The impact of monocytic phenotype and NPM1-mutation status in Acute Myeloid Leukemia when treated with traditional induction chemotherapy compared to azacitidine and venetoclax Free

Patients with acute myeloid leukemia (AML) with monocytic differentiation treated with azacitidine (aza) and venetoclax (ven) have lower response rates and overall survival (OS) compared to those without monocytic differentiation. Additionally, AML patients with NPM1 mutations (NPM1-mut) have better outcomes with aza/ven compared with patients with wild-type NPM1 (NPM1-wt). Recently, it was reported that when these oppositional risk factors co-occur, in the setting of treatment with aza/ven, the adverse risk of monocytic disease is superseded by the positive impact from NPM1-mut, and these patients have improved OS (Lachoweiz et al, Blood Cancer Discovery, 2025). However, it is less clear how the monocytic phenotype affects patient outcomes with traditional induction chemotherapy (7+3), and if NPM1-mut affects monocytic disease when treated with 7+3. Additionally, it is unknown if outcomes for patients with monocytic NPM1-mut AML differ when treated with aza/ven vs 7+3. We sought to answer these questions.

In this retrospective, single-center analysis, we reviewed outcomes of patients with monocytic vs non-monocytic AML treated with 7+3. We then analyzed the effect of NPM1-mut vs NPM1-wt status within patients with monocytic AML only, comparing aza/ven and 7+3 first line therapies. Monocytic AML was classified via pathologic criteria, incorporating both morphologic review and flow cytometric data. NPM1-mutations were identified using next-generation sequencing (NGS). Response rates were determined according to European LeukemiaNet 2022 (ELN-2022) criteria.

We reviewed 196 patients with newly diagnosed AML treated at our center between 2007 and 2025 treated with first line 7+3 or aza/ven. Ninety-four (48%) had monocytic AML, and 102 (52%) had non-monocytic AML. Patients with monocytic AML were 54% female, while patients with non-monocytic AML were 48% female (p=0.4). The median patient age at diagnosis was 62 years for monocytic vs 66 years for non-monocytic (p=0.017).

A preliminary analysis of patients treated with 7+3 included 43 patients with monocytic and 31 with non-monocytic AML. There was no difference in survival at one year (1-year OS): monocytic 1-year OS (70%, 95% confidence interval (CI) 57%-87%) compared to non-monocytic (71%, 95% CI 55%-90%). For monocytic AML patients treated with 7+3, NPM1 status (mutant n=19 vs wt n=24) did not impact 1-year OS (76% vs 65%, p=0.71) or rates of transplant (53% vs 67%, p=0.3).

The median OS of all monocytic patients treated with aza/ven was 8.9 months (95% CI 5.6-29). In patients available for response assessment, those with NPM1-mut (n=21) had significantly higher CR/CRi rates (100% vs 54%, p=0.0009), and improved 1-year OS (65% vs 27%) compared to NPM1-wt (n=30). Similar rates of transplant (29% vs 27%, p=0.9) were observed between the NPM1-mut and NPM1-wt cohorts.

Of patients with NPM1-mut monocytic AML, those treated with aza/ven (n=21) compared to 7+3 (n=19), were significantly older (median 73 yrs vs 43 yrs), and had lower transplant rates (29% vs 53%, p=0.12). Despite this, there was no difference in 1-year OS between the two groups (76%, 95% CI 58-100%; vs 65%, 46-90%; p=0.39).

In an effort to reduce age bias, for patients less than age 70, those with monocytic but NPM1-wt AML, 7+3 led to increased 1-year OS (65% vs 37%, p=0.052), and a trend to higher transplant rates (68% vs 44%, p=0.13) compared to aza/ven.

In this retrospective cohort, monocytic phenotype and NPM1-mut status did not affect patient survival when treated with 7+3. Patients with monocytic disease had worse outcomes when treated with aza/ven, unless they harbored an NPM1 mutation. Those with monocytic NPM1-mut AML had comparable outcomes when treated with 7+3 vs aza/ven, despite increased age and lower transplant rates in the aza/ven-treated patients. With aza/ven becoming more common as first line therapy for AML, our results suggest that clinicians treating patients with monocytic AML, with NPM1-mut, can consider aza/ven as first line therapy, while they should favor traditional 7+3 for patients with NPM1-wt disease (irrespective to monocytic phenotype), especially in younger individuals.