CAR T-cell therapy outcomes in adolescent and young adult patients with non-Hodgkin lymphoma

Abstract Background Chimeric antigen receptor (CAR) T-cell therapies have shown significant clinical benefit for patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL), demonstrating durable remissions in heavily pretreated and treatment-refractory populations. However, most clinical trials have predominantly enrolled older adults, leaving a gap in knowledge regarding age-specific outcomes, particularly for adolescents and young adults (AYAs), defined by the National Cancer Institute as those aged 15–39 years (y). NHL in AYAs is clinically distinct in terms of tumor biology and immune function, with this population experiencing different toxicity profiles and psychosocial needs compared to both their pediatric (<15y) and older adult (≥40y) counterparts. There is a paucity of information on CAR T-cell outcomes in AYAs with NHL, particularly in comparison to older adults. We sought to address this knowledge gap by comparing age-related differences in efficacy, toxicity, and disease-related outcomes associated with CAR T-cell therapy for NHL across age groups within a real-world, single-institution cohort. Methods This was a retrospective matched cohort analysis that included all patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) treated with a CD19-directed CAR T cell product at City of Hope between 2015 and 2024. A total of 49 AYAs were matched 1:6 to 294 non-AYA controls on sex, lymphoma subtype, and year of CAR T-cell therapy. We estimated the adjusted hazard ratio (aHR) for progression-free survival (PFS) comparing AYA to non-AYA using multivariable Fine-Gray subdistribution hazard regression treating death as competing risk, and the aHR for overall survival (OS) using multivariable Cox proportional hazards regression, both adjusted for significant covariables. Conditional logistic regression accounted for the matching factors and other significant covariables was used to estimate the Odds Ratio (OR) of AYA to non-AYA for toxicity profiles, including rates and severity of cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and prolonged cytopenias. Results The mean age was 31y (standard deviation (sd) 5.7y) for AYAs and 63y (sd 9.5y) for non-AYAs. Otherwise, the groups were demographically similar – overall, 65.3% were male, 41% were non-Hispanic white, 30% were Hispanic, and 29% were Asian/Black/other. DLBCL was the predominant subtype (95.9%), with FL accounting for 4.1%. The median number of prior lines of therapy was 3 (range 1-9); AYAs were more likely to have received >5 lines of therapy compared to controls (OR=4.1, 95% CI 1.3-13.3; p=0.019). AYAs were less likely to have advanced-stage disease (stage III/IV) at time of CAR T-cell therapy (OR=0.46, 95% CI 0.23-0.9; p=0.023) but more likely to have primary refractory disease (OR=3.6, 95% CI 1.9-7.0; p=0.0001). There were no significant differences in 2-year PFS (37% [AYAs] vs. 34% [non-AYAs]; p=0.28; aHR=0.81, 95% CI 0.53-1.24, p=0.33, adjusted for Karnofsky Performance Status [KPS], previous lines of treatment, and pre-LD Lactate Dehydrogenase [LDH]) or OS (55% [AYAs] vs. 47% [non-AYAs]; p=0.33; aHR=0.87, 95% CI 0.52-1.43, p=0.57, adjusted for KPS, previous lines of treatment, pre-LD LDH, and transplant post-CAR). CRS rates and severity were similar between groups. However, AYAs had significantly lower odds of any ICANS (OR=0.29, 95% CI 0.14-0.6; p=0.0009) and ≥grade 2 ICANS compared to non-AYAs (OR=0.37, 95% CI 0.17-0.82; p=0.014). AYAs were also less likely to experience prolonged thrombocytopenia (platelet count<50 on day 30 post-CAR T-cell infusion; OR=0.3, 95% CI 0.12-0.8; p=0.015), though rates of prolonged neutropenia were similar. AYAs were nearly three times more likely to undergo hematopoietic cell transplantation following CAR T-cell therapy (OR=2.93; 95% CI 1.11-7.69; p=0.029). Conclusions CD-19 directed CAR T-cell therapy demonstrated similar efficacy in AYAs and older adults with NHL. However, AYAs experienced a more favorable toxicity profile, including lower rates of ICANS and more rapid platelet count recovery. This analysis represents one of the largest single-institution AYA cohorts treated with CAR T-cell therapy reported to date and underscores the need to further investigate long-term outcomes, biologic correlates, and age-adapted treatment strategies in this unique population.