A079 - REAL-WORLD CLINICAL FEATURES OF NEUROTOXICITY COMPLICATING CD19-TARGETED CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY FOR HIGH GRADE LYMPHOMA AND MANAGEMENT INCLUDING THE OFF-LABEL USE OF ANAKINRA (ID 751)
- S. Inam
- S. Mangion
- V. Potter
- R. Benjamin
- A. Kuhnl
- R. Hadden
- R. Sanderson
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the main toxicities complicating CAR T-cell therapy. High dose steroids are the current standard of care, though there remains a clinical need for patients that are refractory to front line treatment. Animal models have supported cytokine targeting therapies that can cross the blood brain barrier such as the IL-1 receptor antagonist anakinra. We report our experience with ICANS in a cohort of patients receiving CD19 CAR T-cells, including the first series of patients treated with anakinra for ICANS.
Patients with relapsed/refractory B cell non-Hodgkin lymphoma received axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisagen) between Jan 2019 and September 2019. Eligibility was determined independently by a panel of clinical experts from NHS England and data collected prospectively. ICANS was graded according to ASTCT Consensus Grading.
A total of 43 patients received treatment (14 transformed FL, 2 PMBCL and 27 DLBCL): 38 received axi-cel and 5 tisagen. 14 of 43 patients (33%) experienced any grade of neurotoxicity, with 7 of 43 (16%) grade 3 or 4, lower than the rate reported in previous trials and real-world data. The most common clinical features were disorientation or confusion, dyspraxia and expressive dysphasia (n=9). Intensive care admission was required for 8 patients, with 3 requiring intubation.
Neuroimaging was performed in 13 patients: five patients with CT brain, five with CT and MRI brain, and three MRI. The only clear acute change was bilateral hippocampal enhancement for one patient on MRI, subsequently attributed to viral encephalitis. Lumbar puncture was performed in six patients: glucose and cytology was normal, with a mild rise in CSF protein (mean 0.96g/L, range 0.25-0.45g/L). One patient was diagnosed with HHV6 encephalitis. EEG was performed in 12 patients, with almost all (92%) displaying encephalopathic features (generalised rhythmic delta activity) and 2 (17%) with epileptiform foci over the left fronto-temporal region. No periodic discharges or seizures were captured.
High dose steroids (dexamethasone up to 40mg daily) was started for 11 patients for treatment of ICANS; all patients had received tocilizumab for prior or concurrent CRS. Anakinra was administered to five patients concurrently with steroids for ICANS that was high grade or not responsive to initial therapy with dexamethasone. The ICANS grade for these five patients at time of treatment was grade 3 for two patients, and grade 4 for three patients. Anakinra was given as 200mg daily subcutaneously, started at a median of 3 days (range 1 to 5) after the commencement of dexamethasone for ICANS treatment, and median number of 5.4 doses given (range 3 to 8). ICANS resolved in all patients surviving to day 30 (n=13), with persistent neurological features in one patient likely sequelae of viral encephalitis and one treatment related death (sepsis).
We describe the clinical features of ICANS in our real-world cohort of patients receiving standard of care CD19 CAR T-cells, and demonstrate the feasibility of anakinra in combination with dexamethasone for treatment ICANS that is severe or not initially responsive to high dose steroids.
Nothing relevant to declare