Management of a patient with mantle cell lymphoma who developed severe neurotoxicity after chimeric antigen receptor T-cell therapy in ZUMA-2

Abstract

Cerebral edema following chimeric antigen receptor (CAR) T-cell therapy can be fatal. ZUMA-2 is a pivotal phase 2, multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T-cell therapy, in relapsed/refractory mantle cell lymphoma. We describe a 65-year-old patient in ZUMA-2 who developed cerebral edema following CAR T-cell therapy and had complete recovery after multimodality clinical intervention including rabbit antithymocyte globulin (ATG). Biomarker results show early and robust CAR T-cell expansion and related induction of inflammatory cytokines, followed by rapid declines in CAR T-cell and proinflammatory cytokine levels after ATG administration. This clinical profile highlights a potential relevance of ATG in treating severe CAR T-cell-related neurotoxicity.

Trial registration: ClinicalTrials.gov NCT02601313.

Keywords: case reports; chimeric antigen.

Conflict of interest statement

Competing interests: MW: honoraria from Pharmacyclics, Janssen, AstraZeneca, OMI, and Targeted Oncology; consultancy or advisory role for Pharmacyclics, Celgene, Janssen, AstraZeneca, MoreHealth, Pulse Biosciences, Nobel Insights, and Guidpoint Global; research funding from Pharmacyclics, Janssen, Novartis, Juno, Celgene, Loxo Oncology, VelosBio, and Verastem; expert testimony for AstraZeneca; and travel support from Janssen, Pharmacyclics, Celgene, and OMI. TLC: honoraria from Kite, a Gilead Company; consultancy or advisory role for Kite, a Gilead Company. AH: employment at M.D. Anderson; stock or other ownership in Caris; consultancy or advisory role for Caris and WCG Oncology; research funding from Merck; patents, royalties, or other intellectual property from Celldex. LZ and AVR: employment with Gilead Sciences. JMR: employment with Kite, A Gilead Company; stock or other ownership in Gilead Sciences.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Timeline of clinical events and interventions in the patient treated with ATG. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATG, antithymocyte globulin; BID, two times per day; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; FLAIR, fluid-attenuated inversion recovery; N/A, not available.

Figure 2

Levels of transaminases, CAR T cells, and cytokines over time. (A) ALT levels in the patient with ATG across the first 17 days post-KTE-X19. (B) Levels of CAR T cells in blood by PCR over the first 6 months following KTE-X19 infusion. In the broader ZUMA-2 population, 66, 65, 59, 65, and 43 patients had data available at days 0 (pre-KTE-X19), 7, 14, 28, and 180, respectively. Levels of IFN-γ (C) and MCP-1 (D) by ELISA over the first 28 days post-KTE-X19. In the broader ZUMA-2 population, 65, 65, 62, 61, 60, and 64 patients had data available at days −4 (pre-conditioning), 0 (pre-KTE-X19), 7, 14, 28, and 180, respectively. ALT, alanine aminotransferase; ATG, anti-thymocyte globulin; CAR, chimeric antigen receptor; ELISA, enzyme-linked immunosorbent assay; IFN-γ, interferon gamma; IL-2, interleukin 2; LOD, limit of detection; MCP-1, monocyte chemoattractant protein 1.