A Retrospective Review of Tocilizumab for the Management of Blinatumomab (a Bispecific T Cell Engager)-Induced Cytokine Release Syndrome (CRS)

Background: Treatment approaches for the management of CRS have been evolving, including the addition of the recently approved tocilizumab (Actemra^®), an interleukin-6 receptor antagonist, for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening CRS. The authors report on the experience with tocilizumab for the management of CRS in patients receiving blinatumomab, a bispecific T cell engager (BiTE^®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage and CD3 expressed on the surface of T cells. Based on this mechanism of action, CRS is a key risk for blinatumomab. CRS symptoms may include coincident signs/symptoms of fever, chills/rigors, nausea/vomiting, headache, hypo-/hypertension, tachycardia, dyspnea, hypoxia, transaminitis/hyperbilirubinemia, and mental status changes. Risk mitigation measures for CRS in study protocols and approved product labeling for blinatumomab include a step-dosing strategy during the first cycle of treatment, prophylactic dexamethasone administration before the start of infusion, and close monitoring of patients during the period when CRS is most likely to occur. Guidance provided for the management of CRS consists of blinatumomab treatment interruptions for Common Terminology Criteria for Adverse Events (CTCAE) grade 3 CRS and permanent discontinuation for grade 4 CRS (Blincyto^® US PI, 2018). While healthcare professional judgment for the management of CRS may include treatment with tocilizumab, no approved labeling guidance exists regarding the use of tocilizumab for CRS outside of the approved indication for CAR T cell-induced CRS.

Methods: A retrospective review was conducted utilizing the Amgen global safety database for individual case safety reports that reported the use of tocilizumab for events suggestive of CRS in patients administered blinatumomab in the clinical trial and postmarket settings.

Results: As of December 20, 2017, 6 cases from clinical trials and 24 cases from the postmarket setting were identified in which tocilizumab was used for the management of blinatumomab-induced CRS. Approximately half of the cases described pediatric patients. As anticipated, based on mechanism of action, most (~80%) of the CRS events occurred early in the first cycle of blinatumomab treatment.

In Amgen-sponsored clinical trials, approximately 1000 patients had been exposed to blinatumomab since the beginning of the development program through December 2017. Of the 39 cases of CRS identified in the clinical trial setting, 6 (15%) reported use of tocilizumab for the management of CRS. The severity of CRS for the 6 cases were grade 2 (n=1), grade 3 (n=2), and grade 4 (n=3); none were fatal. Tocilizumab was administered concurrently with corticosteroids in 3 cases, after corticosteroids in 2 cases, and both before and after corticosteroids in 1 case. For all cases, blinatumomab infusion was interrupted, and in 2 cases, blinatumomab was restarted upon resolution of CRS without reoccurrence of the event. In the other 4 cases, the patients discontinued blinatumomab treatment; 3 patients with grade 4 CRS discontinued per protocol requirements, and 1 patient with grade 3 CRS discontinued per investigator decision. For all 6 clinical trial cases, CRS was reported as resolved.

In the marketed setting, approximately 4500 patients had been exposed to blinatumomab since approval through December 2017. Of the 160 cases of CRS reported in the postmarket setting, the review identified 24 (15%) in which the management of CRS included tocilizumab. Although postmarket cases generally contain less data compared with those in clinical trials, in 15 of 16 cases that had an outcome provided, CRS was reported as resolved, and none described fatal CRS following treatment with tocilizumab. Similarly, some postmarket cases reported that blinatumomab was able to be restarted following treatment interruption and the administration of tocilizumab.

Conclusions: CRS is a key risk associated with blinatumomab for the treatment of acute lymphoblastic leukemia. While clinical investigators and healthcare professionals are familiar with the use of corticosteroids for the management of blinatumomab-induced CRS, our review indicates that tocilizumab has also been used in this setting in conjunction with the established mitigation measures, including interruption of blinatumomab infusion.