Prognostic implications of TET2 variant allele frequency in chronic myelomonocytic leukemia: a multicenter study

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.