A prognostic index called “Severe4” can predict outcomes of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to research published in Blood Advances.

Patients met the criteria for Severe4 if they had a severe comorbidity — a cumulative illness rating scale (CIRS) score of 3 or higher — in the respiratory, upper gastrointestinal, hepatic, or renal system.  

Researchers found that patients with Severe4 had inferior progression-free survival (PFS) and overall survival (OS) after CAR T-cell therapy. 

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The researchers first assessed the prognostic effect of Severe4 in a learning cohort of 550 patients with relapsed/refractory DLBCL who received CAR T-cell therapy. Most  patients (71%) received axicabtagene ciloleucel, 22% received tisagenlecleucel, and 7% received lisocabtagene maraleucel.

At a median follow-up of 21 months, the median PFS was 11 months, and the median OS was 30 months. The rate of cytokine release syndrome (CRS) was 78%, and 7% of patients had grade 3 or higher CRS.

Severe4, which was present in 9% of patients, was independently associated with:

  • Inferior PFS (hazard ratio [HR], 2.15; 95% CI, 1.54-2.99; P <.001)
  • Inferior OS (HR, 1.94; 95% CI, 1.35-2.78; P <.001)
  • A higher risk of grade 3 or higher CRS (odds ratio [OR], 2.88; 95% CI, 1.17-6.42; P =.013). 

To confirm these results, the researchers evaluated Severe4 in a validation cohort of 218 patients with relapsed/refractory DLBCL. Baseline characteristics in this cohort were similar to baseline characteristics in the learning cohort.

Most patients in the validation cohort received axicabtagene ciloleucel (97.7%), and 2.3% received tisagenlecleucel. At a median follow-up of 35 months, the median PFS was 16 months, and the median OS was 25 months. The rate of grade 3 or higher CRS was 17%. 

Severe4 was present in 16% of patients in this cohort. Severe4 was independently associated with inferior PFS (HR, 1.85; 95% CI, 1.24-2.76; P =.003) and inferior OS (HR, 1.70; 95% CI, 1.09-2.66; P =.019) but not grade 3 or higher CRS (OR, 2.05; 95% CI, 0.81-4.90; P =.114).

“[O]ur findings suggest that determining Severe4 should be part of standard of care when selecting patients with DLBCL for CART,” the researchers wrote. “In addition, Severe4 and formal CIRS evaluation could be utilized when assessing risk of CART toxicity for those treated with this promising therapy.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 


Shouse G, Kaempf A, Gordon M, et al. A validated composite comorbidity index predicts outcomes of CAR T-cell therapy in patients with diffuse large B cell lymphomaBlood Adv. Published online February 3, 2023. doi.org/10.1182/bloodadvances.2022009309