Prehabilitation prior to CAR T-cell therapy in non-Hodgkin lymphoma: Baseline physical function and toxicity outcomes

Abstract Background Emerging evidence suggests that baseline physical function may predict the toxicity of chimeric antigen receptor (CAR) T-cell therapy; however, there is no consensus on how best to evaluate physical function in this setting. The prehabilitation program at MD Anderson Cancer Center (MDACC) assesses patients 65 years and older or those with impairment prior to CAR T-cell therapy to assess baseline physical function and optimize physical activity and nutrition, aiming to improve function and reduce treatment-related complications of cellular therapy. This study evaluates the association of baseline physical function with the risk of CAR T-cell-related toxicity outcomes in patients with non-Hodgkin lymphoma (NHL). Methods This is a retrospective single-center study of patients with NHL at MDACC who were evaluated in the prehabilitation program (consisting of comprehensive evaluation by physical medicine and rehabilitation and physical therapy) prior to CAR T-cell therapy between June 2021 and December 2024. Baseline physical function measures included 6-minute walk test (6MWT), five times sit to stand (5XSTS), 10-meter walk test (10MWT), timed up and go (TUG) test, activity measure for post-acute care (AM-PAC) score, and the Edmonton Symptom Assessment Scale (ESAS). Associations between these measures and CAR T-cell toxicity and outcomes, including occurrence and grade of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), hospital length of stay (LOS), ICU admission, discharge disposition, and 90-day readmission, were assessed with univariable and multivariable logistic regression models. Physical function variables were analyzed as dichotomous variables using published normative cutoffs. Multivariable models were adjusted for age, race, sex, lymphoma subtype and CAR T-cell product. Results A total of 131 patients with NHL underwent baseline prehabilitation evaluation prior to CAR T-cell therapy. The median age was 73 years (range 52-86), 70% (n=92) were male, and 91% (n=119) were Caucasian. The majority had large B-cell lymphoma (LBCL, n=99, 76%), followed by mantle cell lymphoma (n=19, 15%), and follicular lymphoma (n=10, 8%). Patients had received a median of two prior lines of therapy (range 1-5). CRS occurred in 103 patients (79%; grade 1, 47%; grade 2, 24%; grade 3, 4%; grade 4, 3%) and ICANS occurred in 68 patients (52%, grade 1, 15%; grade 2, 9.2%; grade 3, 24%, grade 4, 5%). The median hospital LOS was 15 days (range 3-76), 23 patients (18%) required ICU admission, and a majority of patients were discharged home (n=115, 88%), with 11 (8.4%) being discharged to a skilled nursing facility or inpatient rehabilitation. Thirty-seven patients (28%) were re-admitted within 90 days of CAR T-cell infusion. In the multivariable model, shorter 6MWT (<400 meters, odds ratio [OR]: 3.03, 95%CI: 1.33-6.67), slower 10MWT (<1 m/s, OR: 4.55, 95%CI: 1.64-11.1) and longer TUG (≥12 seconds, OR: 11.4, 95%CI: 2.07-62.9) were associated with a significantly increased risk of ICANS. Shorter 6MWT (OR: 4.76, 95%CI: 2.08-11.1) and slower 10MWT (OR: 3.85, 95%CI: 1.49-10.0) were also associated with a longer hospital length of stay. Patients with TUG ≥12 seconds had a significantly higher risk of ICU admission (OR: 4.37, 95%CI: 1.06-18.1) and discharge disposition other than home (OR: 11.2, 95%CI: 1.9-66.2). In contrast, 5XSTS, AM-PAC score, and the ESAS showed no significant association with outcomes. Conclusion This study demonstrates that baseline physical function, as measured by 6MWT, 10MWT, and TUG test, is significantly associated with the risk of ICANS and hospital length of stay in patients receiving CAR T-cell therapy for NHL. Worse performance on the TUG test was additionally associated with an increased risk of ICU admission and non-home discharge. These findings add to the growing evidence of the importance of a comprehensive physical function assessment to appropriately risk stratify patients and guide tailored strategies to reduce the risk of treatment-related morbidity of cellular therapy. Prospective studies are critical to evaluate whether interventions aimed at improving baseline physical function in frail patients can improve outcomes with CAR T-cell therapy.

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