Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma

Abstract

A subset of patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy have poor clinical outcomes. We report serum proteins associated with severe immune-mediated toxicities and inferior clinical responses in 146 patients with DLBCL treated with axicabtagene ciloleucel. We develop a simple stratification based on pre-lymphodepletion C reactive protein (CRP) and ferritin to classify patients into low-, intermediate-, and high-risk groups. We observe that patients in the high-risk category were more likely to develop grade ≥3 toxicities and had inferior overall and progression-free survival. We sought to validate our findings with two independent international cohorts demonstrating that patients classified as low-risk have excellent efficacy and safety outcomes. Based on routine and readily available laboratory tests that can be obtained prior to lymphodepleting chemotherapy, this simple risk stratification can inform patient selection for CAR T-cell therapy.

Significance: CAR T-cell therapy has changed the treatment paradigm for patients with relapsed/refractory hematologic malignancies. Despite encouraging efficacy, a subset of patients have poor clinical outcomes. We show that a simple clinically applicable model using pre-lymphodepletion CRP and ferritin can identify patients at high risk of poor outcomes. This article is featured in Selected Articles from This Issue, p. 80.

Figure 1.

Association between IL6 and risk-stratified groups based on pre-lymphodepletion CRP and ferritin. IL6 levels were measured by ELISA in serum samples collected from patients receiving standard-of-care axicabtagene ciloleucel for large B-cell lymphoma between day −30 and day –6 prior to lymphodepleting chemotherapy. Ferritin (ng/dL) and CRP (mg/dL) were measured in a separate sample collected on day −6 prior to lymphodepletion in a separate sample. Patients were stratified into three risk groups based on baseline (day −6, pre-lymphodepletion) CRP and ferritin in serum as low risk (CRP <4 mg/dL and ferritin <400 ng/mL, n = 33), intermediate (not meeting criteria for high risk or low risk, n = 30), or high risk (CRP ≥4 m/dL and ferritin ≥400 ng/mL, n = 16). The Kruskal–Wallis test was used to test differences among three distinct risk groups. Logarithm transformation of IL6 was used to allow visualization of data points on the graphs.

Figure 2.

Correlation of baseline CRP and ferritin levels with clinical outcomes in three independent cohorts. Patients were stratified into three risk groups based on baseline (day −6, pre-lymphodepletion) CRP and ferritin as low risk (CRP <4 mg/dL and ferritin <400 ng/mL, n = 62), intermediate (not meeting criteria for high risk or low risk, n = 40), or high risk (CRP ≥4 m/dL and ferritin ≥400 ng/mL, n = 27). Overall survival (OS; A) and progression-free survival (PFS; B) in the cohort of 136 patients treated at H. Lee Moffitt Cancer Center which was used for initial model building. Estimated OS (C, E) and PFS (D, F) in validation cohorts of adult patients with DLBCL. C and D, European Union cohort treated with standard-of-care axi-cel (n = 49) or tisagenlecleucel (tisa-cel, n = 90). Patients included were classified as low risk (n = 44), intermediate risk (n = 57) or high risk (n = 38).E and F, Patients treated with axi-cel on Zuma-1 clinical trial (n = 151). Patients included were classified as low risk (n = 47), intermediate risk (n = 68), or high risk (n = 36). The outcomes were compared using Kaplan–Meier curves and subsequent log-rank tests.