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.
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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.
Reference
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
