Frailty's Impact on CAR T-Cell Therapy Outcomes in Patients with Lymphoprolipherative Disorders: Insights from a Spanish Multicenter Pilot Study Conducted on Behalf of the Geth-CT
Authors: Salas Maria Queralt , Ayora Pilar , Ramos Carla , Martinez-Cibrian Nuria , Albiol Nil , Diaz Aizpun Carola , Herruzo Beatriz , Fernandez-Luis Sara , Vega Suárez Leddy Patricia , Abdallahi Lefdil Zahra , Illana Álvaro Veronica , Quintela González María del Carmen , Santamaria Ana , Sanchez Salinas Andres , Alarcón Tomás Ana , Mussetti Alberto , Filafferro Silvia , Balsalobre Pascual , Cedillo Angel , Sureda Balari Ana Maria 
Published: December 2024

Introduction
Limited studies have investigated the impact of frailty on patients undergoing chimeric antigen receptor (CAR) T-cell therapies; all of them showing that frailty correlates with worse outcomes, and suggesting that frailty assessment could be valuable for these patients.
Since June 2023, 7 institutions from the Spanish Group of Hematopoietic Transplantation and Cellular Therapy have been involved in a multicenter, observational, and prospective study to investigate frailty status in adult patients eligible for commercial CAR T-cell therapies and evaluate its impact on therapy outcomes. This abstract summarizes preliminary data collected during the study's first year in a cohort of adults diagnosed with B-Cell Non-Hodgkin Lymphoma (NHL).
Methods
All patients eligible for commercial CAR T-cell therapies were considered eligible for frailty evaluation and included in the study after providing informed consent. For this analysis, only patients NHL were included.
Frailty was assessed at the first consultation (before lymphapheresis) and at CAR T-cell admission using the HCT Frailty Scale. Patients were classified as fit, pre-frail, or frail based on the assessment results. Frailty evaluations were conducted by existing teams of hematologists and nurses without external resources and funding. The median evaluation time per patient was 8-10 minutes, including cognitive (Mini-Cog test) and quality of life (EQ-5D-3L) tests.
Results
A total of 36 adults (17 males and 19 females) with NHL and candidates for commercial CAR T-cell therapies were included in this analysis. The median age was 61 (range: 28-76). Most patients (&gt;85%) were consulted for axicabtagene ciloleucel CAR T-cell therapy. The median time from first consultation to CAR T-cell admission was 41 days (IQR: 21-61). During this period, 88% of patients received at least one cycle of bridge therapy, and 79% underwent CAR T-cell treatment with active disease or progression.
At the first consultation, 7 (19%) patients were classified as fit, 22 (62%) as pre-frail, and 7 (19%) as frail. At CAR T-cell admission, the classification was 8 (22.2%) fit, 16 (44.4%) pre-frail, and 12 (33.3%) frail. Interestingly, some patients transitioned between frailty categories between the first consultation and admission. Specifically, 43% (n=4) of the fit patients remained fit, while 4 (57%) changed to a pre-frail state. Of the 22 pre-frail patients, 23% (n=5) improved to a fit state, 50% (n=11) remained pre-frail, and 27% (n=6) progressed to a frail state. Most frail patients remained frail (n=6, 86%), with only 1 (14%) improving to a pre-frail state.
Frailty's impact on therapy outcomes was assessed based on the frailty status at admission. The proportions of grades 2-4 and 3-4 cytokine release syndrome in fit, pre-frail, and frail patients were 50%, 33%, and 50% (P=0.874) and 0%, 0%, and 8.3% (P=0.325), respectively. There was a trend towards a higher incidence of grades 2-4 and 3-4 immune effector cell-associated neurotoxicity syndrome in frail patients compared to fit and pre-frail ones (Grades 2-4: 67% vs. 20% and 33%, P=0.065; Grades 3-4: 41.7% vs. 12.5% and 0%, P=0.074). ICU admission (50% vs. 24% and 26.7%, P=0.354) and subsequent readmission (50% vs. 0% and 26.7%, P=0.372) were higher in frail patients than in fit and pre-frail ones.
Quality of life assessments at admission in 30 patients (7 fit, 12 pre-frail, and 11 frail) revealed better auto-recorded global health scores in fit patients compared to pre-frail and frail ones (80%, 65%, and 50%, P=0.021).
With a median follow-up of 132 days, 11 (30.5%) patients relapsed, and 8 (22.2%) died. Relapse (50.0% vs. 12.5% and 26.7%, P=0.026) and death (50.0% vs. 12.5% and 13.2%, P=0.050) rates were higher in frail patients than in fit and pre-frail ones. After six months of therapy, OS and RFS of fit, pre-frail, and frail patients were 87.5% and 87.5%, 78.7% and 62.3%, and 48.9% (P=0.069) and 37.0% (P=0.035).
Conclusion
Preliminary results from this multicenter pilot study highlight differences in frailty status among patients with NHL from first consultation to CAR T-cell admission and reveal a significant association between frailty status and therapy outcomes. Continued research and additional studies are needed to refine these findings and develop interventions to mitigate frailty risks in CAR T-cell therapy patients.