Chimeric antigen receptor T-cell (CAR-T) therapy has enabled positive outcomes in some patients with certain relapsed/refractory B-cell malignancies, but cytokine-release syndrome (CRS) is a relatively common adverse event with this treatment approach. Processes resulting in coagulopathy with CRS have been poorly understood, so a research team set out to evaluate coagulation and fibrinolysis parameters in patients with diffuse large B-cell lymphoma (DLBCL) receiving tisagenlecleucel. They reported their findings in an issue of the journal Blood Advances.
This single-center, prospective cohort study was based at Kyoto University Hospital in Kyoto, Japan. In this study, peripheral blood samples were obtained from adults with relapsed/refractory DLBCL treated with tisagenlecleucel at 3 time points over the treatment course. These were prior to lymphocyte-depleting chemotherapy, on day 3 after CAR-T infusion, and on day 13 after CAR-T infusion.
A total of 25 patients were included in the analysis. CRS occurred in 24 of these patients, or nearly all of the cohort. Tocilizumab use was required in 13 patients.
In blood plasma, the level of total plasminogen activator inhibitor 1 (PAI-1) was found to be significantly increased at CRS onset in many patients. The mean level of PAI-1 prior to lymphocyte depletion was 22.5 ng/mL, and on day 3 the mean PAI-1 level had risen to 41.0 ng/mL (P =.02). “Elevation of PAI-1 caused impaired fibrinolysis on day 3, which was the onset of CRS in most cases,” the researchers wrote in their report.
After remission of CRS, total PAI-1 reportedly normalized toward levels seen prior to CAR-T infusion. At day 13, the mean PAI-1 level was 25.1 ng/mL.
With the moderate level of suppression of fibrinolysis soon after CAR-T infusion, the researchers hypothesized this may be accompanied by an enhancement of coagulation. Changes in levels of thrombin-antithrombin complex and antithrombin after tisagenlecleucel infusion appeared to support this hypothesis, and a direct signal suggesting enhanced coagulation could be seen with an increase in soluble fibrin. Mean levels of soluble fibrin across time points were 3.16 mg/mL prior to infusion, 8.04 mg/mL at day 3, and 9.16 mg/mL at day 13 (P <.01).
“In conclusion, we found a hypofibrinolytic and relatively hypercoagulable state concomitant with significant elevation of total PAI-1 in DLBCL patients at the onset of mild CRS,” the researchers wrote in their report. “Subsequent recovery in the later stage of CRS corresponded to normalization of the total PAI-1 level without any sequelae,” they continued.
The researchers considered the study’s findings to provide insight on coagulopathy with CRS in patients treated with CAR-T therapy. They also indicated the results demonstrate the importance of evaluating coagulation parameters in patients receiving CAR-T treatment.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Yamasaki-Morita M, Arai Y, Ishihara T, et al. Relative hypercoagulation induced by suppressed fibrinolysis after tisagenlecleucel infusion in malignant lymphoma. Blood Adv. 2022;6(14):4216-4223. doi:10.1182/bloodadvances.2022007454