Age defining immune effector cell associated neurotoxicity syndromes in aggressive large <scp>B</scp> cell lymphoma patients treated with axicabtagene ciloleucel

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment armamentarium of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Besides its outstanding efficacy, CAR T-cells carry unique immune-mediated adverse events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS); it has a wide spectrum of presentation ranging from aphasia, headache to seizure, and coma.1 Advanced age is identified as a potential predisposing factor of ICANS.2 However, whether age has a differential effect on ICANS manifestation is not well described. Herein, we report detailed neurologic presentations in R/R LBCL patients treated with axicabtagene ciloleucel (axi-cel) and the similarity/difference between older and younger patients to better characterize ICANS in older patients. We conducted a retrospective study including patients with R/R LBCL treated with axi-cel at Mayo Clinic, Rochester, MN, between June 2016, and October 2020. The axi-cel treatment process was in accordance with the productʼs package insert. We described the clinical course of ICANS, including neurologic manifestations, treatments, and outcomes. We divided patients into two age-groups according to their age at the time of infusion; younger (< 60 years) and older (≥ 60 years) groups, and compared their neurological outcomes. Neurologic presentations were stratified into different clusters using the Immune Effector Cell Encephalopathy (ICE) Score as the primary reference. Neurological symptoms which could not be characterized into ICE-based categories were classified as the independent entity (supplementary material). All patients underwent baseline brain magnetic resonance imaging (MRI) and neurological assessment by neurooncologists. Patients were assessed and managed by CAR T-providers using the standardized protocol. The severity of ICANS was reported according to the Common Terminology Criteria for Adverse Events version 4.03 (before January, 2019) and the American Society of Transplant Cellular Therapy (ASTCT) Consensus Criteria (after January, 2019). Incidence of ICANS was defined as the time from CAR T-cell infusion to the onset of ICANS with death from any causes being the competing event. The study was approved by the institutional review board of Mayo clinic. Continuous variables were described as median and range with comparison between groups by the Kruskal-Wallis test. Categorical variables were shown in percentage with comparison between groups by the chi-square or Fisher exact test. The cumulative incidence was analyzed by the competing-risk analysis. Cox proportional hazard analysis was performed to analyze for potential factors associated with ICANS and was reported as Hazard ratio with 95% confidence interval (95%CI). p-values < 0.05 were considered statistically significant. Seventy-eight patients with DLBCL received axi-cel during the study period. The median age at infusion was 58.8 years (26.8–76.5 years) with 32 patients (41%) being ≥ 60 years old. Baseline characteristics were comparable between age-groups except for a higher proportion of high international prognostic index, prior autologous stem cell transplant and underlying cerebral microvascular disease in older patients (Tables S1 and S2). Note, ICANS was observed in 40 patients (51.3%), including 16 and 24 in the older and younger age-groups, respectively. The 30-day incidence of ICANS was comparable between older and younger patients (50%, 95% CI 29.3%–64.6% vs. 52.2%, 95% CI 35.3%–64.6%, p = 0.73) (Figure 1). Also, ICANS grade 3 or higher were observed in 13 patients (n = 8; 17.4% in younger and n = 5; 15.6% in older group). Of 40 ICANS patients, 39 (97.5%) developed CRS preceding the onset of ICANS. The median time from CAR T-cell infusion to the onset of ICANS was similar between two age-groups (p = 0.42). The median time from the onset of ICANS to maximal ICANS severity was within 24 hours and was not statistically different between younger and older cohorts (p = 0.60). The distribution of neurological symptoms and maximal ICANS severity was similar between younger and older patients (Figure 1, Table S3). The three most common initial neurological abnormalities included aphasia, dysgraphia and confusion in both age-groups (Table S3). Speech and writing abnormalities were the most common symptoms in both age-groups. Headache and tremors were more frequent in older patients but not statistically different from younger patients. Of 40 patients with ICANS, two (5.0%) developed seizures (one subclinical non-convulsive seizure and one convulsive seizure). Radiologic investigations were performed after ICANS occurrence in 26 patients, including brain MRI in nine patients (five in the younger cohort and four in the older cohort). Abnormal MRI finding associated with