Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy

Abstract

PURPOSE Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. MATERIALS AND METHODS Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre–CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. RESULTS We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type ( P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. CONCLUSION TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.

Primary progression during frontline CIT associates with decreased efficacy of subsequent CD19 CAR T-cell therapy in LBCL

“… 12 Similarly, for CAR T-cell therapy, Shouval and colleagues found that pretreatment TP53 mutations associated with a poorer outcome. 13 Second, one may speculate that this is in part why efficacy outcomes on the CAR T-cell arms of the ZUMA-7, TRANSFORM, and BELINDA trials treating patients after frontline CIT were, on the whole, similar to efficacy outcomes after CAR T-cell therapy on the single-arm ZUMA-1 (NCT02348216), TRANSCEND (NCT02631044), and JULIET (NCT02445248) trials treating heavily pretreated patients. 2-4 , 14-16 Refractoriness, selected for in the RCTs, is associated with poorer outcomes after CAR T-cell therapy in our data.…”

Enrichment of TP53 alterations within GCB-like DNA subclassifications of diffuse large B-cell lymphoma after transition from de-novo to relapsed or refractory disease

“…The strong EZB/corresponding profile of our RR2 group and consequent enrichment of TP53 alterations highlights the importance of DNA classification models and adds clarity to patterns of rrDLBCL evolution. The rising importance of liquid biopsy monitoring in rrDLBCL patients is made all the greater by the growing indication that TP53 impairment may predict poor response to CAR-T therapy due to the introduction of immunosuppressive pathways, specifically discussed by Shouval and colleagues at the 2021 American Society of Hematology conference [ 15 ]. TP53 mutation status, in combination with other prognostic factors, may therefore be used to identify high-risk patients prior to CAR-T treatment.…”

Combination of baseline PET/CT total metabolic tumor volume, lesion dissemination and TP53 mutations predicts rapid progression of diffuse large B-cell lymphoma

“…The ndings from this monocentric retrospective study indicate that TP53 mutation status does not affect outcomes in DLBCL patients treated with CAR T-cells. Shouval et al [41] studied 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T. They found that TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariate and multivariate regression models.…”