Clinical, tumor, and product features associated with outcomes after axicabtagene ciloleucel therapy in follicular lymphoma
Researchers from MD Anderson investigated why some follicular lymphoma (FL) patients experience benefit from axicabtagene ciloleucel (axi-cel) while others relapse or develop severe toxicities. Using the ZUMA-5 dataset (n=124 FL patients), they integrated product phenotype, serum biomarkers, clinical features, and tumor transcriptional programs to build multivariable models of efficacy and safety. Overall, low preinfusion systemic inflammation, lower total metabolic tumor volume (TMTV), a naïve-skewed CAR-T product, and robust postinfusion expansion tracked with longer progression-free survival. Conversely, inflammatory cytokine surges and interferon-rich, checkpoint-laden tumor microenvironments marked resistance and toxicity, suggesting that combining clinical risk scores with simple blood and product measurements can sharpen patient selection and guide next-generation CAR-T strategies in FL patients.
CAR-T has transformed relapsed/refractory FL, but ~50% of patients eventually progress, and a minority develop grade ≥3 cytokine release syndrome (CRS) or neurologic events (NE). Traditional tumor burden metrics (sum of product diameters) incompletely capture risk, and prior correlative studies were small or product-specific. In this current study, pretreatment covariates and postinfusion kinetics were linked to outcomes and tumor biopsies probed resistance biology. The investigators also tested whether augmenting the FLIPI score with biology (TNF-α, TMTV, T-naïve content) improves risk stratification.
Key quantitative signals emerged, with Day-0 TNF-α being the strongest pretreatment correlate of progression; higher TNF-α reduced the probability of ongoing response and shortened PFS, while higher hemoglobin and greater infused T-naïve cells (CCR7+CD45RA+) improved outcomes. Postinfusion, greater CAR-T expansion (peak and AUC) was associated with ongoing response and longer PFS, whereas higher TNF-α, IL-12p40, IL-16, and VCAM1 AUC was associated with relapse. Tumors from nonresponders showcased elevated IFN-α/γ signatures and higher LAG3/TIM-3 expression, while IFNG IO360 was linked to worse PFS (P<0.05). Safety analyses showcased grade ≥3 NE in 15% and CRS in 6%, with co-occurrence (χ² P=0.021), with GM-CSF (peak/AUC), IL-6 AUC, IL-15 peak, and TNF-α peak being the greatest toxicity correlates. Combining FLIPI with TNF-α, TMTV, or T-naïve content improved risk stratification; notably, a naïve-rich product benefited patients with high TMTV, whereas low TNF-α particularly helped those with low TMTV.
Reference:
Poddar S, Yan J, Tiwari G, et al. Clinical, tumor, and product features associated with outcomes after axicabtagene ciloleucel therapy in follicular lymphoma. J Clin Invest. 2025;135(16):e181893. Published 2025 Aug 15.