Neurotoxicity—CAR T-cell therapy: what the neurologist needs to know

2020 ◽  
Vol 20 (4) ◽  
pp. 285-293 ◽  
Author(s):  
Lorna Neill ◽  
Jeremy Rees ◽  
Claire Roddie

Chimeric antigen receptor (CAR) T-cell therapy is one of the most innovative therapies for haematological malignancies to emerge in a generation. Clinical studies have shown that a single dose of CAR T-cells can deliver durable clinical remissions for some patients with B-cell cancers where conventional therapies have failed.A significant complication of CAR therapy is the immune effector cell-associated neurotoxicity syndrome (ICANS). This syndrome presents a continuum from mild tremor to cerebral oedema and in a minority of cases, death. Management of ICANS is mainly supportive, with a focus on seizure prevention and attenuation of the immune system, often using corticosteroids. Parallel investigation to exclude other central nervous system pathologies (infection, disease progression) is critical. In this review, we discuss current paradigms around CAR T-cell therapy, with a focus on appropriate investigation and management of ICANS.

Author(s):  
Raphael Teipel ◽  
Frank P Kroschinsky ◽  
Michael Kramer ◽  
Theresa Kretschmann ◽  
Katharina Egger-Heidrich ◽  
...  

Inflammation plays an important role in CAR-T-cell therapy, especially in the pathophysiology of cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Clonal hematopoiesis of indetermined potential (CHIP) has also been associated with chronic inflammation. The relevance of CHIP in the context of CAR-T-cell treatment is currently widely unknown. We longitudinally evaluated the prevalence of CHIP, using a targeted deep sequencing approach in a cohort of patients with r/r B-NHL before and after CAR-T-cell treatment. The aim was to define the prevalence and variation of CHIP over time and to assess the influence on clinical inflammation syndromes (CRS/ICANS), cytopenia and outcome. Overall, 32 patients were included. CHIP was found in 11 of 32 patients (34 %) before CAR-T-cell therapy. CHIP progression was commonly detected in the later course. Patients with CHIP showed a comparable response rate to CAR-T-cell treatment but had an improved OS (not reached vs. 265 days, p=0.003). No significant difference was observed in terms of the occurrence and severity of CRS/ICANS, therapeutic usage of tocilizumab and glucocorticosteroids, paraclinical markers of inflammation (except ferritin) or dynamics of hematopoietic recovery. CHIP is commonly observed in patients undergoing CD19-directed CAR-T-cell therapy and is not associated with an inferior outcome.


2021 ◽  
Vol 12 ◽  
Author(s):  
Lele Miao ◽  
Zhengchao Zhang ◽  
Zhijian Ren ◽  
Yumin Li

The application of chimeric antigen receptor (CAR) T-cell therapy as a tumor immunotherapy has received great interest in recent years. This therapeutic approach has been used to treat hematological malignancies solid tumors. However, it is associated with adverse reactions such as, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), off-target effects, anaphylaxis, infections associated with CAR-T-cell infusion (CTI), tumor lysis syndrome (TLS), B-cell dysplasia, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) and coagulation disorders. These adverse reactions can be life-threatening, and thus they should be identified early and treated effectively. In this paper, we review the adverse reactions associated with CAR-T cells, the mechanisms driving such adverse reactions, and strategies to subvert them. This review will provide important reference data to guide clinical application of CAR-T cell therapy.


ESMO Open ◽  
2020 ◽  
Vol 4 (Suppl 4) ◽  
pp. e000746 ◽  
Author(s):  
Lucrecia Yáñez ◽  
Ana Alarcón ◽  
Miriam Sánchez-Escamilla ◽  
Miguel-Angel Perales

Chimeric antigenreceptor (CAR) T cell therapy has demonstrated efficacy in B cell malignancies, particularly for acute lymphoblastic leukaemia (ALL) and non‑Hodgkin lymphomas. However, this regimen is not harmless and, in some patients, can lead to a multi organ failure. For this reason, the knowledge and the early recognition and management of the side effects related to CAR-T cell therapy for the staff is mandatory. In this review, we have summarised the current recommendations for the identification, gradation and management of the cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, as well as infections, and related to CAR-T cell therapy.


2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A692-A692
Author(s):  
Matthew Frigault ◽  
Megan Cartwright ◽  
Krista Marcello ◽  
Timothy Quill ◽  
Daniel DeAngelo ◽  
...  

BackgroundChimeric antigen receptor (CAR) T-cell therapy has been a major innovative breakthrough for hematologic malignancies. These therapies are associated with unique and potentially serious toxicities, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity (ICANS), that require vigilance, prompt recognition, and appropriate management to ensure patient safety and optimal therapeutic benefit. We developed an online tool to give healthcare providers (HCPs) case-specific, evidence-based expert guidance on the management of adverse events (AEs) from CAR T-cell therapy. Here, we report an updated analysis comparing CAR T-cell toxicity management among HCPs using the tool vs the expert consensus recommendations.1MethodsIn March 2019, 5 experts provided consensus guidance for the screening, prophylaxis, monitoring, and management of CRS and ICANS in patients considering or receiving CAR T-cell therapy. This information was used to build the interactive online tool. To use this tool, HCPs enter the AE of interest, the severity of the event,2 and their planned management approach. The HCPs were then shown the expert recommendation for that specific scenario. After viewing the expert recommendation, HCPs were asked if it affected their intended approach.ResultsBetween May 2019 and July 2020, 282 HCPs entered 431 unique case scenarios into the tool. Of the entered cases, 56% were HCPs seeking expert recommendations on pretreatment screening and prophylaxis/monitoring strategies for patients not yet experiencing an AE. Of 188 cases entered for patients who received CAR T-cell therapy and experienced an AE, 67% were CRS and 33% were neurotoxicity/ICANS. Overall the planned toxicity management strategy of HCPs matched the expert recommendations in 57% of cases, with a similar rate of concordance for both CRS and ICANS events. There was no significant difference in concordance rates with expert recommendations by toxicity severity (figure 1) nor among HCPs who indicated they practiced at authorized centers vs those who did not (P = 0.7184). Among HCPs who answered the optional survey on the impact of the tool on their management plan, 30% indicated that the expert recommendations changed their approach.Abstract 655 Figure 1Planned management of HCPs compared with expert recommendations, by gradeConclusionsThese data suggest that many HCPs are challenged to optimally manage CAR T-cell therapy toxicities in concordance with expert recommendations. Use of an online tool providing easy access to evidence-based consensus expert recommendations may improve care and safety in patients treated with CAR T-cell therapy. A detailed analysis of the tool including planned management vs expert recommendations for each toxicity and grade will be presented.ReferencesFrigault MJ, Cartwright M, Marcello K, Quill T, DeAngelo DJ, Galinsky IA, Paul S, Park JH. Management of CAR T-Cell toxicities: concordance and divergence between healthcare providers and expert recommendations. Blood 2019:134:2199.Lee DW, Santomasso BD, Lock FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019;25:625–638.


Author(s):  
Mei Luo ◽  
Hongchang Zhang ◽  
Linnan Zhu ◽  
Qumiao Xu ◽  
Qianqian Gao

Sign in / Sign up

Export Citation Format

Share Document