CAR T-Cell Therapy in the Older Person: Indications and Risks.

PURPOSE OF REVIEW: Validated metrics to optimize older adult patient selection for Chimeric Antigen Receptor T-cell therapy (CART) are lacking; however, some preliminary data suggests that geriatric assessments and cumulative illness rating score may be useful tools. In addition, interventions capable of enhancing outcomes in older adults receiving CART have yet to be elucidated. The purpose of this review is to present data extrapolating from other diseases and therapeutic modalities, related to product selection, toxicity mitigation strategies, comprehensive coordinated models of care, and functional optimization of patients. RECENT FINDINGS: The most robust data in older adults are among relapsed and refractory (r/r) diffuse large B-cell lymphoma (DLBCL) patients where three products are available with the longest clinical follow up and the most abundant real-world evidence (RWE). Data for the approved CART products for follicular lymphoma (FL) and mantle cell lymphoma (MCL) are relatively new and RWE is lacking in general. Data for CART products in multiple myeloma (MM) and B-cell acute lymphoblastic leukemia (B-ALL) are even more recent, but preliminary data in older adults seem to follow the trend of excellent efficacy in this age group with age-stratified toxicity data limited. Landmark trials and RWE studies indicate that the high response rates of CART for older adult patients, age 65 years and older, are maintained, while toxicity may be amplified. Clinically important toxicities include grade 3 or higher cytokine release syndrome (CRS), neurotoxicity, and infections.

A validated composite comorbidity index predicts outcomes of CAR T-cell therapy in patients with diffuse large B-cell lymphoma.

Chimeric antigen receptor T-cell therapy (CART) has extended survival of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, limited durability of response and prevalent toxicities remain problematic. Identifying patients who are at high risk of disease progression, toxicity, and death would inform treatment decisions. Although the cumulative illness rating scale (CIRS) has been shown to correlate with survival in B-cell malignancies, no prognostic score has been independently validated in CART recipients. We retrospectively identified 577 patients with relapsed/refractory DLBCL indicated for CART at 9 academic centers to form a learning cohort (LC). Random survival forest modeling of overall survival (OS) and progression-free survival (PFS) was performed to determine the most influential CIRS organ systems and severity grades. The presence of a severe comorbidity (CIRS score ≥ 3) in the respiratory, upper gastrointestinal, hepatic, or renal system, herein termed "Severe4," had the greatest impact on post-CART survival. Controlling for other prognostic factors (number of prior therapies, Eastern Cooperative Oncology Group performance status, BCL6 translocation, and molecular subtype), Severe4 was strongly associated with shorter PFS and OS in the LC and in an independent single-center validation cohort (VC). Severe4 was also a significant predictor of grade ≥3 cytokine release syndrome in the LC, while maintaining this trend in the VC. Thus, our results indicate that adverse outcomes for patients with DLBCL meant to receive CART can be predicted using a simplified CIRS-derived comorbidity index.