were 47.8% (95%>CI, 39.7-55.9) versus 42,7% (95%>CI, 34.8-50.8) with 60 mg/m2 (p=0.29). Adverse events (AE) were documented in 89.8% of patients in Dauno90 and 86.6% in Dauno60. AEs ≥ grade 3 were registered in 20.3% and 16.2%, respectively. The incidence of early deaths within 14 days after start of induction was 1.3% and 0.6%, whereas 28-day early mortality was 3.2% and 1.3% in Dauno90 and Dauno60, respectively (p=0.251).
Conclusion
Our results provide randomized evidence that in a standard 7+3 induction, a dose escalation of daunorubicin from 60 to 90 mg/m2 does not result in a significant increase in response rates. The tolerability was similar in both dose levels with no obvious signs of excess toxicity. Survival follow-up is ongoing. Our preliminary results support the use of 60 mg/m2 daunorubicin in 7+3 induction.
Session topic: 4. Acute myeloid leukemia - Clinical
Keyword(s): Dose intensity, Induction chemotherapy, Anthracycline
Abstract: S861
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 17:00 - 17:15
Location: Room A2
Background
Seven days of cytarabine plus three days of anthracycline, most commonly daunorubicin, remains the standard approach for curative treatment of acute myeloid leukemia (AML). Two randomized trials have shown a survival benefit for a daunorubicin dose of 90 mg/m2 versus 45 mg/m2 as part of a standard 7+3 schedule using seven days of continuous cytarabine (c.i.) and three subsequent days of daunorubicin. However, a daunorubicin dose of 60 mg/m2 rather than 45 mg/m2 has been an established standard in many countries, posing the question if 90 mg/m2 would still be a superior approach. The NRCI-AML 17 study explored 90 mg/m2 versus 60 mg/m2 in a 10+3 induction using cytarabine bolus infusion twice daily plus daunorubicin on days 1, 3, 5 followed by diverse induction and consolidation options, but showing no differences in complete remission (CR) rates, early death or survival.
Aims
In order to compare 90 mg/m2 versus 60 mg/m2 in a standard 7+3 induction regimen, we set up the randomized multicenter DaunoDouble trial.
Methods
Patients with newly diagnosed AML without previous anthracycline treatment, normal cardiac and organ function and 18-60 years of age were randomly assigned to receive induction treatment with seven days of cytarabine 100 mg/m2 c.i. plus daunorubicin infusion on days 3-5, either with 90 mg/m2 (Dauno90) or with 60 mg/m2 (Dauno60). Response assessment in bone marrow was done 15 days after commencement of chemotherapy. A blast count <5% was defined as good response. Responses were compared using Chi squared test and multivariable logistic regression analyses accounting for established prognostic factors. Incidence and grade of adverse events and early mortality were compared between Dauno90 and Dauno60. Patients with good response were eligible for a second randomization to proceed to a routinely administered second induction with 7+3 or to no further induction. This second part of the DaunoDouble trial is ongoing and results will be presented in the future.
Results
Between April 2014 and August 2017, 314 patients were randomized, 157 in each arm. The median age was 48 years, 87% had de novo AML, NPM1 mutation was present in 41% of patients, FLT3-ITD in 20%, CEBPA double mutation in 5%; favorable, intermediate and adverse risk (ELN 2017) was present in 7%, 73% and 20% of patients, respectively. No significant imbalances were observed between the two treatment arms. Response rates after 7+3 induction with 90 mg/m2 daunorubicin were 47.8% (95%>CI, 39.7-55.9) versus 42,7% (95%>CI, 34.8-50.8) with 60 mg/m2 (p=0.29). Adverse events (AE) were documented in 89.8% of patients in Dauno90 and 86.6% in Dauno60. AEs ≥ grade 3 were registered in 20.3% and 16.2%, respectively. The incidence of early deaths within 14 days after start of induction was 1.3% and 0.6%, whereas 28-day early mortality was 3.2% and 1.3% in Dauno90 and Dauno60, respectively (p=0.251).
Conclusion
Our results provide randomized evidence that in a standard 7+3 induction, a dose escalation of daunorubicin from 60 to 90 mg/m2 does not result in a significant increase in response rates. The tolerability was similar in both dose levels with no obvious signs of excess toxicity. Survival follow-up is ongoing. Our preliminary results support the use of 60 mg/m2 daunorubicin in 7+3 induction.
Session topic: 4. Acute myeloid leukemia - Clinical
Keyword(s): Dose intensity, Induction chemotherapy, Anthracycline