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

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.

Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells.

CD19-targeted chimeric antigen receptor-modified T cell (CAR-T cell) therapy has shown excellent antitumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy remain unknown. Here we report late adverse events-defined as starting or persisting beyond 90 days after CAR-T cell infusion-in patients who survived at least 1 year after therapy. The median duration of follow-up was 28.1 months (range, 12.5 to 62.6 months). At last follow-up, 73% of patients were still alive and 24% were in ongoing complete remission (CR). The most common late adverse event was hypogammaglobulinemia (IgG <400 mg/dL or i.v immunoglobulinm (IVIG) replacement, observed in 67% of the patients with available data. Infection density was .55 infection/100 days at risk (2.08 per patient-year). The majority (80%) of the infections were treated in the outpatient setting, and 5% necessitated admission to the intensive care unit (ICU). Subsequent malignancies occurred in 15% of patients, including 5% with myelodysplastic syndrome (MDS). Among patients with ongoing CR and with no MDS, 16% experienced prolonged cytopenia requiring transfusions or growth factor support. Graft-versus-host disease occurred in 3 of 15 patients (20%) who had undergone previous allogeneic hematopoietic cell transplantation. Most of the late events observed in this cohort were not severe, and many could be related to previous or subsequent therapies, suggesting a safe long-term profile of CD19-targeted CAR-T cell immunotherapy.