The clinical significance of <i>TET2</i> -driven clonal hematopoiesis ( <i>TET2</i> -CH) in ICI-treated melanoma patients.

Abstract

9549 Background: Clonal hematopoiesis (CH) arises from age-related somatic mutations in hematopoietic stem cells and has been linked to altered immune function and clinical outcomes in solid tumors. While recent studies in colorectal and lung cancers suggest TET2 -mutant CH may enhance immunotherapy responses, the impact of CH genotype on melanoma outcomes remains unclear and potentially context-dependent. Methods: We performed a retrospective cohort study of 361 patients with unresectable stage III/IV melanoma who underwent whole blood sequencing prior to anti-PD-1-based immunotherapy (2014-2024). CH was defined as somatic mutations in CH driver genes with variant allele fraction (VAF) &gt; 2%. Progression-free survival (PFS) and overall survival (OS) were measured from ICI initiation; patients without events were censored at last follow-up. Kaplan-Meier curves and multivariable Cox models adjusted for age, sex, BRAF V600E status, stage, and prior therapy estimated hazard ratios (HRs) compared to patients without CH. Chi-squared analysis assessed CH prevalence among melanoma patients compared to a healthy control cohort (n = 12,346) matched for age and sex. Results: CH prevalence was significantly elevated in melanoma patients compared to age and sex-matched healthy controls (27.7% vs. 21.4% χ² = 7.94, p = 0.004). Among 361 patients, 32 (8.9%) harbored TET2 -driven CH, 48 (13.3%) had DNMT3A -CH, and 20 (5.5%) had other CH mutations. TET2 -CH was associated with significantly worse OS compared to patients without CH (HR = 1.79, p = 0.014) and a trend toward inferior PFS (HR = 1.42, p = 0.119). In contrast, neither DNMT3A -CH (N = 48) nor other CH genotypes demonstrated significant associations with clinical outcomes ( DNMT3A -CH: OS HR = 1.38, p = 0.11; PFS HR = 1.21, p = 0.32), establishing genotype-specific effects. Conclusions: In this cohort of patients with unresectable Stage III/IV melanoma receiving ICI therapy, TET2 -CH was associated with inferior survival outcomes, while no significant survival differences were found among patients with DNMT3A -CH or other CH genotypes. Incorporating CH genotyping into pre-treatment risk stratification may identify high-risk melanoma patients who could benefit from alternative or intensified therapeutic strategies. Mechanistic studies are warranted to elucidate the biological basis for these genotype-specific effects and explore therapeutic interventions targeting CH-driven immune dysfunction. Multivariable PFS and OS hazard ratios by clonal hematopoiesis genotype in ICI-treated melanoma patients. CH Group Number (N) PFS HR (95% CI) PFS p-value OS HR (95% CI) OS p-value No CH 261 1.00 (reference) - 1.00 (reference) - CH 100 1.21 (0.92-1.60) 0.178 1.48 (1.10-1.99) 0.010 TET2- CH 32 1.42 (0.91-2.19) 0.119 1.79 (1.12-2.84) 0.014 Non- TET2 CH 68 1.13 (0.82-1.56) 0.445 1.36 (0.97-1.92) 0.079 DNMT3A -CH 48 1.21 (0.83-1.74) 0.319 1.38 (0.93-2.03) 0.108