Introduction The randomized-controlled SAL DaunoDouble trial (NCT02140242) showed no significant differences in complete remission (CR) rates or survival between 60 mg/m² and 90 mg/m² of daunorubicin (Dauno), or between single and double induction in patients (pts) with newly diagnosed AML eligible for intensive chemotherapy (Röllig et al., JCO, 2024). To further study the impact of Dauno dose-escalation and the number of induction cycles in more detail, and to evaluate possible implications for post-remission therapy, we aimed to retrospectively analyze NPM1 measurable residual disease (MRD) kinetics in this study population.

Methods Pts treated within DaunoDouble were retrospectively screened for data on NPM1 MRD. MRD was assessed within standard of care on bone marrow (BM) samples using a quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay at the central reference laboratory. The assay achieves a validated sensitivity of 0.001%; pts were analyzed based on a threshold of 0.1% NPM1/ABL1. Time-to-event variables were estimated using the Kaplan-Meier method. Statistical analyses were performed using R v4.5.0.

Results Data on post-induction MRD were available for 79 pts with NPM1-mutated AML who achieved a CR/CRi. The median age of this cohort was 51 years (range, 24-64), 49 pts (62%) were female. Most pts (97%) had de-novo AML. According to the European LeukemiaNet (ELN) 2017 risk classification, 78%, 22%, and 0% of pts had favorable, intermediate, and adverse risk disease, respectively. A FLT3-ITD co-mutation was observed in 31% of pts. Eighteen pts (23%) underwent allogeneic hematopoietic cell transplantation (alloHCT) in CR1.

The median post-induction NPM1 load showed no significant differences after induction with Dauno 60 mg/m2 versus 90 mg/m2 (0.6% vs. 0.3%, p=0.601). Likewise, rates of MRD-negative remission did not significantly differ between pts receiving Dauno 60 mg/m2 and those receiving 90 mg/m2 (27% vs. 30%, p=0.804). In contrast, when comparing one versus two induction cycles, we detected a significantly lower post-induction MRD load in pts receiving double induction (0.1% vs. 1.5%, p<0.001). Pts receiving two cycles were significantly more likely to attain MRD-negative remissions (40% vs. 15%, p=0.015).

As per March 22nd 2025, after a median follow-up of 43.7 months, the median overall survival (OS) of the entire cohort was not reached, with a corresponding 2-year OS rate of 86%. The 2-year relapse-free survival (RFS) rate of the entire cohort was 59%.

When analyzing the entire cohort irrespective of post-remission treatment, the RFS in pts achieving MRD-negative CR was numerically longer when compared to pts being MRD-positive (median RFS (mRFS), NR vs. 42.5 months, 2-year RFS rate, 77% vs. 52%, p=0.084). When focusing on pts with cytarabine-based consolidation in CR1, the RFS benefit in MRD-negative pts was more pronounced and significantly longer than in MRD-positive pts (median RFS, NR vs. 15.3 months, 2-year RFS rate, 78% vs. 39%, p=0.014).

With respect to the benefit of alloHCT in CR1, RFS was relevantly longer in MRD-positive pts undergoing alloHCT compared to chemotherapy consolidation (2-year RFS rate 83% vs. 41%, p=0.059). In contrast, alloHCT in CR1 did not improve RFS in pts considered MRD-negative post-induction (2-year RFS rate 69% vs. 67%, p=0.597).

In terms of OS, we did not observe any relevant differences in pts with positive versus negative NPM1 MRD, regardless of post-remission therapy.

Conclusions Dauno dose escalation from 60 to 90 mg/m2 in first induction did not improve depth of response in terms of NPM1 MRD levels. However, pts with double induction were more likely to achieve MRD-negative remissions and attained a higher reduction in their MRD load.

Pts achieving MRD-negative remissions showed improved RFS which was statistically significant in pts not undergoing alloHCT in CR1. Regarding RFS, MRD-positive pts seemed to benefit from alloHCT in CR1, whereas MRD negative pts did not. Post-induction MRD status was not predictive of OS, most likely due to retained chemosensitivity and high efficacy of salvage alloHCT in pts with relapsed NPM1-mutated AML.

Our results confirm that 60 mg/m² of Dauno is equipotent to 90 mg/m² on a molecular level, and sufficient for induction therapy. In addition, we demonstrate the predictive value of NPM1 MRD on relapse risk, as well as the value of alloHCT in pts with an insufficient response to induction.

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2025
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