Decreased serum phosphate levels are a useful biomarker to predict occurrence and severity of cytokine release syndrome in chimeric antigen receptor T-cell therapy

概要

CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy is an innovative treatment1 for patients with diffuse large B-cell lymphoma (DLBCL). CAR-T-specific complications have yet to be fully controlled; among potential complications, cytokine release syndrome (CRS) is most commonly observed.2 It would be extremely useful to be able to predict for each patient, the probability of CRS and its anticipated grade and timing using parameters related to the CAR-T cell itself or in vivo responses immediately after CAR-T infusion. Therefore, we performed a retrospective cohort study to identify possible biomarkers using comprehensive screening, to evaluate its accuracy and to reveal relevant mechanisms.

Patients with DLBCL who received tisagenlecleucel (tisacel) or lisocabtagene maraleucel (liso-cel) from 2018 to 2021 at Kyoto University Hospital were consecutively included in this study. CAR-T was infused on Day 0, and the general coagulation and chemistry tests were included in biomarker screening. A difference of >10% (either gain or decrease) between Days −1 and 3 was considered significant in primary screening in order to obtain high sensitivity and specificity. In secondary screening, a change of ≥30% before the occurrence of CRS compared with Day −1 was treated as a positive change in order to obtain the higher specificity

As a result, we enrolled 48 patients treated with tisa-cel (46 patients) or liso-cel (two patients; Table 1). In the total cohort, CRS was observed in almost all patients (N = 46, 95.8%) at a median (range) of 3 (1–6) days after CAR-T infusion. In the primary screening (Figure S1), significant changes were observed in serum inorganic phosphate (iP), potassium (K), and magnesium (Mg) levels (all decreased). As a result of the secondary screening, an iP decrease was significantly related to higher incidence of severe CRS (Grade ≥2) with Fisher's exact test (40.0% vs 0.0%, p< 0.01; Table S1). Decreased iP after infusion was independent of other patient characteristics and parameters (Table S2), and these observations indicated that serum iP can be used as an early predictive biomarker for subsequent severe CRS.