# Allostatic Load Predicts Immune-Related Toxicity and Survival in Melanoma Patients Receiving Immune Checkpoint Inhibitors

## TL;DR

Higher pre-treatment physiological stress predicts more side effects and worse survival in melanoma patients receiving immunotherapy.

## Contribution

Allostatic load is shown to be a novel pre-treatment marker of immunotherapy outcomes in melanoma patients.

## Key findings

- Higher allostatic load is linked to increased immune-related toxicity in melanoma patients.
- Patients with higher allostatic load have a 26% higher mortality risk during immunotherapy.
- Allostatic load correlates with poorer treatment response and faster disease progression.

## Abstract

Immune checkpoint inhibitors improve survival in melanoma, but patients differ in their ability to tolerate treatment and benefit from therapy. We examined whether allostatic load, a measure of cumulative physiological stress derived from routine clinical tests, was associated with outcomes in melanoma patients receiving immunotherapy. Patients with higher allostatic load before treatment were more likely to develop immune-related side effects and had poorer survival. These findings suggest that baseline physiological vulnerability may influence immunotherapy outcomes and could help identify patients who need closer monitoring.

Background: Host physiological factors may influence immune response, treatment tolerance, and survival during immune checkpoint inhibitor (ICI) therapy. Allostatic load (AL) summarizes cumulative physiological dysregulation across multiple biological systems. We evaluated whether pre-treatment AL is associated with immune-related toxicity and clinical outcomes among patients with advanced melanoma receiving ICIs. Methods: We analyzed 399 patients with melanoma treated with ICIs at the University of Virginia Cancer Center (2013–2025). AL was derived from routinely collected clinical laboratory biomarkers measured prior to treatment initiation. Multinominal logistic and Cox regression models assessed associations between AL and immune-related adverse events (irAEs), treatment response, disease progression, and overall survival (OS), adjusting for demographic, clinical, and treatment factors. Results: The mean AL score was 4.43. Each 1-unit increase in AL was associated with higher odds of grade ≥ 2 toxicity (adjusted odds ratio [OR] = 1.30; 95% confidence interval [CI]: 1.08–1.57). Among patients who developed irAEs, higher AL was associated with poorer treatment response (adjusted OR = 1.24; 95% CI: 1.01–1.54) and increased risk of disease progression (adjusted hazard ratio [HR] = 1.14; 95% CI: 0.98–1.33). Higher AL was also associated with shorter OS, with a 26% higher mortality risk per 1-unit increase in AL (adjusted HR = 1.26; 95% CI: 1.14–1.39). Conclusions: Higher pre-treatment AL was associated with increased immune-related toxicity and poorer survival in melanoma patients treated with ICIs. AL represents a feasible pre-treatment marker of host physiological vulnerability that may complement existing clinical predictors. Prospective studies are needed to validate these findings and assess clinical utility.