Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy

Abstract

Cytokine release syndrome (CRS) is a systemic inflammatory response associated with chimeric antigen receptor T-cell (CAR-T) therapies. In severe cases, CRS can be associated with coagulopathy and hypofibrinogenemia. We present our global multicenter experience with CRS-associated coagulopathy after tisagenlecleucel therapy in 137 patients with relapsed or refractory B-cell acute lymphoblastic leukemia from the ELIANA and ENSIGN trials. These trials included clinical guidelines for fibrinogen replacement during CRS-associated coagulopathy. Hypofibrinogenemia requiring replacement was observed only in patients with severe CRS. A higher percentage of patients who required replacement were <10 years old, compared with those who did not require replacement. Twenty-three patients received replacement for hypofibrinogenemia (<1.5 g/L); 9 of them developed marked hypofibrinogenemia (<1 g/L). Very low fibrinogen levels (<1 g/L) were documented in patients before maximal CRS (n = 1), during maximal CRS (n = 7), and at CRS improvement (n = 1). Although hypofibrinogenemia was the most clinically significant coagulopathy, some patients also developed prolonged prothrombin time and activated partial thromboplastin time and increased international normalized ratio, further increasing the risk of bleeding. Hypofibrinogenemia was effectively managed using fibrinogen concentrate or cryoprecipitate replacement; severe (grade 4) bleeding events were rare (n = 2). CRS-associated coagulopathy with hypofibrinogenemia is manageable according to empiric guidelines of fibrinogen replacement for CAR-T trials. Fibrinogen concentrate should be used when cryoprecipitate is not reliably available. Monitoring fibrinogen levels in patients with moderate or severe CRS is essential for avoiding potentially fatal bleeding events. These trials were registered at www.clinicaltrials.gov as #NCT02435849 and #NCT02228096.

Conflict of interest statement

Conflict-of-interest disclosure: J.B. has received personal fees, grants, and nonfinancial support from and has served as a trial investigator, a consultant, and an advisory board member for Novartis Pharmaceuticals Corporation. S.A.G. has received grant support and personal fees from Novartis Pharmaceuticals Corporation; has received study support and consulting fees from and has served on study steering committees and science advisory boards for Vertex, Adaptimmune, CBMG, Cure Genetics, Humanigen, Jazz, Kite, Roche, and Servier; and holds a patent (WO 2014011984 A1) related to toxicity management for antitumor activity of CARs managed according to University of Pennsylvania policies. D.T.T. has received nonfinancial support from Novartis Pharmaceuticals Corporation and has served on advisory boards for Janssen, La Roche, Amgen, and Humanigen. S.R. has received personal fees and nonfinancial support from and has served on study steering committees for Novartis Pharmaceuticals Corporation; has served as a trial investigator, a consultant, and an advisory board member for Jazz Pharmaceutical; has received personal fees and nonfinancial support from and has been an advisory board member for Shire; and has received personal fees and nonfinancial support from and served as a trial investigator and an advisory board member for Celgene. T.W.L. has received personal fees from Novartis Pharmaceuticals Corporation, Bayer, Loxo Oncology, and Eli Lilly and grant support from Novartis, Bayer, and Pfizer. P.W. was employed by Novartis during the conduct of the trial. R.A., L.Y., A.C.-A., and L.K.E. are employed by Novartis. B.D.M. has served as a trial investigator and an advisory board member for Novartis Pharmaceuticals Corporation and has received nonfinancial support from Jazz Pharmaceuticals. The remaining authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Time course of treatment of CRS-associated coagulopathy on patients treated with tisagenlecleucel. Patient 1 (A), patient 2 (B), patient 3 (C). Days after tisagenlecleucel infusion; day 1, infusion day. Arrows, the day of blood product replacement with fibrinogen concentrate; orange triangles, CRS onset by grade; blue triangles, CRS resolution. ALL, acute lymphoblastic leukemia; Gr, grade; ICU, intensive care unit; s/p, status post; SCT, stem cell transplantation.

Figure 2.

Guidelines for use of replacement to treat CRS-associated hypofibrinogenemia or coagulopathy. Fibrinogen concentrate (A), cryoprecipitate (B). *Minor bleeding events include epistaxis, intramuscular bleeding, and menorrhagia. †From RiaSTAP Prescribing Information. ‡Major bleeding events include head trauma and intracranial hemorrhage. For patients without bleeding, fibrinogen levels should be monitored and maintained at >1.5 g/L. §Each unit of cryoprecipitate contains at least 150 mg fibrinogen per unit. Two units of cryoprecipitate per 10 kg body weight generally increases fibrinogen concentration by 1 g/L, except in cases of DIC or continued bleeding with massive transfusion.