Background: Hypomethylating agents (HMA) combined with venetoclax (VEN) are the current standard-of-care lower-intensity therapy (LIT) for newly diagnosed (ND) patients with acute myeloid leukemia (AML) who are ineligible for intensive therapy. In older patients (>60 years), medical fitness remains the primary factor guiding the choice between intensive chemotherapy (IC) and LIT. In 2024, the European LeukemiaNet (ELN) introduced a new risk stratification system specifically for patients receiving LIT. However, no molecular risk stratification tool is currently available to guide frontline treatment selection —LIT vs. IC— using driver gene mutations for patients who would be a candidate for either LIT or IC. We aimed to identify mutations associated with improved real-world overall survival (rwOS) with either a LIT or IC approach in a subset of patients with normal karyotype AML (NK-AML), and to assess the impact of upfront therapy on allogeneic hematopoietic cell transplant (allo-HCT) outcomes.

Methods: Patients > 60 years old at diagnosis with ND NK-AML and available molecular data were included using the US-based Flatiron Health Research Database. Available demographics data included base ECOG and age at diagnosis. Patients were classified as IC or LIT based on upfront treatment choice, with IC including regimens defined by standard- or high-dose cytarabine-containing regimens and/or anthracyclines. The remainder of therapies were classified as LIT, which included HMA/VEN combination.

Real-world overall survival (rwOS) with IC and LIT were compared by multivariate Cox proportional hazards modeling. Pairwise comparisons between IC and LIT were performed to assess rwOS differences in the presence of allogeneic hematopoietic cell transplantation (allo-HCT) with Tukey's HSD. Interaction testing was performed to determine if LIT or IC resulted in improved rwOS in the presence of common molecular abnormalities. The Benjamini-Hochberg method was used to calculate a q-value (False Discovery Rate adjusted p-value) in interaction testing.

Results: A total of 2,501 patients were included, and 60% were male. Most patients received LIT (1,629, 65%), of which 139 (8.5%) received allo-HCT, and 872 received IC, of which 299 (34%) received allo-HCT. The most common mutations overall were NPM1 (n=655, 26%), TET2 (n=464, 19%), DNMT3A (n=462, 18%), FLT3-ITD (n=429, 17%), and RUNX1 (n=374, 15%). The most common backbone for IC was the standard combination of antimetabolite/anthracycline (n=584, 67%). The most common backbone for LIT was HMA/VEN with either azacitadine or decitabine (n=780, 48%). HMA monotherapy was also common in 33% of patients (n=535).

Treatment with IC resulted in improved rwOS (median: 1.45y) compared to LIT (median: 0.84y) for the overall cohort (p = 0.01; HR 0.78, 95% CI 0.64 – 0.94). In those who were not transplanted, IC also resulted in improved rwOS (p = <0.001; HR 0.74, 95% CI 0.61 – 0.90). In patients who were transplanted, IC (median: 2.59y) and LIT (median: 1.97y) had no difference in rwOS (p = 0.510; HR 1.29, 95% CI 0.802 – 2.07). Presence of DNMT3A resulted in worse response with IC compared to LIT (q = 0.00225; HR 1.79, 95% CI 1.33 – 2.39). The presence of NPM1 mutation did show a signal for improved outcomes with IC (p = 0.044, HR 0.75, 95% CI 0.57 – 0. 99); however, upon multiple testing correction, NPM1 was no longer significant (q = 0.522). However, presence of NPM1 mutation in allo-HCT recipients receiving upfront IC resulted in worse outcomes (p = 0.03; HR 2.9, 95% CI 1.1 – 7.8). The presence of FLT3-ITD did not modify the effect of NPM1 on IC vs. LIT outcomes (p = 0.69). Outcomes between IC and LIT remained similar with exclusion of HMA monotherapy from the LIT group.

Conclusions: Real-world outcomes of a large cohort of older patients with AML demonstrate a survival advantage for treatment with upfront IC vs. LIT after adjusting for age and baseline ECOG. A minority (8.5%) of patients receiving LIT proceed to allo-transplant in the real-world setting. In the non-transplant setting, upfront IC improves rwOS, while the upfront treatment choice had no impact on transplant outcomes in our cohort. DNMT3A was the only mutation independently predicting improved outcomes with LIT over IC. NPM1+ patients may particularly benefit from upfront IC in the non-transplant setting, though LIT appears preferred for transplant. Subanalyses investigating the impact of ELN22 and ELN24 will be presented at the meeting.

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2025
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