Impact of Neurological and Psychiatric Comorbidities on Toxicity and Outcomes of Patients with DLBCL Who Receive Axicabtagene Ciloleucel
Authors: Albuquerque Rebecca , Shamis Anna , Tsalatsanis Athanasios , Kumar Ambuj , Ahmad Zain , Ovais Hasiq , Lazaryan Aleksandr , Khimani Farhad , Faramand Rawan , Freeman Ciara Louise , Shah Bijal D , Gaballa Sameh , Chavez Julio C. , Perna Fabiana , Ochoa-Bayona Jose L. , Locke Frederick L. , Jain Michael D. , Nishihori Taiga , Mirza Abu-Sayeef 
Published: December 2024

Introduction:
Axicabtagene ciloleucel (axi-cel) is a CD-19-directed chimeric antigen therapy (CAR) T-cell therapy that has demonstrated efficacy in several malignancies including relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain significant treatment related adverse events. In particular, the predictors of ICANS remain elusive. We hypothesized that neurological or psychiatric comorbidities may impact post-CAR-T toxicities and outcomes.
Methods:
We conducted a retrospective study of patients with R/R DLBCL who received commercial axi-cel at Moffitt Cancer Center in 2015-2023. Information on clinically significant pre-existing neurological and psychiatric comorbidities requiring medical management prior to axi-cel infusion were captured. Neurological comorbidities included cerebrovascular disease, demyelinating disorder, migraine, neurological infection, epileptic disorder, neurological neoplasms, neuromuscular disorder, and neuropathy. Psychiatric comorbidities included neurodevelopmental disorder, psychotic disorder, mood disorder, anxiety disorder, neurocognitive disorder, and insomnia. Cumulative incidences of toxicities were calculated for patients with and without comorbidities. Cox proportional hazards model and Kaplan Meier estimates were used to study survival post-CAR-T cell therapy.
Results:
From 279 patients with R/R DLBCL, the median age was 65 years (range: 20-86 years) and 61% were men. Nearly 50% of patients (139/279) had neurological comorbidities and 35% of patients (98/279) had psychiatric comorbidities.
Incidence of any grade CRS for patients with neurological comorbidities was 86%, with 6% experiencing grade 3-5 CRS compared to patients without neurological comorbidities with an incidence of 93% any grade CRS with 4% experiencing grade 3-5 CRS. Incidence of any grade ICANS for patients with neurological comorbidities was 60%, with 25% experiencing grade 3-5 ICANS, compared to patients without neurological comorbidities had an incidence of any grade ICANS of 56%, with 22% patients experiencing severe ICANS. Median duration of ICANS was 5 (range: 1-92) days compared to 3 (range: 1-59) days for patients with and without neurological comorbidities, respectively (p=0.27). Having a history of neurological comorbidity did not predict for development of CRS (p=0.07) or ICANS (p=0.45).
Incidence of all grades of CRS for patients with psychiatric conditions was 91%, with 7% experiencing grade 3-5 CRS compared to an incidence of 89% with 4% experiencing grade 3-5 CRS for patients without psychological comorbidities. Incidence of any grade of ICANS was 62%, with 24% experiencing grade 3-5 ICANS compared to any grade ICANS of 56% with 24% experiencing severe ICANS for patients without psychiatric comorbidities (p=0.32). Median duration of ICANS was 3 (range: 1-61) days compared to 5 (range: 1-92) days for patients with and without psychiatric comorbidities, respectively. Having a psychiatric history did not predict for development of CRS (p=0.69) or ICANS (p=0.33).
Patients with neurological comorbidity had worse overall survival (OS), HR 1.39, 95% CI 1.02 - 1.91, (p = 0.04) but psychiatric comorbidity did not impact OS (p=0.81). Among patients who experienced ICANS, patients with neurological comorbidity did not have significantly different OS (p=0.4). However, among patients who did not experience ICANS, patients with neurological comorbidities had decreased OS at 3 years compared to patients without neurological comorbidities (p=0.03). There was no difference in progression free survival (PFS) for patients with neurological (p=0.7) and psychiatric (p=0.8) comorbidities.
Conclusions:
Neurological and psychiatric comorbidities are common but do not seem to impact the incidence or severity of CRS and ICANS. However, patients with neurological comorbidities had worse OS but there was no difference in PFS, warranting further investigation. Patients with neurological comorbidities who did not experience any ICANS had increased mortality, implicating that the lack of toxicity may be due to the lower CAR-T cell activity. Future studies will explore the management of neuro-psych comorbidities before, during, and after ICANS and its impact on post-CAR-T complications.