IL-6 Is Not Significantly Associated with Quality of Life Symptoms in Allogeneic Hematopoietic Cell Transplant Recipients Following Tocilizumab

Abstract

Introduction Hematopoietic stem cell transplantation (HCT) produces pro-inflammatory cytokines including IL-6 which can activate central nervous system (CNS) pathways to cause depressed mood, anxiety, fatigue, and sleep disturbance. Tocilizumab (toci), an IL-6 receptor antagonist, is an FDA approved treatment for cytokine release syndrome (CRS), a serious complication of CAR-T cell therapy. However, toci results in transient elevations of IL-6 in the CNS and there is concern that this may worsen neurotoxicity. Objective We hypothesized that increased circulating IL-6 levels would be associated with more severe symptoms among a cohort of alloHCT recipients receiving toci. Methods Data were obtained from a parent clinical trial evaluating the effectiveness of toci to prevent aGVHD in a cohort of 35 patients undergoing alloHCT. A subset of 25 patients from this cohort completed quality of life (QOL) measures pre-HCT and at day +28 post-transplant (D+28). IL-6 levels were measured pre-HCT and at D+28. The relationships between IL-6 and depression, anxiety, fatigue, and sleep were correlated in four ways using Spearman correlation: 1) cross-sectionally at baseline and at D+28; 2) change in both QOL and IL-6 from baseline to D+28; 3) baseline IL-6 level with D+28 QOL; and 4) baseline IL-6 level with change in QOL from baseline to D+28. Results Contrary to the hypothesis, IL-6 was not significantly associated with any of the QOL measures at baseline or D+28. There was a trend toward a relationship between depression and IL-6 at baseline (Fig 1; r=-0.40; p=0.06), although the association was not in the hypothesized direction; i.e., higher IL-6 was associated with less depression. Similarly, the correlations between baseline to D+28 change in IL-6 and change in QOL, baseline IL-6 and D+28 QOL, and baseline IL-6 and change in QOL were not significant. Conclusions IL-6 was not significantly associated with depression, anxiety, pain, or sleep in this cohort of alloHCT recipients receiving toci, although there was a trend toward an association between higher IL-6 and lower depression at baseline. This finding suggests that the symptoms and neurotoxicity experienced by individuals who receive toci for CRS may not be IL-6 mediated. Blockade of peripheral IL-6 receptors may lead to increased release of other cytokines, increased CNS IL-6 levels, or actions of other physiological systems and warrants further investigation.