The correlation between cardiac biomarkers and serum cytokines after CAR-T therapy

Abstract Introduction As Chimeric Antigen Receptor T cell (CAR-T) therapy gains its clinical advantage in the management of diffuse large B cell lymphoma (DLBCL), accumulating evidence shows that it often accompanies cardiac dysfunction. Previous retrospective studies indicated the potential involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy. Inflammatory cytokines such as IL1βand IL-6 are generally considered as cytokines involved in CRS after CAR-T therapy, but no prospective study has reported which cytokines correlated with change of cardiac biomarkers after CAR-T therapy. Purpose The objectives of this study are to prospectively examine the sequential changes in cardiac biomarkers and serum cytokines overtime after CAR-T therapy and to clarify the association between cardiac biomarkers and serum cytokines. Methods In this prospective observational study, 30 DLBCL patients who underwent CAR-T therapy were enrolled and classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely the low-CRS group (CRS<2) and the high-CRS group (CRS≧2). Before and after the treatment, the level of cardiac biomarkers and cytokines levels were sequentially collected. Results The average age of participants was 59.6 years, and 9 patients (30%) were female. The average duration of DLBCL was 2.7 years. The number of patients in the low- and high-CRS groups was 13 and 17, respectively. The high-CRS group showed significantly higher NT-proBNP levels compared to the low-CRS group on days 3 and 7 after CAR-T therapy (p<0.001 and p=0.003, respectively), whereas troponin T level did not show any differences. The levels of IL-6 and IL-1β on day 3 were significantly higher in the high-CRS group compared to those of the low-CRS group (p=0.001 and p=0.008, respectively). After day 3, the serum level of IL-6 reduced to near the baseline value, whereas the serum level of IL-1β increased further from day 3 to day 7. Given that the significant increase of NT-proBNP level on days 3 was a consequence of CRS, the correlation between culprit cytokine and NT-proBNP levels at the prior time point was expected. Therefore, we analyzed the correlation between NT-proBNP and serum cytokine levels on day 3. NT-proBNP levels were significantly correlated with serum IL-6 (r=0.644, p<0.001) and IL-1β levels (r=0.628, p<0.001). Conclusion In the patients who underwent CAR-T therapy for DLBCL, the elevation of NT-proBNP level and IL-6 level were observed on day3 and they were strongly correlated. These data supported the hypothesis that IL-6 was central to the causal mechanisms of CRS cardiotoxicity after CAR-T therapy.Sequential changes in IL-6 and IL-1βCorrelation of NT-proBNP and cytokines