Context Clonal hematopoiesis (CH) is an age-associated phenomenon which has been implicated in vascular diseases and hematologic malignancies. Recent evidence demonstrates that CH potentially influences treatment efficacy through altered myeloid cell infiltration and tumor microenvironment remodeling. For BRAF-mutated melanoma patients who have both targeted therapy (BRAF/MEK inhibitors) and immunotherapy options, understanding how CH status affects treatment outcomes becomes crucial for optimal sequencing decisions. Furthermore, BRAF mutations are known to amplify inflammatory signaling within the tumor microenvironment, which may exacerbate immune-related toxicity and modulate responses to immune checkpoint inhibitors (ICIs). Given that CH-derived myeloid cells exhibit enhanced inflammatory properties and preferential tumor infiltration, and that BRAF signaling can modulate immune responses, the interaction between these factors may significantly impact both the efficacy and safety profile of immunotherapy. This study aims to characterize these interactions to develop risk-stratified treatment algorithms that maximize therapeutic benefit in this vulnerable population.

Design In a cohort of 361 unresectable Stage III or Stage IV melanoma patients who underwent pre-treatment blood‐based genomic sequencing, CH was defined as somatic mutations in clonal hematopoiesis-associated genes with VAF > 2%. PFS and OS were measured from ICI initiation. Patients were further categorized into four subgroups based on CH and BRAF mutation status: CH+/BRAF+, CH+/BRAF−, CH−/BRAF+, and CH−/BRAF−. Multivariable Cox proportional hazard models adjusted for age, sex, and baseline characteristics were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Chi-squared analysis was conducted to assess CH prevalence among melanoma patients (n=361) when compared to a healthy control cohort (n=12,346) matched for age and sex, at an average 1:18 matching ratio.

Results Among 361 melanoma patients receiving ICI, 100 (28%) had CH clones and 261 (72%) did not. The most common CH mutations within this cohort were DNMT3A (16.6% of patients), TET2 (11.6% of patients), ASXL1 (2.2% of patients), and TP53 (1.4% of patients). CH prevalence was significantly higher among melanoma patients compared to matched healthy controls (27.7% vs. 21.4%; χ²=7.94, p=0.004). For progression-free survival, the CH+/BRAF+ subgroup demonstrated a statistically significant association with worse PFS compared to the CH−/BRAF− reference group (HR=1.61, 95% CI: 1.05-2.47, p=0.029). The CH+/BRAF− group showed a trend toward worse PFS (HR=1.20, 95% CI: 0.83-1.73, p=0.34), and the CH−/BRAF+ group was not significantly different (HR=1.24, 95% CI: 0.92-1.69, p=0.16). For overall survival, the CH+/BRAF+ subgroup was strongly associated with worse OS compared to the CH−/BRAF− reference group (HR=1.58, 95% CI: 0.99-2.52, p=0.056). The CH+/BRAF− group showed a trend toward worse OS (HR=1.28, 95% CI: 0.87-1.87, p=0.21), while CH−/BRAF+ was not significantly different (HR=0.89, 95% CI: 0.63-1.26, p=0.51).

Conclusion CH prevalence was higher among melanoma patients compared to age and sex-matched healthy controls. Combined CH+/BRAF+ mutational status among melanoma patients receiving ICIs was associated with significantly worsened progression-free survival and strongly trended towards worsened overall survival compared to other subgroups within the melanoma cohort. This finding suggests a synergistic negative prognostic effect when CH and BRAF mutations co-occur, potentially due to converging immunomodulatory mechanisms. Future studies are warranted to elucidate the biological basis of this interaction and evaluate its predictive utility in clinical decision-making. Incorporation of CH and BRAF profiling may enhance risk stratification to inform immunotherapy decision-making and maximize therapeutic benefit among melanoma patients.

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2025
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