ICANS (diffuse T2 enhancement in subcortical white matter) was noted in one patient from the older age-group who developed ICANS ASTCT grade 3 (Figure S1). Of all patients who developed ICANS, one patient (2.5%), from the younger age-group, required intubation due to severe altered mental status. Twenty-four patients (60.0%) received systemic steroids for the management of ICANS, including seven (17.5%) requiring pulse methylprednisolone for dexamethasone-resistant ICANS. The median total dose of corticosteroids (prednisone-equivalent) was 1.80 mg/m2/day, not different between younger and older patients (1.94 vs. 1.31 mg/m2/day, p = 0.65). Both younger and older patients received systemic corticosteroid for a median duration of 4 and 2 days, respectively (p = 0.54). Overall, there was no difference in ICANS treatment, and inflammatory markers (lactate dehydrogenase, c-reactive protein, ferritin) between age-groups (Tables S2 and S3). All ICANS resolved with the median duration of 5 days (1–20 days) comparable between the younger and older cohort cohorts (5 vs. 6 days, p = 0.18). The interval change of ICE score during the ICANS course was not different between age-groups (Figure S2). In the univariate Cox proportional hazard analysis (Supplementary Table S4), severe CRS grade ≥ 2 was the only factor associated with ICANS in the entire cohort and in the younger age-group but not in the older cohort. Poor performance status was also associated with higher risk of ICANS in younger patients. Otherwise, other factors including age, history of central nervous system (CNS) involvement, and underlying cerebral microvascular disease were not associated with ICANS. Relapse incidence, non-relapse mortality, event free survival and overall survival were similar irrespective of ICANS occurrence or age-groups (Figures S3 and S4). Our study explored the age effect on characteristics and outcomes of CAR T-cell associated ICANS. The incidence of ICANS in our cohort was 51.3%, comparable to previous studies.3 Recently, Lin et al. reported similar safety and tolerability of older patients with lymphoma treated with commercial CD19 CAR T-cells to younger patients aged 65 years old or younger.4 Since there were only 16 patients aged older than 65 years in our cohort (eight had ICANS), we performed the primary analysis using the age cut-off of 60 years old. Secondary analysis comparing < 65 versus ≥ 65 years-old patients showed similar findings (Tables S5–S8 and Figures S5–S7). Like previous studies, we observed no difference in the incidence and manifestations between two cohorts. So, ICANS had a highly variable clinical spectrum with aphasia, altered consciousness and agraphia being common neurological dysfunctions in both older and younger patients similar to previous reports.2 We also observed a high percentage of patients experiencing headaches and other extrapyramidal manifestations like the recent study.5 Although some neurologic presentations are not included in ICANS diagnostic criteria, they may result in considerable morbidity and be used to track ICANS progression. We did not see the correlation between ICANS and short-term outcomes although previous studies demonstrated the association between severe ICANS and poor outcomes.6 Besides the potential effect on neurological and survival outcomes, older patients might also be at a higher-risk of developing toxicities from treatments of ICANS. Currently, data on impact of ICANS including its treatments on long-term neurological status, and physical function are limited. There was no difference in treatment patterns between age-groups. However, due to the retrospective design, we did not have data on delayed neurological function, physical recovery, and quality of life of our patients. The long-term aspects of ICANS including predictive biomarkers and prophylactic strategies have been actively explored by several groups. In our cohort, the occurrence of CRS especially grade ≥2 was the only factor associated with the development of ICANS similar to other studies.1, 2 However, we did not observe the difference in the incidence of ICANS by the receipt of tocilizumab and corticosteroids for CRS management. Other than CRS, we did not observe the correlation between ICANS and other clinical factors. The limitations of our study include the retrospective design and small sample-size with limited implication to axi-cel. The retrospective abstraction of neurological symptoms could affect the distribution of ICANS presentations. However, the main study objective was to describe ICANS characteristics based on the cliniciansʼ observation but not to re-define it. The strengths of our study are that it is one of the largest cohorts that describes real-world data of ICANS and the first to highlight the effect of age on ICANS. In conclusion, ICANS was a common immune-mediated event that had a wide range of manifestation. The