Grading and management of cytokine release syndrome in patients treated with tisagenlecleucel in the JULIET trial

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy yields durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Cytokine release syndrome (CRS) is a CAR-T therapy-related adverse event. To date, clinical trials of different CAR-T products have not been aligned on CRS grading scales and management algorithms. We assessed concordance between the Penn, Lee, and American Society for Transplantation and Cellular Therapy (ASTCT) grading systems by retrospectively regrading CRS events in the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Four medical experts with experience treating patients with 3 different CAR-T products independently regraded individual patient-level CRS events from the phase 2, global, pivotal JULIET trial (#NCT02445248). As of 8 December 2017, a total of 111 patients with r/r DLBCL underwent infusion with tisagenlecleucel. Sixty-four patients had CRS events graded per the Penn scale; on retrospective review, 63 and 61 patients had CRS events regraded per the Lee and ASTCT criteria, respectively. The Lee scale yielded concordance for 39, lower grade for 20, and higher grade for 5 events compared with the Penn scale. The ASTCT criteria provided concordance for 37, lower grade for 23, and higher grade for 4 events compared with the Penn scale. Sixteen (14%) of 111 patients in the JULIET trial received tocilizumab, all for severe events (Penn grade 3/4 CRS). This study is the first to assess concordance between 3 CRS grading scales using the same patient data set and to compare tocilizumab use according to the Lee scale in the JULIET trial and the ZUMA-1 (Long-Term Safety and Activity of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma) trial. This analysis describes key differences between grading scales and may inform CRS management practices.

Conflict of interest statement

Conflict-of-interest disclosure: S.J.S. reports consultancy, honoraria, membership on an entity’s Board of Directors or advisory committees, and research funding from Celgene; consultancy and honoraria from Dava Oncology; honoraria and research funding from Genentech; membership on an entity’s Board of Directors or advisory committees for Gilead and Pfizer; consultancy, honoraria, and research funding from Merck; honoraria, membership on an entity’s Board of Directors or advisory committees, and research funding from Novartis; consultancy, honoraria, and membership on an entity’s Board of Directors or advisory committees from Nordic Nanovector; and honoraria from OncLive and Physicians’ Education Source, LLC. R.T.M. reports honoraria, membership on an entity’s Board of Directors or advisory committees, and research funding from Novartis; consultancy and honoraria from CRSPR Therapeutics, Incyte, and Juno Therapeutics; honoraria from Kite Therapeutics; patents and royalties from Athersys, Inc.; and employment by Oregon Health & Science University. R.T.M. also provided consultant services to and received payment from Novartis; this potential conflict of interest has been reviewed and managed by Oregon Health & Science University. E.S.R. is employed by Novartis. J.L. and J.E.S. are employed by the Analysis Group, Inc., which received funding from Novartis. V.V.R. is employed by Novartis. F.L.L. is a scientific advisor for Kite Pharma and Novartis; and reports consultancy for the Cellular BioMedicine Group Inc. D.G.M. receives research funding from Kite Pharma, a Gilead Company, and Celgene; receives research funding from and has patents licensed or pending with Juno Therapeutics, a Celgene/Bristol-Myers Squibb company; has participated in advisory board and/or protocol-specific data monitoring committee meetings for BioLine RX, Kite Pharma, Gilead, Genentech, Novartis, Juno Therapeutics, and Celgene and received honoraria; and is a member of the A2 Biotherapeutics Scientific Advisory Board and has stock options.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Regrade of JULIET trial patient-level data showed 64 patients as having any-grade CRS by Penn scale, 63 patients by Lee scale, and 61 patients by ASTCT criteria. (A) Frequency of CRS event grades by the Penn, Lee, and ASTCT grading scales (N = 111). The numbers inside of the columns refer to absolute number of patients. (B) Cross-classification of CRS according to the 3 grading scales: Penn, Lee, and ASTCT.

Figure 2.

Number of patients by maximum CRS grade by Lee scale who did or did not receive tocilizumab in the JULIET and ZUMA-1 trials. JULIET: Of the 16 patients who received tocilizumab in JULIET, 6 patients received 1 dose and 10 patients received 2 doses. ZUMA-1: Of the 49 patients who received tocilizumab in ZUMA-1, 30 patients received 1 dose, 13 patients received 2 doses, 2 patients received 3 doses, 2 patients received 4 doses, and 2 patients received 5 doses.