Clinical Outcomes of Transformed Follicular Lymphoma with CAR T-Cell Therapy: A US Multicenter Real-World Analysis

Background: Chimeric Antigen Receptor T-cell therapy (CART) has substantially improved outcomes for patients (pts) with relapsed/refractory (R/R) aggressive B-cell lymphomas, with impressive overall response rates (ORR) and 3+ year complete remission rates (CRR) ranging from 30-40%. As a result, CART is now FDA-approved for the treatment of R/R diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (tFL). In registrational clinical trials (e.g. ZUMA-1/ZUMA-7, TRANSCEND NHL 001/TRANSFORM, JULIET/BELINDA) these biologically distinct lymphomas were included and analyzed together. As such, the prognostic impact of tFL histology with respect to CART outcomes has remained largely unknown and warrants clarification.

Methods: We performed a retrospective cohort study of pts with de novo DLBCL (dnDLBCL) and tFL treated with CD19-directed CART from 2015 to 2024 across 14 US academic institutions, with follow-up through June 30, 2024. All cases were pathologically-confirmed locally, with dnDLBCL defined as DLBCL without clinicopathologic evidence of an antecedent or concurrent low-grade lymphoma and tFL as DLBCL arising from an antecedent classical follicular lymphoma. Cases were also sub-classified by “double hit” lymphoma (DHL) or “double expressor” lymphoma (DEL) status. Differences in patient, clinical, and treatment characteristics were examined using chi-square and Wilcoxon rank sum tests. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier survival curves, and de novo DLBCL and tFL pts were compared using log-rank tests. Cox proportional hazards models were used for multivariable analyses.

Results: Of the 691 pts included in this analysis, 552 had dnDLBCL (88 with DHL, 90 with DEL) and 139 had tFL (27 with DHL, 22 with DEL). There was no significant difference between dnDLBCL and tFL cohorts in median age (60, range 21-85 years), gender, race, ECOG performance status, IPI score, primary refractory disease (14 vs 16%) or early relapse <1 year after frontline therapy (28 vs 27%), requirement for bridging therapy, or DEL/DHL status. Compared to dnDLBCL, fewer pts with tFL received anthracycline-based treatments (66% vs 87%), whereas more tFL pts received bendamustine-based therapy (24% vs 6%). The 33 tFL pts with prior bendamustine exposure had a decreased 3-year OS rate (51% with vs 61% without bendamustine, p=0.15). There was no significant difference in the number of lines of prior therapy (median of 2 for both) or prior autologous transplant.

There were no significant differences in CAR T-cell construct used, proportion of pts treated on clinical trials, vein-to-vein time, or rates or timing of CRS or ICANS. At 180 days post-CART, best response rates were significantly better for tFL (ORR 52%, CRR 45%) than dnDLBCL (ORR 36%, CRR 31%; p<0.01). Post CAR T relapse rates were correspondingly lower for tFL (40%) compared with dnDLBCL (56%, p <0.01), with similar median times to relapse (98 days vs 91 days, p=0.16) and rates of CD19-negativity at relapse (39% vs 35%, p=0.68).

At a median follow-up of 29.3 months, pts with tFL had significantly better 3-year OS than those with dnDLBCL (59% [tFL] vs 39% [dnDLBCL], p-value <0.01) and 3-year PFS (54% [tFL] vs 39% [dnDLBCL], p-value <0.01). This survival difference remained in pts with primary refractory disease or early relapse (3-year OS 51% [tFL] vs 35% [dnDLBCL], p=0.02; 3-year PFS 46% [tFL] vs 35% [dnDLBCL], p=0.04). Interestingly, pts with DHL from tFL appeared to have better survival outcomes than DHL from dnDLBCL (3-year OS 57% [tFL] vs 39% [dnDLBCL], p =0.03; 3-year PFS 50% [tFL] vs 39% [dnDLBCL], p=0.06), while pts with DEL had inferior outcomes in both cohorts (3-year OS 33% [tFL] vs 37% [dnDLBCL], p=0.63).

Conclusion: This is the largest “real-world” retrospective multicenter cohort study of pts with tFL treated in the United States, with over 2 years of median follow-up. Our findings strongly suggest that pts with tFL have improved survival with CART when compared with patients with de novo DLBCL, and CART appears to overcome some of the adverse prognostic impact of DHL in tFL pts. The clinicopathologic and molecular features underlying these differential responses requires further investigation.