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CIRS is predictive of outcomes in CAR T-cell recipients with R/R DLBCL

Dr Geoffrey Shouse, City of Hope Comprehensive Cancer Center, USA
ASH 2021
A large, real-world evidence (RWE) study demonstrated that the Cumulative Illness Rating Scale (CIRS) is predictive of outcomes in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) receiving CAR T-cell therapy [1]. A composite index comprising 4 CIRS organ systems (“Severe4”) showed independent prognostic significance in CAR T-cell recipients.

Chimeric antigen receptor (CAR) T-cell therapy has dramatically improved outcomes, e.g., durable responses, in patients with R/R DLBCL [2;3]. A recent retrospective comparison showed that CAR T-cell therapy was superior to other R/R DLBCL therapies, resulting in an improved progression-free (PFS) and overall survival (OS) [4]. Nevertheless, due to the progression of the disease, the majority of patients have poor outcomes after CAR T-cell therapy. On top of that, inherent disease characteristics may predispose patients to toxicities of CAR T-cell therapy.
Searching for predictive tools

Tools quantifying frailty and comorbidities have not been verified in large patient cohorts. The Comprehensive Geriatric Assessment was found to be predictive of outcomes in patients with DLBCL receiving CAR T-cell therapy. CIRS is another comprehensive tool that has been found to predict outcomes in various B-cell malignancies [5].

Dr Geoffrey Shouse (City of Hope Comprehensive Cancer Center, USA) and others used a machine-learning algorithm to rank the prognostic impact of specific comorbidities, measured by CIRS. Furthermore, they assessed survival and toxicities in patients treated with different CAR T-cell products. They performed a retrospective RWE analysis of patients with R/R DLBCL who underwent leukapheresis for CAR T-cell therapy. A high comorbidity burden was defined using a published cut-off of CIRS score ≥7. In total, 577 patients (median age: 63 years) were analysed. The majority of patients (90%) had a good performance status (ECOG 0–1). Previously, patients received a median of 3 prior therapies, and 25% of patients underwent a prior autologous stem cell transplant. The median CIRS score was 7, with 54% having CIRS ≥7.
“Severe4” was predictive

A PFS event was observed in 56% of the patients and 41% of the patients died. The median survival estimates were 11 months (95% CI 8–15) for PFS and 30 months (95% CI 23–NA) for OS. In a univariable analysis, CIRS ≥7 was significantly associated with PFS (hazard ratio 1.26; see Figure 1A) and OS (HR 1.35; see Figure 1B).

“Severe4” was defined as severe comorbidity (CIRS grade 3 or 4) in any of the 4 key CIRS categories: respiratory, upper gastrointestinal, renal and hepatic. “Severe4” was found in 9% of patients and was independently and significantly correlated with inferior PFS (HR 2.45; P<0.001; see Figure 1D) and OS (HR 2.30; P<0.001; see Figure 1E).

In addition, the researchers found that patients with “Severe4” had a higher rate of grade ≥3 cytokine release syndrome (CRS, 16% vs 6%; P=0.013). In addition, the development of grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) was associated with CIRS scores ≥7 (26% vs 12%; P<0.001).

Given these results, CIRS evaluation and “Severe4” may be considered for risk assessment prior to the administration of CAR T-cell infusion in patients with R/R DLBCL.

    1. Shouse GP, et al. Impact of Comorbidities on Outcomes and Toxicity in Patients Treated with CAR T-Cell Therapy for Diffuse Large B Cell Lymphoma (DLBCL): A Multicenter Rwe Study. Abstract 529, ASH 2021 Annual Meeting, 11-14 Dec.

    2. Crump M, et al. Blood. 2017;130:1800-1808.

    3. Locke FL, et al. Lancet Oncol. 2019;20:31-42.

    4. Sermer D, et al. Blood Adv. 2020;4:4669-4678.

    5. Salvi F, et al. J Am Geriatr Soc. 2008;56:1926-31.


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