Association of Ferritin Levels With Cytokine Release Syndrome in CAR T-Cell Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Ferritin elevation is frequently observed during cytokine release syndrome (CRS) following CAR T-cell therapy; however, its independent clinical utility as a predictive or prognostic biomarker remains uncertain. We performed a systematic review critically evaluating the timing-specific and context-dependent role of ferritin in CRS risk stratification and outcomes. METHODS: We systematically searched PubMed, Web of Science, and Scopus for studies evaluating ferritin in CAR T-cell recipients. We performed structured qualitative synthesis with semi-quantitative comparison across studies, including direction-of-effect analysis and threshold stratification. We also performed a meta-analysis on the association of progression-free survival (PFS) and overall survival (OS) based on pre-infusion ferritin levels using a random-effects model. RESULTS: Fifteen studies (n = 1671) were included. Elevated pre-infusion ferritin (commonly ≥ 400 ng/mL) was associated with higher CRS incidence and severity in most studies (10/12), but its independent predictive value was inconsistent. Post-infusion ferritin demonstrated a consistent association with CRS severity across all studies (9/9), with extreme elevations (> 10,000 ng/mL) observed in high-grade CRS. However, ferritin lacked specificity as a standalone biomarker and performed more robustly when integrated into multimarker models (e.g., cytokines, EASIX score). Survival associations were heterogeneous and likely confounded by disease burden and systemic inflammation. Interestingly, meta-analysis showed that pre-infusion ferritin levels were significantly associated with worse PFS [HR: 2.18 (1.74-2.73), p < 0.00001, I2 = 0%] and worse OS [HR: 2.97 (2.22-3.97), p < 0.00001, I2 = 0%]. Potential publication bias was not identified in this analysis. CONCLUSION: Ferritin is best interpreted as a dynamic inflammatory correlate rather than an independent predictor of CRS. Its clinical utility in CRS prediction lies in risk enrichment when combined with other biomarkers and clinical scores, rather than as a standalone decision tool. Nevertheless, pre-infusion levels may be useful in predicting worse PFS and OS given the standardization of timing, thresholds, and integration into predictive models.