Impact of body mass index on toxicity and outcomes after CD19-directed CAR-T therapy for non-Hodgkin lymphoma.

Background: CAR-T therapy has improved outcomes for patients with R/R B-cell lymphomas; however, in overweight and obese patients, retrospective studies have suggested an increase in inflammatory toxicities, thereby narrowing therapeutic index in this population. [Cordas dos Santos et al. Haematologica, 2022.] Considering >70% of individuals have an elevated BMI in the US, additional real-world analysis is needed to further characterize the safety and efficacy of CAR-T therapy for these patients. Methods: This single-center, retrospective study compares safety and efficacy among patients with BMI ≥ 25 compared to patients with BMI <25 treated with CD19 directed CAR-T cell therapy for non-Hodgkin lymphoma from 10/1/2018 to 4/14/2025. Results: A total of 77 patients treated with CD19 directed CAR-T therapy were included in the final analysis with an average BMI of 28.7 (17-53). 48 patients had a BMI ≥25 (median 32, range 25.24-53.12) while 29 had a BMI <25 (median 23.5, range 17.07-24.9). Hypertension and diabetes were independently present in 57.1% and 23.4% of patients, respectively. 37.7% (29) of patients had BMI ≥ 25 and hypertension while 20.8% (16) patients had BMI ≥ 25 with diabetes. After controlling differences in CAR-T product used, there was no difference in rates of all-grade CRS (66.7% vs 69%, p=0.835) or ICANS (20.8% vs 20.7%, p=0.964) among patients with BMI ≥ 25 vs <25, respectively. Likewise, there was no difference between G3-4 CRS (0 in both groups) and ICANS (6.3% vs 10.3%, p=0.67). There was no difference in rates of all-grade CRS in patients with BMI ≥ 25 with diabetes vs those without diabetes (25% vs 34.4%, p=0.48) or ICANS (37.5% vs 16.4%, p=0.06). Patients with BMI ≥ 25 and hypertension had no difference in rates of all-grade CRS (62.1% vs 70.8%, p=0.426) or ICANS (17.2% vs 22.9%, p=0.55) as well. When comparing efficacy, overall (89.6% vs 75%, p=0.11) & complete (68.4% vs 31.6%, p=0.06) response rates were numerically higher in the high vs low BMI cohort, respectively. Furthermore, patients with elevated BMI had longer median PFS (27.53 vs 5.61 months, p= 0.0023) and OS (not reached vs 9.9 months, p < 0.001). Conclusions: In this single-center analysis, BMI ≥25 was not associated with increased inflammatory toxicity following CD19 CAR-T therapy, contrasting with some prior reports. Toxicity was similar regardless of diabetes or hypertension being present, suggesting that BMI may be the primary factor driving these outcomes; however, conclusions are limited by sample size. Patients with BMI <25 experienced inferior outcomes, potentially due to lower physiologic reserve and altered metabolic states that may affect both the tolerability and efficacy of therapy. The improved clinical outcomes in patients with BMI ≥25 align with emerging evidence of an "obesity paradox" in CAR-T therapy, though the mechanisms underlying this association remain unclear and warrant further investigation.