Prognostic implications of TET2 variant allele frequency in chronic myelomonocytic leukemia: a multicenter study
Year: 2026
Type: article
Study design: Observational Study
Abstract: Chronic myelomonocytic leukemia (CMML) is a heterogeneous myeloid neoplasm with a highly variable prognosis. TET2 is mutated in ∼60% of cases, with several studies linking TET2 mutations and mutation burden to favorable outcomes. However, no prior study has quantitatively characterised TET2 variant allele frequency (VAF) as a continuous, non-linear prognostic variable across large multi-institutional cohorts, nor leveraged it to refine contemporary CMML risk-stratification systems. We examined the prognostic role of TET2 VAF in 1,206 CMML patients across a UK discovery cohort (DC, TET2 -mutated: 433/645, 67%), an international validation cohort (VC1, TET2 -mutated: 141/291, 48%), and a French CD14+ monocyte-sequenced cohort (VC2, TET2 -mutated: 176/270, 65%). Segmented regression of TET2 VAF distributions reproducibly identified two inflection points (DC 32%/55%; VC1 33%/54%; VC2 36%/56%), implying consistent subdivision of TET2 mutation burden across CMML of epidemiological (and potentially biological) relevance. Restricted cubic spline Cox regression revealed a non-linear relationship between TET2 VAF and survival, with risk lowest near VAF 39% (the empirical first quartile), whilst TET2 wild-type patients had hazards comparable to high-VAF cases. Capitalising on this continuous relationship, we constructed TET2 -VAF-adjusted CPSS-Mol, GFM, and MMM scores by adding a per-integer-VAF adjustment to each patient's original score. Across cohorts and prognostic tools, the adjusted scores improved discrimination (Harrell's C-index gain in 16/18 comparisons, IDI significant in 18/18, p<0.01), and group-level stratification for overall survival and acute myeloid leukemia-free survival. These findings suggest that TET2 VAF represents a continuous prognostic variable in CMML and provide a robust, reproducible framework for refining standard risk-stratification systems.
Source: Blood Neoplasia
Authors: Yu-Hung Wang, Dorothée Selimoglu-Buet, Carmelo Gurnari, Matthew T. Villaume, Somedeb Ball, Nathalie Droin, Hussein Awada, Andres Jerez, Andrius Zucenka, Chi-Yuan Yao, Chien-Chin Lin, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien, Jaroslaw P. Maciejewski, Michael R. Savona, Eric Solary, Kiran Batta, Daniel H. Wiseman
Institutions: National Taiwan University, University of Manchester, National Taiwan University Hospital, Inserm, Institut Gustave Roussy, University of Rome Tor Vergata, Cleveland Clinic, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Vall d'Hebron Hospital Universitari, Vilnius University, Vilnius University Hospital Santariskiu Klinikos, Far Eastern Memorial Hospital
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
Awards: Exploring Cytokine Expression and Immune Cell Constitution in the Bone Marrow Microenvironment in Patients with Myelodysplastic Syndrome and Their Clinical Significance( III ), G2700669654, Investigating the Pathogenesis of Hopx in T-Acute Lymphoblastic Leukemia by a Conditional Knock-Out Mouse Model, Exploring the Biological Effects of Phf6 Loss Combined with Runx1 Mutations in Hematopoiesis and the Development of Blood Malignancies( I )
OpenAlex ID: W7202350635