Tocilizumab administration in cytokine release syndrome is associated with hypofibrinogenemia after chimeric antigen receptor T-cell therapy for hematologic malignancies

Abstract

Chimeric antigen receptor (CAR) T-cell therapy causes serious side effects including cytokine release syndrome (CRS). CRS-related coagulopathy is associated with hypofibrinogenemia that has up to now been considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated the incidence and risk factors for hypofibrinogenemia in 41 consecutive adult patients with hematologic malignancies (median age 69 years, range 38-83 years) receiving CAR T-cell therapy between January 2020 and May 2023 at the University Medical Center Regensburg. CRS occurred in 93% of patients and was accompanied by hypofibrinogenemia already from CRS grade 1. Yet DIC and liver dysfunction mainly occurred in severe CRS (≥ grade 3). After an initial increase during CRS, fibrinogen levels dropped after administration of tocilizumab in a dose-dependent manner (r = -0.44, P=0.004). In contrast, patients who did not receive tocilizumab had increased fibrinogen levels. Logistic regression analysis identified tocilizumab as an independent risk factor for hypofibrinogenemia (odds ratio = 486, P<0.001). We thus hypothesize that fibrinogen synthesis in CRS is up-regulated in an interleukin-6-dependent acute phase reaction compensating for CRS-induced consumption of coagulation factors. Tocilizumab inhibits fibrinogen upregulation resulting in prolonged hypofibrinogenemia. These observations provide novel insights into the pathophysiology of hypofibrinogenemia following CAR T-cell therapy, and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS.

Figure 1.

Hypofibrinogenemia occurs in all grades of cytokine release syndrome, whereas disseminated intravascular coagulation is characteristic only for high-grade cytokine release syndrome. (A) Fibrinogen, (B) D-dimers, (D) platelet, (E) international normalized ratio (INR), and (F) partial thromboplastin time (PTT) values are altered in cytokine release syndrome (CRS) patients, but only fibrinogen levels are already decreased in low-grade CRS. (C) Fibrinogen negatively correlates with increased D-dimers. Dashed lines represent Common Terminology Criteria for Adverse Events grades in (A). sec: second.

Figure 2.

Impairment of liver synthesis characterizes high-, but not low-grade cytokine release syndrome. (A-C) Gamma glutamyltransferase (gGT), alanine transaminase (ALT), and choline esterase (CHE) are affected in high-grade cytokine release syndrome (CRS), while (D) albumin, a sensitive marker for inflammation and liver synthesis, steadily decreases with increasing CRS grades.

Figure 3.

Hypofibrinogenemia is associated with tocilizumab administration. (A) Lowest observed fibrinogen levels after chimeric antigen receptor (CAR) T-cell therapy decrease with increasing CRS grade in patients who received tocilizumab (turquoise), whereas they increase in patients who did not receive tocizliumab (red). (B, C) Cumulative tocilizumab dosage significantly correlates with the minimum fibrinogen levels and the duration of fibrinogen recovery from lowest to normal levels after CAR T-cell therapy. (D) Average severity of hypofibrinogenemia is mild to moderate after ≤2 doses, and severe after ≥3 doses. Dotted, horizontal lines represent severity levels according to Common Terminology Criteria for Adverse Events.

Figure 4.

Proposed pathophysiology of tocilizumab-induced hypofibrinogenemia in cytokine release syndrome patients. During cytokine release syndrome (CRS), inflammation mediated by various cytokines leads to consumption of coagulation factors, which is compensated by IL-6-dependent upregulation of fibrinogen synthesis (left). When tocilizumab is used for the treatment of CRS, the IL-6 stimulus for increased fibrinogen synthesis in the liver is diminished. Therefore, consumption and production of fibrinogen are disparate, resulting in a persistent state of hypofibrinogenemia (right). The figure was created with BioRender.com. DIC: disseminated intravascular coagulation; IL-6R: interleukin-6 receptor; GP130: glycoprotein 130.