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TP53 Alterations in Predicting Response to Immunotherapy for Large B-Cell Lymphoma

By: Julia Fiederlein
Posted: Tuesday, February 15, 2022

According to Roni Shouval, MD, PhD, of the Memorial Sloan Kettering Cancer Center, New York, and colleagues, TP53 alterations may be a prognostic and potentially predictive marker in patients with large B-cell lymphoma who underwent CD19-directed chimeric antigen receptor (CAR) T-cell therapy. The results of this analysis were presented during the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 710).

“Gene-expression profiling suggests that TP53 alterations result in an immunosuppressive tumor microenvironment and impaired apoptosis signaling,” the investigators commented. “[This] could lead to decreased CAR T-cell efficacy.”

The investigators focused on 136 heavily pretreated patients with relapsed or refractory large B-cell lymphoma who underwent CD19-directed CAR T-cell therapy. The best overall response rate was 78%, the median duration of overall survival was 22.7 months, and the median duration of progression-free survival was 6.2 months in the complete cohort; these outcomes seemed to be consistent with pivotal trials.   

A total of 37% of patients harbored TP53 alterations. Among tumor-intrinsic factors, TP53 alterations alone seemed to be predictive of complete response in univariable and multivariable logistic regression analyses; no association was reported with cytogenetic and histologic features. Based on univariable and multivariable Cox regression analyses, TP53 alterations also appeared to be predictive of overall survival (1-year overall survival rate in TP53-altered vs. wild-type: 48% vs. 75%; P = .039). After adjustment for age, performance status, and primary refractory disease, multivariable Cox regression analysis revealed that CD19-directed CAR T-cell therapy with axicabtagene ciloleucel seemed to be associated with superior overall survival compared with aggregated 4-1BB products in patients harboring TP53 alterations (hazard ratio = 3.40). Transcriptomic analysis of samples from newly diagnosed patients (n = 562) suggested that TP53 alterations may be associated with dysregulation of pathways involved in CAR T-cell cytotoxicity.

Disclosure: For full disclosures of the study authors, visit ash.confex.com.


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