Real-Time Kinetics of Interleukin-6 (IL-6) Predict Cytokine Release Syndrome (CRS) in Patients Receiving Chimeric Antigen Receptor (CAR) T-cell Therapy for relapsed/refractory B-cell Malignancies.

Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are common, potentially life-threatening toxicities after CAR T-cell therapy. Elevated IL-6 is mechanistically linked to CRS, yet most studies have retrospectively assessed static or peak cytokine levels. We hypothesized that real-time IL-6 measurement is feasible and that early IL-6 kinetics could predict CRS and ICANS. We prospectively enrolled 42 patients (pts) with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) treated with commercial CAR T-cell products. Serum samples were collected at predefined timepoints [apheresis, day −5 of lymphodepletion (LD), day 0 (infusion), 12 h post-infusion (day 0.5), and days 1, 2, 4, and 7] for real-time IL-6 assay (Beckman Coulter). IL-6 log-slope was calculated using log-transformed values from day 0 to the last sample before toxicity onset, excluding samples drawn after CRS onset or tocilizumab/steroid use. CRS and ICANS were graded per ASTCT criteria. Associations were analyzed using nonparametric tests, logistic regression, and ROC analysis; optimal cutoffs were derived via Youden's index. Of 42 pts, 18 (43%) had MM and 24 (57%) NHL; median age was 67 y (39–84), 19% ECOG ≥2, and 36% had prior autologous transplant. CAR T-cell products included cilta-cel (43%), liso-cel (24%), axi-cel (21%), and brexu-cel (12%); 71% received fludarabine/cyclophosphamide LD. CRS occurred in 30 pts (71%) and ICANS in 13 (31%), with grade ≥2 events in 53% and 62%, respectively. Median time to onset was 5 d for CRS and 6 d for ICANS. Median IL-6 turnaround time was 1.7 d (IQR 0.6–3.5). Day 1 IL-6 was higher in ≥G2 CRS (20 vs 8 pg/mL, p=0.013), and peak IL-6 correlated with CRS (33 vs 12 pg/mL, p=0.002) and severity (p=0.005). IL-6 log-slope was higher in CRS (0.77 vs 0.30, p<0.001) and ≥G2 CRS (0.92 vs 0.47, p=0.009). ROC analysis demonstrated that IL-6 log-slope predicts CRS with an area under the curve (AUC) of 0.88. An optimal log-slope cutoff of 0.64 -corresponding to a daily IL-6 increase of ≈90% per day-yielded 89% sensitivity and 92% specificity. For ICANS, ROC analysis demonstrated that IL-6 log-slope predicts ICANS with an AUC of 0.72. A cut-off of 0.25 (increase by ≈29% per day)- yielded sensitivity and specificity of approximately 67% for predicting ICANS. Early IL-6 kinetics over the first 4–7 days post-infusion, are significantly associated with the development and severity of CRS, and potentially predictive signal for ICANS. A slope threshold of 0.058, corresponding to a modest ∼6% daily rise, identified patients at high risk for CRS with high specificity. Incorporation into real-time monitoring could enable preemptive tocilizumab use, guide outpatient vs inpatient management, and improve safety in high-risk patients. Further prospective validation in larger cohorts is warranted.