A validated composite comorbidity index predicts outcomes of CAR T-cell therapy in patients with diffuse large B cell lymphoma.

Chimeric antigen receptor T-cell therapy (CART) has extended survival of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, limited durability of response and prevalent toxicities remain problematic. Identifying patients at high risk of disease progression, toxicity, and death would inform treatment decisions. Although the cumulative illness rating scale (CIRS) has been shown to correlate with survival in B-cell malignancies, no prognostic score has been independently validated in CART recipients. We retrospectively identified 577 patients with relapsed/refractory DLBCL indicated for CART at 9 academic centers to form a learning cohort (LC). Random survival forest modeling of overall survival (OS) and progression-free survival (PFS) was performed to determine the most influential CIRS organ systems and severity grades. The presence of a severe comorbidity (CIRS score ≥3) in the respiratory, upper gastrointestinal, hepatic, or renal system - herein termed "Severe4" - had the greatest impact on post-CART survival. Controlling for other prognostic factors (number of prior therapies, Eastern Cooperative Oncology Group performance status, BCL6 translocation, molecular subtype), Severe4 was strongly associated with shorter PFS and OS in the LC (hazards ratio [HR]=2.15 and 1.94, respectively; p<0.001) and in an independent single-center validation cohort (VC) (n=218; HR=1.85, p=0.003; HR=1.70, p=0.019, respectively). Severe4 was also a significant predictor of grade ≥3 cytokine release syndrome in the LC (odds ratio [OR]=2.43, p=0.042), while maintaining this trend in the VC (OR=2.05, p=0.114). Thus, our results indicate that adverse outcomes for patients with DLBCL meant to receive CART can be predicted using a simplified CIRS-derived comorbidity index.