Early Prediction of Severe Icans after CD19 CAR T-Cell Therapy Based on Serum Ferritin Levels

Chimeric antigen receptor T-cell (CAR-T) therapy has become an integral strategy for treating patients with B-cell malignancies. However, patients can develop life-threatening complications including immune effector cell-associated neurotoxicity (ICANS). We hypothesized that after CAR-T infusion, early changes in ferritin levels, a biomarker associated with hemophagocytic lymphohistiocytosis, which has overlapping features with CAR T-cell toxicities, may predict the risk of developing severe ICANS.The development set consisted of patients with relapsed/refractory B-cell malignancies treated at our center with axicabtagene ciloleucel (axi-cel) or lisocabtagene maraleucel (liso-cel). Logistic regression was used to predict the occurrence of grade ≥3 ICANS. An independent validation set consisted of patients treated on a phase I/II clinical trial of an investigational CD19 CAR-T product (JCAR014). Discrimination of prediction models were assessed in both the development and validation set using the area under the ROC curve.The development set included 145 patients, all with non-Hodkin lymphoma (NHL), of whom 70 (48%) experienced any grade ICANS and 29 (20%) experienced grade ≥3 ICANS. Median age was 63.6 years (range 25.7 – 83.3). The validation set included 188 patients with acute lymphoblastic leukemia (57, 30%), chronic lymphocytic leukemia (47, 25%), and NHL (84, 45%). Seventy-two patients (38%) experienced any grade ICANS, and 37 (20%) experienced grade ≥3 ICANS. Median age was 55.5 years (range 20.0 – 76.0).We measured early, rapid and sustained elevations of serum ferritin levels in patients with grade ≥3 ICANS compared to patients with grade 0-2 ICANS, as demonstrated using estimated scatterplot smoothing (Fig. 1). Univariate logistic regression modeling showed a strong association between day +3 ferritin levels and grade ≥3 ICANS (OR = 9.67; 95% CI, 3.15 – 36.10; p<0.001) and high discrimination (C-index = 0.75; Fig. 2). Ferritin day +3 values of 2000 ng/mL, 3000 ng/mL, and 4000 ng/mL were associated with 51%, 87%, and 98% probabilities of grade ≥3, respectively (Fig. 3). A logistic regression model refitted to our validation set also showed strong association between day +3 ferritin levels and severe ICANS (OR = 2.60; 95% CI, 1.26-5.75; p=0.013). The discriminative ability of day +3 ferritin to predict grade ≥3 ICANS was also confirmed in our validation set (C-index = 0.61).Serum ferritin levels on day +3 are strongly associated with severe ICANS after CD19 CAR T-cell therapy with axi-cel and liso-cel, and was validated in an external cohort including clinical trial patients treated with JCAR014. Validated predictive models using point-of-care assessments create an opportunity to identify high-risk patients who could benefit from early or prophylactic interventions.