Genetic Risk Stratification and Outcomes Among Treatment-Naive AML Patients Treated with Venetoclax and Azacitidine

Academic Background

Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy, with prognosis closely related to the genetic characteristics of patients. The European LeukemiaNet (ELN) 2017 and 2022 risk stratification systems for AML are based on patient responses to intensive chemotherapy, primarily designed for younger patients. However, the applicability of these systems to older AML patients who are ineligible for intensive chemotherapy, particularly those treated with Venetoclax and Azacitidine, remains unclear. Venetoclax, a highly selective BCL-2 inhibitor, combined with Azacitidine, has been approved for the treatment of newly diagnosed AML patients who are unfit for intensive chemotherapy. Although this combination therapy has shown high complete remission rates and prolonged overall survival (OS) in clinical trials, the effectiveness of the ELN risk stratification system in predicting outcomes for Venetoclax-Azacitidine-treated patients remains controversial.

This study aims to evaluate the applicability of the ELN 2017 and 2022 risk stratification systems in the context of Venetoclax-Azacitidine treatment by analyzing the genetic characteristics of AML patients and to develop new molecular markers for better prognostic prediction.

Source of the Paper

This paper was co-authored by Hartmut Döhner and other scholars from several internationally renowned institutions, including the University Hospital of Ulm in Germany, the University of Pennsylvania, and the MD Anderson Cancer Center at the University of Texas. The paper was published in the journal Blood on November 21, 2024.

Study Design and Methods

Study Population and Design

This study is a retrospective analysis that included patient data from two clinical trials: the Viale-A trial (NCT02993523) and the Phase 1b study (NCT02203773). The Viale-A trial was a Phase III randomized controlled trial, while the Phase 1b study was an open-label, non-randomized trial. All patients were newly diagnosed with AML and ineligible for intensive chemotherapy. Patients received either Venetoclax or placebo in combination with Azacitidine.

Genetic Risk Assessment

The study used the ELN 2017 and 2022 risk stratification systems to classify patients and developed new molecular markers through bioinformatics algorithms to differentiate the prognosis of Venetoclax-Azacitidine-treated patients. The study analyzed 31 genetic markers and ultimately identified the mutation status of four key genes (TP53, FLT3-ITD, NRAS, and KRAS) to categorize patients into high-benefit, intermediate-benefit, and low-benefit groups.

Data Analysis

The study used the Kaplan-Meier method to assess overall survival (OS) and calculated hazard ratios (HR) using the Cox proportional hazards model. The study also analyzed complete remission rates (CR/CRi) and measurable residual disease (MRD) response rates.

Key Results

Limitations of ELN Risk Stratification

The study showed that the ELN 2017 and 2022 risk stratification systems failed to effectively differentiate prognosis in Venetoclax-Azacitidine-treated patients. Although Venetoclax-Azacitidine outperformed placebo-Azacitidine across all ELN risk groups, the ELN system was unable to effectively predict OS in Venetoclax-Azacitidine-treated patients.

Development of New Molecular Markers

Using bioinformatics algorithms, the study identified the mutation status of four genes (TP53, FLT3-ITD, NRAS, and KRAS) to categorize patients into high-benefit, intermediate-benefit, and low-benefit groups. The median OS for the high-benefit group was 26.5 months, 12.1 months for the intermediate-benefit group, and 5.5 months for the low-benefit group. This new molecular marker effectively differentiated the prognosis of Venetoclax-Azacitidine-treated patients.

Clinical Characteristics of Different Benefit Groups

The high-benefit group comprised 52% of Venetoclax-Azacitidine-treated patients, the intermediate-benefit group 25%, and the low-benefit group 23%. The CR/CRi rate was 77.2% in the high-benefit group, 59.2% in the intermediate-benefit group, and 47.6% in the low-benefit group. The low-benefit group primarily consisted of patients with TP53 mutations, often accompanied by complex cytogenetic abnormalities.

Conclusions and Significance

This study is the first to develop a prognostic model based on the mutation status of four genes in Venetoclax-Azacitidine-treated AML patients, effectively differentiating patient outcomes. This model provides a new risk stratification tool for Venetoclax-Azacitidine-treated AML patients, with significant clinical application value.

Highlights of the Study

1. Limitations of ELN Risk Stratification: The ELN 2017 and 2022 risk stratification systems failed to effectively differentiate prognosis in Venetoclax-Azacitidine-treated patients.
2. Development of New Molecular Markers: The new model based on the mutation status of TP53, FLT3-ITD, NRAS, and KRAS effectively predicts the prognosis of Venetoclax-Azacitidine-treated patients.
3. Potential for Clinical Application: This model provides a new risk stratification tool for Venetoclax-Azacitidine-treated AML patients, aiding in personalized treatment decisions.

Research Value

This study provides a new prognostic assessment tool for Venetoclax-Azacitidine-treated AML patients, with significant scientific and clinical application value. Future research should validate the applicability of this model in larger independent datasets and further explore the efficacy differences of Venetoclax-Azacitidine treatment across different genetic backgrounds.