CRS Associated With Coagulation Disorders in CAR T-Cell Therapy in Multiple Myeloma

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A retrospective analysis of patients receiving chimeric antigen receptor (CAR) T-cell therapy identified risk factors and potential indicators for serious coagulopathy related to therapy, according to published findings from the phase 1 LEGEND-2 study (NCT03090659).¹

Of 51 patients treated in LEDEND-2, 49% developed coagulation disorders during treatment with B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, with risk factors associated with coagulopathy including severe cytokine release syndrome (CRS), abnormal liver function, and high tumor burden.

The study included patients with relapsed/refractory multiple myeloma beginning in March 2016, with a data cut-off of November 3, 2022, for the data that were reported. Following lymphodepleting therapy, patients received the LCAR-B38M CAR T-cell therapy in 3 doses over 7 days.

Six patients were excluded from the retrospective study due to having disseminated intravascular coagulation (DIC) prior to CAR T-cell infusion. Of the 51 patients evaluated, the median age was 54 years. They had received a median of 3 prior lines of therapy, and 17% had received autologous stem cell transplant.

Among the 51 patients, 21 (41%) had increased D-dimer, 16 (31%) had prolonged activated partial thromboplastin clotting time (APTT), 11 (22%) had decreased fibrinogen, and 2 (4%) had prolonged prothrombin time (PT). Fifteen patients (29%) were diagnosed with DIC based on the Chinese DIC Scoring System, but by the International Society on Thrombosis and Haemostatsis score, 13 (25%) were diagnosed with DIC.

CRS was reported in 45 patients (88%); it was grade 1 in 25 (56%), grade 2 in 17 (38%), and grade 3 in 3 patients (6%). The investigators found that patients with grade 2 or 3 CRS had significantly increased levels of PT, international normalized ratio (INR), APTT, and D-dimer, and decreased fibrinogen compared with patients with grade 1 or no CRS. A Spearman’s correlation analysis of the patients with CRS showed that serum IL-6 and IL-2R levels were similarly correlated with coagulation disorders, though no correlation was found between IL-2R and D-dimer level. There were also correlations observed between tumor necrosis factor­–α levels and coagulation parameters. IL-8 and IL-10 were not significantly correlated to any coagulation parameters.

A multivariate analysis showed increased coagulation disorders in patients with these indicators and a 6.667 times higher occurrence rate in patients with grade 2 or 3 CRS than those who did not (95% CI, 1.476-30.106; P = .014).

Twenty-five patients also had abnormal liver function; those with impaired liver function also had higher PT, INR, APTT, D-dimer, and decreased fibrinogen. Correlations were also observed between some coagulation parameters and liver function tests including alanine aminotransferase, aspartate aminotransferase, and bilirubin. The rate of coagulation disorder was 3.937 times higher in patients with abnormal liver function (95% CI, 1.182-13.117; P = .026).

The median time to onset of CRS was 8 days from CAR T-cell infusion; coagulation disorders and abnormal liver function occurred 2 to 5 days later, with a duration of 5 to 7 days. The peak time of CRS appeared to occur at the start of abnormal liver function as well as coagulation disorders.

Out of 25 patients with at least 1 abnormal coagulation parameter, 15 developed DIC. Three of these patients with DIC had grade 3 or 4 bleeding and 5 had hypotension. Nine patients received tocilizumab (Actemra) to treat DIC. Coagulopathy appeared to resolve after CRS was controlled.

Investigators studied whether responses to CAR T-cell therapy were associated with DIC or coagulation disorders. Overall response rates and complete response rates were slightly higher, but short-term and long-term Kaplan-Meier analyses found no significant difference in survival between patients who had this toxicity or not (P > .05).

The investigators noted that other studies of BCMA-targeted CAR T-cell therapies had higher rates of coagulopathy, which they potentially attributed to only using cyclophosphamide for lymphodepletion and a low dose of CAR T cells.

Based on these outcomes, investigators concluded that certain indicators, most notably serum IL-6 and ALT, could be used to monitor patients at risk for DIC. Controlling CRS, protecting liver function, and managing overactive coagulation could protect patients from serious coagulopathy. Although coagulopathy due to CAR T-cell therapy was serious in the short term, it was manageable with standard treatment if physicians responded in time.

_REFERENCE:

_{1. Liu R, Lv Y, Hong F, et al. A comprehensive analysis of coagulopathy during anti-B cell maturation antigen chimeric antigen receptor-T therapy in multiple myeloma, a retrospective study based on LEGEND-2 [published online ahead of print, 2023 Apr 25]. Hematol Oncol. 2023;10.1002/hon.3155. doi:10.1002/hon.3155}