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Double Induction With Daunorubicin Shows No OS Benefit Over Single Induction in Newly Diagnosed AML
Results from the Randomized Controlled Phase 3 SAL Dauno-Double Trial
Results from the Randomized Controlled Phase 3 SAL Dauno-Double Trial
The use of 90 mg daunorubicin in the context of classical 7+3 induction did not lead to higher remission rates or longer survival than 60 mg in patients with newly diagnosed acute myeloid leukemia (AML), according to findings from the phase 3 DaunoDouble trial.
At the 2022 ASH Annual Meeting and Exposition in New Orleans, LA, Christoph Röllig, MD, Universitätsklinikum Carl Gustav Carus, Dresden, Germany presented the data from the 2-part, 2-arm, open-label multicenter prospective randomized trial.
“A combination of cytarabine plus anthracycline according to the 7+3 schedule is the standard treatment backbone of fit, newly diagnosed AML patients,” Röllig and colleagues wrote, “A daunorubicin dose of 90 mg/m2 is superior to 45 mg/m2, whereas little difference seems to be between 60 mg/m2 and 90 mg/m2. Double induction is commonly performed in younger patients in order to maximize dose intensity upfront. However, for patients with a good early response after first induction, there is no prospective randomized evidence on the necessity or value of a second induction cycle.”
The study explored whether 60 mg/m2 is sufficient for induction or if 90 mg/m2 is more efficacious. They also explored the question of whether good responders after the first 7+3 induction can be spared a second induction cycle.
In the trial, patients received a first induction cycle with 7 days of cytarabine plus 3 days of daunorubicin (“7+3”) with a 1:1 stratified randomization for 60 vs 90 mg/m2 (Dauno60 vs Dauno90). Response assessment in bone marrow was evaluated by cytology on day 15. In the study, a blast count <5% was defined as good response, which was the primary end point of this first randomization step.
Good responders were randomized to receive a second induction cycle (arm D) or no second induction cycle (arm S). In arm D, the second induction cycle contained 60 mg/m2 after Dauno60 and 45 mg/m2 after Dauno90. The primary end point of the second randomization was complete response (CR) or CR with incomplete count recovery (CRi) after completion of induction. They assumed non-inferiority of single induction in terms of CR/CRi rate, based on a margin of 7.5%.
Between 2014 and 2022, 864 patients were enrolled and received the first induction cycle with 7+3. The median age was 52 years, 88% had de novo AML. Favorable, intermediate and adverse risk (ELN 2017) was present in 37%, 46% and 17% of patients, respectively. No significant imbalances were observed between the 2 treatment arms, except for a higher NPM1 mutant rate in the Dauno90 arm (32.4% vs 41.7%; P = .034).
A pre-planned interim analysis after the first randomization of 218 patients revealed a statistically and clinically non-significant difference of 42% vs 49% good responders after first induction with 60 vs 90 mg/m2 daunorubicin (P = .341). Based on this result, the first randomization step was suspended and all consecutive patients received 60 mg/m2 in induction 1.
At the end of enrollment, 707 and 157 patients have received 60 or 90 mg/m2, with a corresponding proportion of good early responders of 44.4% vs 47.8% (P = .930) and a CR rate of 89.6% vs 88.5% after the end of induction (P = .691). After a median follow-up of 43.6 months, 3-year relapse-free survival (RFS) after Dauno60 vs Dauno90 was 53.8% vs 50.1% (P = .561) and 3-year overall survival (OS) 65.2% vs 58.3% (P = .196). During first induction, 57% of patients in Dauno60 and 58% in Dauno90 experienced an adverse event (AE) of grade ≥3 (P = .877); mortality in induction I was 2.3% and 4.7%, respectively (P = .109).
After induction cycle 1, a marrow blast clearance below 5% on day 15 was achieved in 389 patients (45%), providing eligibility for the second randomization. Of these patients, 189 were randomized into arm S and 187 into arm D (ITT population). CR/CRi rates at the end of induction were 85.2% after single induction and 85.6% after double induction, resulting in a CR difference of 0.4% (P for non-inferiority test, 0.0269). The CR/CRi rates in 326 pre-defined per-protocol patients (PP) were 86.8% vs 91.5%, resulting in a CR difference of 4.7% (P = .205). Until the end of induction, 58% of patients in the S arm and 65% of patients in the D arm experienced an AE of grade ≥3 (P = .195). Early mortality 60 days after induction start was 0.6% in both arms.
After a median follow-up time of 43.6 months, the 3-year RFS after single vs double induction was 51% vs 60%, which was non-significant in the ITT population (HR 1.35; P = .074) and borderline significant in the PP population (HR, 1.43; P = .05), but not significant in multivariable analyses. OS after 3 years was identical with 77% vs 75% after single or double induction in the ITT (HR, 1.02; P = .914) and 77% vs 76% in the PP population (HR, 1.12; P = .628).
“The use of 90 mg daunorubicin in the context of classical 7+3 induction did not lead to higher remission rates or longer survival than 60 mg. In patients with a good early response after first induction, a second induction had only limited impact on RFS,” Röllig and coauthors concluded, “Double induction did not lead to an overall survival benefit in patients with a good early response first 7+3 induction.”
Source:
Röllig C, Steffen B, Schliemann C. 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 the ASH Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA. Abstract 217.