characteristics and short-term outcomes of ICANS were not affected by patientʼs age. Our findings could serve as a complimentary resource to develop patient-oriented management strategies of ICANS. Future studies integrating prospective outcome measurement, symptom monitoring and risk/biomarker-adapted intervention are warranted to improve treatment experience. We thank the patients and their families for their participation in our research study. We appreciate all the hard work, excellent patient care and data collection of the nursing staff, advanced practice providers, the staff at Mayo Clinic Cell Therapy Group at Rochester, MN. K.W. receives partial funding and sabbatical support from the King Chulalongkorn Memorial Hospital Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand. There are no fundings or grants associated with this work. Kitsada Wudhikarn, Arushi Khurana, Radhika Bansal, Matthew A. Hathcock, Sherri A. Braksick, Jonas Paludo, Jose C. Villasboas. and Patrick B. Johnston has no conflict of interest. Yucai Wang receives research funding from Incyte, InnoCare, Novartis, Genentech and serves on the advisory board of Eli Lilly. N. Nora Bennani served on advisory boards for Acrotech, Verastem, and Daiichi Sankyo, Inc. Yi Lin provides consultation service to Kite/Gilead, Celgene/BMS, Juno/BMS, BlueBird Bio, Janssen, Legend BioTech, Gamida Cells, Novartis, Lovance, Takeda, Fosun Kite, reports received research support from Kite/Gilead, Celgene/BMS, BlueBird Bio, Janssen, Legend Biotech, Merck, Takeda and Boston Scientific and served on Drug safety monitoring board of Sorrento. All financial supports and funding are paid to Mayo clinic. Kitsada Wudhikarn, and Yi Lin designed the study and wrote the manuscript. Kitsada Wudhikarn conducted the statistical analysis. Radhika Bansal, Arushi Khurana and Matthew A. Hathcock participated in data collection. Sherri A. Braksick, Arushi Khurana, N. Nora Bennani, Jonas Paludo, Yucai Wang, Jose C. Villasboas, Patrick B. Johnston, and Stephen M. Ansell took care of the patients. All the authors reviewed and approved the manuscript. The data will be available upon request to the corresponding author at [email protected]. Appendix S1. Supporting Information. Figure S1. Magnetic Resonance Imaging of Brain in a patient who developed ICANS. MRI brain shows diffuse T2 hyperintensity of the cerebral white matter, extending inferiorly to involve the external capsules and posterior internal capsules, and temporal lobes. Figure S2. Kinetics and trends of ICE score over the course of axicabtagene ciloleucel therapy of (A) the entire cohort, (B) age <60 versus ≥60 and (C) age <65 versus ≥65 years old Figure S3. Event free survival, overall survival, non-relapse mortality and relapse incidence as stratified by the occurrence of ICANS (A) Event free survival. (B) Overall survival. (C) Non-relapse mortality. (D) Relapse incidence Figure S4. Event free survival, overall survival, non-relapse mortality and relapse incidence as stratified by age cut-off <60 years versus ≥60 years old. (A) Event free survival. (B) Overall survival. (C) Non-relapse mortality. (D) Relapse incidence Figure S5. Event free survival, overall survival, non-relapse mortality and relapse incidence as stratified by age cut-off <65 years versus ≥65 years old. (A) Event free survival. (B) Overall survival (C). Non-relapse mortality. (D) Relapse incidence Figure S6. Distribution of ICANS (A) severity, (B) manifestation by age <65 versus ≥65 years old. (C) The incidence of ICANS by age as stratified by age <65 versus ≥65 years old (51.6% vs. 50.0%, p = 0.79) Figure S7. Distribution and overlapping features of ICANS manifestation by age <65 versus ≥65 years old Table S1. Baseline characteristics of 78 patients with aggressive B cell lymphoma treated with axicabtagene ciloleucel stratified by age <60 versus ≥60 years old Table S2. Characteristics of 40 patients who developed ICANS after axicabtagene ciloleucel stratified by age of CD19 CAR T-cell therapy by age <60 versus ≥60 years old Table S3. Detailed symptomatic characterization of ICANS as stratified by age <60 versus ≥60 years old Table S4. Cox proportional Hazard regression analysis of factors associated with the development of ICANS by age <60 versus ≥60 years old Table S5. Baseline characteristics of 78 patients with aggressive B cell lymphoma treated with axicabtagene ciloleucel stratified by age <65 versus ≥65 years old Table S6. Characteristics of patients who developed ICANS after axicabtagene ciloleucel stratified by age of CD19 CAR T-cell therapy stratified by age <65 versus ≥65 years old Table S7. Detailed symptomatic characterization of ICANS as stratified by age <65 versus ≥65 years old Table S8. Cox proportional Hazard regression analysis of factors associated with the development of ICANS Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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