Baseline Tumor Transcriptional Features and Event-Free Survival After Anti-CD19 CAR T-Cell Therapy with Axicabtagene Ciloleucel in Large B-Cell Lymphoma: An Exploratory Reanalysis of the Randomized ZUMA-7 Trial

Abstract

Background/Objectives: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (axi-cel) improves outcomes in relapsed/refractory large B-cell lymphoma (LBCL), but many patients relapse despite retained CD19 expression. We explored baseline tumor transcriptional features associated with event-free survival (EFS) after axi-cel. Methods: We reanalyzed baseline NanoString IO 360 profiles from the randomized ZUMA-7 trial (axi-cel, n = 134; standard of care [SOC], n = 122) using differential expression, gene set enrichment, MCP-counter deconvolution, Kaplan–Meier and Cox models adjusted for tumor burden and cell of origin, and gene-by-treatment interaction models. Results: T-cell exhaustion and HLA transcripts were not associated with response in either arm, and no transcript passed FDR correction in differential expression. In the axi-cel arm, 13 of 14 modeled transcripts remained associated with EFS after adjustment; eight (MS4A1, CD19, TNFRSF17, HLA-DOB, CD45RA, DUSP5, KLRD1 and WNT11) were FDR-supported at every survival-analysis stage within the 25 prioritized candidates, but not panel-wide. Consistent with the primary ZUMA-7 report, higher B-cell transcript expression was associated with longer EFS. Interaction testing gave borderline support for a differential association between arms only for KLRD1 and DUSP5 (FDR = 0.049), robust to arm-stratified models; other candidates showed no or only nominal specificity. Apart from the B-lineage score (FDR = 0.029), no estimated immune or stromal population was associated with response. Conclusions: Baseline B-cell transcriptional programs and a small set of gene-level candidates are associated with EFS after axi-cel in ZUMA-7. These exploratory findings do not establish predictive value and require independent validation.