Measurable Residual Disease as a Prognostic Biomarker in Frontline Azacitidine and Venetoclax-Treated AML: Insights from the French VENAURA Registry

Highlight

Measurable residual disease (MRD) negativity achieved during frontline treatment with azacitidine and venetoclax (AZA/VEN) strongly correlates with improved overall survival (OS) and reduced relapse in AML patients. Dual MRD negativity by multiparametric flow cytometry (LAIP/LSC) confers superior outcomes. MRD status mitigates adverse molecular risk, supporting MRD integration into clinical decision-making.

Study Background

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by clonal proliferation of myeloid blasts in the bone marrow. Despite advances in therapy, outcomes remain suboptimal, particularly for older or unfit patients who are unfit for intensive chemotherapy. The combination of azacitidine, a hypomethylating agent, with venetoclax, a BCL-2 inhibitor, has transformed frontline therapeutic approaches in such populations, offering improved remission rates and survival compared to azacitidine monotherapy.

Measurable residual disease (MRD) assessment, through highly sensitive methods such as multiparametric flow cytometry (MFC) and molecular assays (e.g., NPM1 RT-qPCR), has emerged as a crucial prognostic biomarker in AML. MRD negativity post-therapy associates with longer remission and survival following intensive regimens. However, its prognostic relevance specifically in patients treated frontline with AZA/VEN in real-world settings remains insufficiently defined.

Study Design

This retrospective analysis examined 220 newly diagnosed AML patients from the French VENAURA registry who underwent frontline treatment with azacitidine and venetoclax. All patients achieved a composite complete remission (CR) and had MRD evaluations performed via multiparametric flow cytometry—using leukemia-associated immunophenotypes (LAIP) and leukemic stem cell (LSC) detection—and/or NPM1 RT-qPCR molecular testing.

Key endpoints included rates of cumulative MRD negativity, overall survival (OS), and cumulative incidence of relapse, stratified by MRD status. Subgroup analyses assessed the prognostic value of dual MRD negativity (LAIP/LSC) versus single positivity or negativity status, impact on different European LeukemiaNet (ELN) 2024 risk groups, MRD kinetics (early vs late responders), and the effect of granulocyte colony-stimulating factor (G-CSF) adjunctive use.

Key Findings

Among evaluated patients, cumulative MRD negativity was achieved in 62-67%, whether assessed by flow cytometry or NPM1 molecular testing. Critically, achieving MRD negativity at any time following frontline AZA/VEN correlated strongly with better overall survival. Specifically, patients with LAIP negativity had a median OS of 31.3 months versus 15.7 months if positive (hazard ratio [HR] = 0.47, p < 0.001). Similarly, NPM1 MRD negativity conferred OS not reached versus 10.8 months in positive cases (HR = 0.38, p < 0.001).

Dual negativity of LAIP and LSC markers (NEG/NEG) identified the subgroup with the most favorable outcomes. Survival was significantly better compared to those with discordant MRD results: NEG/POS (HR = 0.36, p = 0.02), POS/NEG (HR = 0.24, p < 0.001), though POS/POS endpoint had a non-significant HR = 0.26 (p = 0.26), likely reflecting smaller sample size.

Remarkably, MRD response status modulated the prognostic impact of ELN 2024 molecular risk classification. MRD-negative patients in intermediate or poor-risk groups demonstrated survival outcomes comparable to patients with favorable-risk profiles, indicating MRD negativity supersedes baseline genetic risk stratification when achieved.

Analysis of MRD kinetics revealed no significant differences in survival between early versus late MRD responders, suggesting timing of MRD clearance is less critical than the achievement itself. Additionally, the adjunctive use of G-CSF was associated with improved rates of MRD negativity conversion and better OS, suggesting support for its use in this therapeutic context.

Expert Commentary

This comprehensive real-world study confirms the pivotal prognostic role of MRD assessment in AML patients treated with frontline azacitidine and venetoclax. The findings underscore the clinical utility of incorporating both flow cytometry (LAIP/LSC) and molecular (NPM1 RT-qPCR) MRD monitoring to refine risk stratification and guide subsequent therapeutic decisions.

The observation that MRD negativity can overcome the adverse impact of ELN molecular risk categories is particularly noteworthy. This suggests that therapeutic response at the level of residual disease burden might be a more dynamic and powerful prognostic biomarker than static baseline genetic risk classification. Consequently, integration of MRD into treatment algorithms could facilitate more personalized and adaptive strategies, such as escalation or de-escalation of therapy or consideration for allogeneic hematopoietic stem cell transplantation.

It is also important to acknowledge limitations inherent to retrospective registry data, including potential selection biases and heterogeneity in MRD assessment timing and techniques. Larger prospective studies with standardized MRD monitoring are warranted to validate these findings.

Conclusion

The French VENAURA registry analysis establishes that deep MRD negativity, as measured by multiparametric flow cytometry and NPM1 RT-qPCR, is the dominant prognostic determinant for AML patients undergoing frontline AZA/VEN therapy. Achieving MRD negativity confers significant survival advantage and diminished relapse risk, even in patients with unfavorable baseline molecular risk. These results strongly support the adoption of MRD-guided, response-adapted management strategies in routine clinical practice to optimize outcomes in AML.

Funding and ClinicalTrials.gov

The study cited is a retrospective registry analysis with no specific prospective funding disclosed. The French VENAURA registry serves as a valuable resource for real-world evidence generation in AML treated with lower-intensity regimens. Prospective clinical trial registration data were not provided.

References

1. Heiblig M, Gross Z, Belhabri A, et al. Prognostic impact of measurable residual disease in AML patients treated frontline with azacitidine and venetoclax: results from the French VENAURA registry. Leukemia. 2026 Jul 17. PMID: 42469476.
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3. Fenwarth L, Jatiani S, Loke J, et al. Measurable Residual Disease in Acute Myeloid Leukemia: Practical Considerations and Future Directions. Curr Hematol Malig Rep. 2023;18(1):40-53.