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CNL and aCML should be considered as a single entity based on molecular profiles and outcomes
Gonzalo Carreño-Tarragona1, Alberto Álvarez-Larrán2, Claire Harrison3
1Hematology Department, Hospital Universitario 12 de Octubre, I+12, Centro Nacional de Investigaciones Oncológicas, Complutense University, Centro de Investigación Biomédica en Red de Oncología, Madrid, Spain.
Insights
Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are similar rare myeloid disorders. Molecular profiles suggest they are a disease continuum, with specific gene mutations impacting patient risk.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid neoplasms presenting diagnostic and management challenges.
- Understanding their relationship is crucial for accurate classification and treatment strategies.
Purpose of the Study:
- To investigate the clinical and molecular similarities and differences between CNL and aCML.
- To identify prognostic molecular markers for risk stratification in these disorders.
Main Methods:
- A multicenter international study analyzing a large case series of CNL (n=24) and aCML (n=37).
- Comprehensive clinical data collection and mutational profiling of 53 cases.
- Multivariate analysis to identify high-risk mutated genes.
Main Results:
- No significant differences were observed in clinical presentation or outcomes between CNL and aCML.
- Both entities share complex mutational profiles involving epigenetic, splicing, and signaling pathways.
- CSF3R mutations are important, with CEBPA, EZH2, NRAS, and U2AF1 identified as high-risk mutations.
Conclusions:
- CNL and aCML represent a disease continuum within myelodysplastic/myeloproliferative neoplasms.
- Molecular profiling, particularly of CSF3R, CEBPA, EZH2, NRAS, and U2AF1, is essential for risk stratification.
- Findings support a molecular-based classification for improved management of these rare leukemias.
Abstract:
Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences between these disorders, we undertook a multicenter international study of one of the largest case series (CNL, n = 24; aCML, n = 37 cases, respectively), focusing on the clinical and mutational profiles (n = 53 with molecular data) of these diseases. We found no differences in clinical presentations or outcomes of both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing, and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms. We identified 4 high-risk mutated genes, specifically CEBPA (β = 2.26, hazard ratio [HR] = 9.54, P = .003), EZH2 (β = 1.12, HR = 3.062, P = .009), NRAS (β = 1.29, HR = 3.63, P = .048), and U2AF1 (β = 1.75, HR = 5.74, P = .013) using multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases.
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