A higher dose of daunorubicin does not improve outcomes in fit patients with newly diagnosed acute myeloid leukemia (AML) receiving 7+3 induction, and patients with a good response to the first induction cycle do not benefit from a second cycle, according to research published at the 2022 ASH Annual Meeting.
Researchers conducted the phase 3 DaunoDouble trial (ClinicalTrials.gov Identifier: NCT02140242) to evaluate whether standard induction with 90 mg/m2 of daunorubicin is more efficacious than 60 mg/m2 of daunorubicin and if patients with good response after the first induction cycle can be spared a second induction cycle.
The study included patients aged 18 to 65 years with newly diagnosed AML who had normal cardiac and organ function. Patients were randomly assigned to receive an initial induction cycle with cytarabine and daunorubicin at 60 mg/m2 or 90 mg/m2. The primary endpoint of this part of the study was response in bone marrow on day 15, with less than 5% blasts defined as a good response.
A total of 864 patients, with a median age of 52 years, received the first induction cycle. Patient characteristics were well balanced between the 60 mg/m2 and 90 mg/m2 arms, except for a higher NPM1 mutation rate in the 90 mg/m2 arm (32.4% vs 41.7%; P =.034).
Results With 60 mg/m2 vs 90 mg/m2
During a pre-planned interim analysis after the randomization of 314 patients, the investigators found no significant difference in the proportion of good responders after first induction with 60 mg/m2 vs 90 mg/m2 (43.3% vs 47.8%; P =.29). Based on this result, the team suspended the first randomization step of the study and administered 60 mg/m2 in the first induction cycle to all consecutive patients.
At the end of enrollment, 707 patients had received the 60 mg/m2 dose, and 157 had received the 90 mg/m2 dose. The proportion of good early responders was 44.4% with the 60 mg/m2 dose and 47.8% with the 90 mg/m2 dose (P =.930).
The complete response (CR) rate was 75.0% with the 60 mg/m2 dose and 81.8% with the 90 mg/m2 dose (P =.157). At a median follow-up of 44 months, there was no significant difference between the arms in overall survival (hazard ratio [HR], 1.19; P =.196) or relapse-free survival (HR, 1.08; P =.561).
The rate of grade 3 or higher adverse events was 17.9% in the 60 mg/m2 dose arm and 19.5% in the 90 mg/m2 dose arm. The rate of early mortality was 2% and 5%, respectively.
Results With Single vs Double Induction
In the second part of the study, the investigators randomly assigned patients with good response to receive a second induction cycle or no further induction. In the double-induction arm, patients received daunorubicin at 60 mg/m2 if they had received that dose in the first cycle. Patients who had received 90 mg/m2 in the first cycle received 45 mg/m2 in the second cycle.
A total of 376 patients had less than 5% blasts on day 15. These patients underwent the second randomization, with 189 patients in the single-induction arm and 187 in the double-induction arm. The primary endpoint was CR or CR with incomplete hematologic recovery (CRi) after completion of induction.
In the intent-to treat population, the CR/CRi rate was 85.2% with single induction and 85.6% with double induction (P for non-inferiority =.027). In the per-protocol population, the CR/CRi rate was 86.8% with single induction and 91.5% with double induction (P for non-inferiority =.205).
At a median follow-up of 44 months, there was no significant difference between the single and double arms for overall survival in the intent-to-treat population (HR, 1.02; P =.914) or the per-protocol population (HR, 1.12; P =.628).
In the per-protocol population, the rate of grade 3 or higher adverse events was 16.5% in the single-induction arm and 18.8% in the double-induction arm.
Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Röllig, C, Steffen B, Schliemann C, et al. Single versus double induction with “7+3” containing 60 versus 90 mg daunorubicin for newly diagnosed AML: Results from the randomized controlled SAL Dauno-Double trial. Presented at ASH 2022. December 10-13, 2022. Abstract 217.
This article originally appeared on Cancer Therapy Advisor