Impact of Pre-Existing Mental Health Disorders (MHD) on CAR T-Cell Therapy Outcomes in Patients with Large B-Cell Lymphoma
Authors: Gouni Sushanth , Lionel Anath , Feng Lei , Gaulin Charles , Reddy Tejaswini , Gonugunta Amrit S. , Chu Victoria , Hopper Taylor , Ayers Amy A. , Jackson Inimfon , Al Zaki Ajlan , Hildebrandt Michelle A.T. , Nastoupil Loretta , Chihara Dai , Nze Chijioke , Ramdial Jeremy , Shpall Elizabeth J. , Westin Jason R. , Flowers Christopher R. , Strati Paolo , Neelapu Sattva S. , Lynn Rachel , Ahmed Sairah 
Published: December 2024

Introduction
Chimeric antigen receptor T-cell therapy (CAR-T) has improved outcomes for relapsed/refractory (r/r) large B-cell lymphoma (LBCL) but is associated with a unique toxicity profile. Pre-existing mental health disorders (MHD) negatively impact prognosis in various hematological malignancies, including de-novo LBCL. However, the effect of MHDs on outcomes in r/r LBCL treated with CAR-T remains unexplored. Given the expansion of indications and number of patients eligible for CAR-T, MHD represents a potentially modifiable risk factor and evaluation of this relationship is an unmet need.
Methods
This single-center retrospective study included adult patients with r/r LBCL who received CAR-T from 2018 to 2023. Pre-existing MHD was defined as any DSM-5 psychiatric illness requiring treatment or counseling within 4 weeks prior to CAR-T infusion. Baseline patient characteristics, disease, and CAR-T variables were obtained from institutional databases, while MHD variables, psychotropic drug usage, and clinical correlates extracted via chart review. Prolonged hospital admission was defined as &gt;30 days. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria, with severe CRS and ICANS defined as grade ≥3. CAR-T response was assessed per Lugano 2014. Patient data were summarized descriptively. Associations were evaluated using Chi-square, Fisher's exact, or Wilcoxon rank-sum tests. Kaplan-Meier and Log-rank tests analyzed PFS and OS, with Cox models for multivariable analysis. Logistic regression estimated covariate effects on severe CRS/ICANS
Results
441 LBCL CAR-T recipients were identified, of which 153 (35%) had a pre-existing MHD. The cohort comprised of 297 (67%) males, 342 (79%) White, 25 (6%) Black, and 24 (5%) Asians. 68 (16%) identified as Hispanics/Latinos. 288 (76%) had stage ≥ III disease, 40 (16%) had ECOG ≥ 2, 176 (58%) had an international prognostic index (IPI) ≥3, and 237 (69%) had a lactate dehydrogenase level (LDH) &gt; upper limit of normal (UNL). 380 (86%) received axicabtagene ciloleucel, 42 (10%) received lisocabtagene maraleucel, 19 (4%) received tisagenlecleucel. 206 (54%) required bridging therapy, 74 (17%) had prolonged hospital stays, and 127 (29%) required ICU care.
Compared to patients without MHD, those with MHD were more likely to be female (40% vs. 29%, p=0.0185), have higher rates of prolonged hospitalization &gt;30 days (26% vs. 12%, p=0.0001) and ICU admissions (42% vs. 22%, p&lt;0.0001). No statistically significant differences were found with respect to race, performance status, BMI, substance use, distance from treating facility, stage, IPI, LDH, refractory disease status, prior hematopoietic stem cell transplant, prior CNS directed therapy including use of IT chemotherapy, intracranial radiation, or CAR-T product.
Patients with MHD had a higher incidence of grade ≥3 CRS (19% vs. 9.4%, p=0.0040) and grade ≥3 ICANS (51% vs. 26%, p&lt;0.0001), as well as higher use of anakinra (14% vs. 5%, p=0.0019) and corticosteroids (65% vs. 46%, p=0.0001) for CAR-T related toxicity. Multivariable logistic regression indicated that patients with MHD had 2.19 times higher odds of severe CRS (OR=2.19, 95% CI: 1.24-3.86; p=0.0071) and 2.84 times higher odds of severe ICANS (OR=2.84, 95% CI: 1.88-4.30; p&lt;0.0001) compared to those without MHD with adjustment of CAR-T product.
After a median follow up of 19.8 months (95% CI: 16.8 ~ 24.6 months), there was no significant difference in OS and PFS when comparing patients with MHD vs no MHD from multivariable Cox proportional hazard models; HR = 1.34, 95% CI: 0.99 ~ 1.82; p = 0.063) and HR =1.20 95% CI: 0.94~ 1.53; p = 0.14 respectively. 90 day complete response rate was not different between MHD and non-MHD (46% vs 51%; p=0.32).
Conclusions
To our knowledge, this is the largest study to date examining the impact of MHD in adult patients with r/r LBCL receiving CAR-T cell therapy. Patients with MHD experienced higher rates of severe CRS and ICANS, prolonged hospitalization and increased rate of ICU admissions, however the overall efficacy of CAR-T was comparable to patients without MHD. This data supports access to CAR-T for patients with MHD and underscore the need for integrated psychiatric care and close monitoring to reduce adverse events. Future research should assess if targeted interventions can mitigate CAR-T related toxicity in patients with MHD.