AML Research From ASH 2022: Novel Combinations and Evidence That “Less is More”

Higher Dose of Daunorubicin, Second Induction Provide No Benefit

In the phase 3 DaunoDouble trial, a daunorubicin dose of 90 mg/m² did not improve outcomes over a dose of 60 mg/m², and a second induction did not provide a benefit over single induction among patients who were “good responders” to the first induction.² 

The 2-part trial (ClinicalTrials.gov identifier: NCT02140242) included 864 adults with newly diagnosed AML. The median age at baseline was 52 (range, 43-58) years, 34.1% of patients had NPM1 mutations, and 20.7% had FLT3-ITD AML.

Patients received 7+3 (7 days of cytarabine plus 3 days of daunorubicin) with either 60 mg/m² or 90 mg/m² of daunorubicin in the first randomization step. Good responders were then assigned to receive a second induction or forgo a second induction.  

A preplanned interim analysis demonstrated a nonsignificant difference in the number of good responders in each group, so all subsequent patients received daunorubicin at 60 mg/m². A total of 707 patients received 60 mg/m², and 157 patients received 90 mg/m². 

The primary endpoint of the first randomization step was good early response (defined as a blast count <5% on day 15). A good early response was observed in 44.4% of the 60 mg/m² group and 47.8% of the 90 mg/m² group (P =.930).  

The CR rate after first induction was 75.0% with 60 mg/m² and 81.8% with 90 mg/m² (P =.157). Among good responders, CR rates were 91.2% with 60 mg/m² and 98.6% with 90 mg/m² (P =.08).

At a median follow-up of 44 months, there was no significant difference in relapse-free survival (RFS; P =.561) or OS (P =.196) between the dosing groups. The rate of grade 3 or higher AEs was 17.9% in the 60 mg/m² group and 19.5% in the 90 mg/m² group.

“Based on a lack of additional efficacy and slightly more toxicity with 90 mg, this dose can be omitted in favor of 60 mg,” said study presenter Christoph Röllig, MD, of University Hospital Carl Gustav Carus in Dresden, Germany. “The previously published⁵ beneficial effect of 90 mg in FLT3-mutant AML could not be reproduced by the DaunoDouble data.” 

“These findings help us better incorporate the results of the RATIFY trial⁶ into everyday practice since that study used a daunorubicin dose of 60 mg,” said Aaron Gerds, MD, of the Cleveland Clinic Taussig Cancer Institute in Ohio, who was not involved in the DaunoDouble trial. 

The second part of the DaunoDouble trial included 376 patients, of whom 187 were assigned to receive a second induction and 189 were not.² Of those receiving a second induction, patients who had received daunorubicin at 60 mg/m² initially again received 60 mg/m². Patients who had received 90 mg/m² in the first induction received 45 mg/m² for the second induction.

The primary endpoint was CR or CR with incomplete count recovery (CRi). In the ITT population, the rate of CR/CRi was 85.2% in the single induction group and 85.6% in the double induction group (P for noninferiority =.027). In the per-protocol population, the rate of CR/CRi was 86.8% after single induction and 91.5% after double induction (P for noninferiority =.205).

In the ITT population, the 3-year RFS rate was 51% with single induction and 60% with double induction (hazard ratio [HR], 1.35; P =.074). In the per-protocol population, the 3-year RFS rate was 52% and 60%, respectively (HR, 1.43; P =.05). 

In the ITT population, the 3-year OS rate was 77% with single induction and 75% with double induction (HR, 1.02; P =.914). In the per-protocol population, the 3-year OS rate was 77% and 76%, respectively (HR, 1.12; P =.628).

In the per-protocol population, grade 3 or higher AEs occurred in 16.5% of patients in the single induction arm and 18.8% of those in the double induction arm. 

This trial “clearly shows that the increased daunorubicin dose is, if anything, detrimental, and that intensifying induction chemotherapy in general is probably not beneficial,” said Mark Levis, MD, PhD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who was not involved in this study. 

“The concept of giving more and more chemotherapy to AML patients is an outdated one, and, with this trial result, we are perhaps at last hearing the final feeble roars of that dinosaur,” he said.

This article originally appeared on Cancer Therapy Advisor