Inflammatory Biomarker Clusters May Provide a New Means for Risk Stratification of Patients with LBCL Receiving CAR-T Therapy

Disease persistence and relapse remain challenges following CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy in large B-cell lymphoma (LBCL). Identification of factors increasing the risk of CAR-T failure could provide evidence to support personalized treatment approaches; therefore, a predictive tool informative of adverse CAR-T therapy outcomes was developed. Findings were presented at the 64th American Society of Hematology Annual Meeting and Exposition.

Investigators aimed to develop an objective, summative measure of baseline systemic inflammation utilizing standard laboratory and cytokine measurements, as well as inflammatory markers, collected prior to CAR-T infusion (day 0) that can predict disease response and survival. An unbiased evaluation of pre-infusion laboratory findings revealed 2 distinct biomarker clusters: inflammatory and noninflammatory. The inflammatory cluster was enriched for patients with high levels of inflammatory markers such as interleukin-6, C-reactive protein, and ferritin, with suppressed negative acute phase reactants, such as albumin; these patients also had suppressed blood counts, such as platelets and absolute neutrophil count. In contrast, patients in the noninflammatory cluster did not have elevated inflammatory markers, with higher blood counts. Compared to the noninflammatory cluster, the inflammatory cluster was enriched with aggressive disease features, including a higher proportion of patients with primary refractory disease, higher disease stage at apheresis, and higher pre-infusion lactate dehydrogenase (LDH). Day 100 complete response (CR) rate, significant toxicity (defined as grade ≥3 cytokine release syndrome, grade ≥3 immune effector cell–associated neurotoxicity syndrome, ICU admission, blood stream infection, or death by day 30), and overall survival (OS) after multivariate adjustment for CAR-T costimulatory domain, age, primary refractory disease, and pre-lymphodepletion LDH were studied.

In a single-center cohort of 177 patients with LBCL treated with CD19-directed CAR-T therapy at Memorial Sloan Kettering Cancer Center (axicabtagene ciloleucel, 55% [n = 97]; tisagenlecleucel, 29% [n = 53]; lisocabtagene maraleucel, 16% [n = 28]), median age was 65 (interquartile range, 56-72), 18% had high-grade B-cell lymphoma, and 76% received bridging therapy; median OS was 23 months. The day 100 CR rate was 59% in the overall population, with 52% of patients experiencing significant toxicity. After multivariate adjustment, the inflammatory cluster was associated with decreased OS (hazard ratio [HR], 3.30; 95% confidence interval [CI], 2.06-5.27; P <.0001) and response. The day 100 CR rate for the noninflammatory cluster was 71% versus 32% for the inflammatory cluster (odds ratio [OR], 5.52; 95% CI, 2.72-11.6). The clusters were then evaluated in a large independent validation cohort of Israeli patients (Sheba Medical Center; n = 150) for generalizability—with the caveat that in the latter center, pre-infusion inflammatory marker and cytokine measurements are neither standard of care nor widely available pre-infusion. A random forest model was used for statistical analysis adjustment. The inferred pre-infusion clusters in the independent validation cohort were found to maintain associations with response and survival after multivariate adjustment, with day 100 CR rates of 37% and 67%, respectively, for the inflammatory and noninflammatory clusters (OR, 3.17; 95% CI, 1.19-9.06). The inflammatory cluster was also associated with decreased OS (HR, 2.93; 95% CI, 1.06-8.14; P <.05).

In conclusion, 2 pre-infusion (day 0) biomarker clusters were identified and found to be tightly associated with CAR-T outcomes. Upon validation in an independent cohort, these findings were maintained, potentially providing a new means for risk stratification of patients with LBCL prior to CAR-T infusion.

Source:

Raj S, Perales M, Fein JA, et al. Inflammatory biomarker clusters are predictive of response and toxicity in large B-cell lymphoma treated with CD19 CAR-T cell therapy. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA. Oral presentation 263.