Prognostic implications of TET2 variant allele frequency in chronic myelomonocytic leukemia: a multicenter study.
14 affiliations
- 1Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom.
- 2Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan.
- 3Department of Hematological Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
- 4INSERM U1287, Gustave Roussy Cancer Center, Villejuif, France.
- 5Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
- 6Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy.
- 7Division of Hematology and Oncology, Vanderbilt Ingram Cancer Center and Vanderbilt University School of Medicine, Nashville, TN.
- 8Haematology Department, University Hospital Vall d'Hebron, Barcelona, Spain.
- 9Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.
- 10Hematology and Oncology Department, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
- 11Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- 12Division of General Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- 13Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
- 14Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
Abstract
Chronic myelomonocytic leukemia (CMML) is a heterogeneous myeloid neoplasm with highly variable prognosis. TET2 is mutated in ∼60% of patients, previously linked to favorable outcomes. However, no study has quantitatively characterized TET2 variant allele frequency (VAF) as a continuous, nonlinear prognostic variable, nor leveraged it to refine contemporary CMML risk stratification systems. We examined the prognostic role of TET2 VAF in 1206 patients across a UK discovery cohort (DC; TET2-mutated, 433/645 [67%]), an international validation cohort (validation cohort 1 [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 nonlinear relationship between TET2 VAF and survival, with risk lowest near VAF 39% (the empirical first quartile), whereas patients with TET2 wild-type status had hazards comparable to patients with high VAF. Capitalizing on this continuous relationship, we constructed TET2-VAF-adjusted CMML-specific Prognostic Scoring System-Molecular, Groupe Francais des Myelodysplasies model, and Mayo Molecular Model 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 C-index gain in 16/18 comparisons; integrated discrimination improvement significant in all 18 comparisons; P < .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.
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BibTeX
@article{wang2026prognostic,
title = {{Prognostic implications of TET2 variant allele frequency in chronic myelomonocytic leukemia: a multicenter study.}},
author = {Yu-Hung Wang and Dorothée Selimoglu-Buet and Carmelo Gurnari and Matthew T Villaume and Somedeb Ball and Nathalie Droin and Hussein Awada and Andres Jerez and Andrius Zucenka and Chi-Yuan Yao and Chien-Chin Lin and Hsin-An Hou and Wen-Chien Chou and Hwei-Fang Tien and Jaroslaw P Maciejewski and Michael R Savona and Eric Solary and Kiran Batta and Daniel H Wiseman},
journal = {Blood neoplasia},
year = {2026},
month = aug,
doi = {10.1016/j.bneo.2026.100286},
url = {https://europepmc.org/article/MED/42904085},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Prognostic implications of TET2 variant allele frequency in chronic myelomonocytic leukemia: a multicenter study.
AU - Yu-Hung Wang
AU - Dorothée Selimoglu-Buet
AU - Carmelo Gurnari
AU - Matthew T Villaume
AU - Somedeb Ball
AU - Nathalie Droin
AU - Hussein Awada
AU - Andres Jerez
AU - Andrius Zucenka
AU - Chi-Yuan Yao
AU - Chien-Chin Lin
AU - Hsin-An Hou
AU - Wen-Chien Chou
AU - Hwei-Fang Tien
AU - Jaroslaw P Maciejewski
AU - Michael R Savona
AU - Eric Solary
AU - Kiran Batta
AU - Daniel H Wiseman
PY - 2026
DA - 2026/08/13
JO - Blood neoplasia
DO - 10.1016/j.bneo.2026.100286
UR - https://europepmc.org/article/MED/42904085
AB - Chronic myelomonocytic leukemia (CMML) is a heterogeneous myeloid neoplasm with highly variable prognosis. TET2 is mutated in ∼60% of patients, previously linked to favorable outcomes. However, no study has quantitatively characterized TET2 variant allele frequency (VAF) as a continuous, nonlinear prognostic variable, nor leveraged it to refine contemporary CMML risk stratification systems. We examined the prognostic role of TET2 VAF in 1206 patients across a UK discovery cohort (DC; TET2-mutated, 433/645 [67%]), an international validation cohort (validation cohort 1 [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 nonlinear relationship between TET2 VAF and survival, with risk lowest near VAF 39% (the empirical first quartile), whereas patients with TET2 wild-type status had hazards comparable to patients with high VAF. Capitalizing on this continuous relationship, we constructed TET2-VAF-adjusted CMML-specific Prognostic Scoring System-Molecular, Groupe Francais des Myelodysplasies model, and Mayo Molecular Model 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 C-index gain in 16/18 comparisons; integrated discrimination improvement significant in all 18 comparisons; P < .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.
SN - 2950-3280
ER -