Management of Coagulopathy Associated with CTL019 CAR T-Cell Therapy

Introduction: CTL019 (tisagenlecleucel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that has demonstrated high durable response rates and a manageable safety profile in pediatric/young adult patients (pts) with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). CTL019-associated cytokine-release syndrome (CRS), a systemic inflammatory response caused by elevated serum cytokine levels, occurred in 81% of pts treated in 2 multicenter trials (Maude et al, Haematologica . 2017;120(s2): [abstract P517]). Coagulopathy has been associated with CRS and macrophage activation syndrome (MAS) in previous reports of CTL019 from a single-center US study, and similar coagulopathy has been reported in cases of MAS/hemophagocytic lymphohistiocytosis associated with other events such as infections or chemotherapy. Here, we outline the treatment guidelines established and US and global multicenter experience with CTL019-associated coagulopathy in 97 pts treated with CTL019.

Methods: Pooled data from 2 single-arm, multicenter phase II trials of CTL019 in pediatric/young adult pts with r/r B-ALL (ELIANA, NCT02435849 and ENSIGN, NCT02228096) were used to further characterize coagulopathy during CTL019-associated CRS.

Results: Maximal grades 1-2, 3, and 4 CRS occurred in 36, 19, and 24 pts, respectively. Median lowest fibrinogen levels were 3.5 g/L and 3.3 g/L in pts with maximal grade 1-2 and 3 CRS, respectively, while median lowest fibrinogen level in pts with maximal grade 4 CRS was 1.2 g/L. 3%, 11%, and 25% of pts with maximal grades 1-2, 3, and 4 CRS, respectively, had lowest reported fibrinogen levels of ≥ 1 to < 1.5 g/L. Very low fibrinogen levels (<1 g/L) were observed in 33% of pts with maximal grade 4 CRS, with 2 pts having unmeasurable levels of fibrinogen, but not in any pt with maximal grade 1-3 CRS. Very low fibrinogen levels (<1 g/L) could occur before maximal CRS grade (n=1), during maximal CRS grade (n=6), or at the time of CRS improvement (n=1). Near the time of very low fibrinogen levels (<1 g/L) onset, only 1 pt had concurrent grade 3 increased INR and aPTT; the other 7 pts had grade 0-2 increased INR and aPTT.

Given that hypofibrinogenemia was the most notable coagulopathy, cryoprecipitate was the mainstay of treatment in the US. In addition, administration of large volumes of fresh frozen plasma can be problematic in pts with CRS, fluid overload, and capillary leak. Guidelines for fibrinogen concentrate (FC) use were developed for the ELIANA global trial for CTL019-associated coagulopathy since cryoprecipitate is not readily available in Japan and some European countries. FC was available at 7/25 sites and administered to 3/7 pts with grade 4 CRS, and none of 8 pts with grades 1-3 CRS, out of 20 infused pts. Cryoprecipitate was available in 18/25 sites and administered to 12/17 pts with grade 4 CRS, 2/15 pts with grade 3 CRS, and none of 32 pts with grades 1-2 CRS, out of 77 infused pts.

In pediatric pts with r/r B-ALL, the risk of bleeding from CTL019-associated hypofibrinogenemia can be increased by co-morbid thrombocytopenia and the use of anticoagulants, including those used in veno-venous hemofiltration (CVVH). Within 1 day of onset of very low fibrinogen levels (<1 g/L), 5/8 pts had concurrent grade 3 or 4 decreased platelets. 1 fatal case (1/97 infused pts=1%) of intra-parenchymal cranial hemorrhage was seen during resolving CRS with grade 3 hypofibrinogenemia, ongoing thrombocytopenia, and CVVH with citrate.

Conclusions: Clinical recommendations and guidelines were developed for the use of FC and cryoprecipitate for the treatment of CTL019-associated coagulopathy with hypofibrinogenemia. During CTL019-associated coagulopathy, fibrinogen levels were disproportionately low as compared with INR/PTT. Hypofibrinogenemia was observed more frequently in pts with higher CRS grades, could be seen either during or when CRS was improving or resolution, and was effectively managed by FC or cryoprecipitate replacement. Rarely, fatal bleeding can be seen. Frequent monitoring of fibrinogen, INR/PTT, platelets, and signs of clinical bleeding, as well as appropriate fibrinogen replacement are needed in pts with grade 3 and 4 CRS associated with CAR T-cell therapies.