In a single-center retrospective study reported in the Journal of Clinical Oncology, Shouval et al found that the presence of TP53 alterations was associated with poorer outcomes in patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell therapy (CD19–CAR-T) for relapsed or refractory large B-cell lymphoma (LBCL).
As stated by the investigators, “Tumor-intrinsic features may render LBCL insensitive to CD19–CAR-T. We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19–CAR-T.”
The study included 153 adult patients treated with CD19–CAR-T at Memorial Sloan Kettering Cancer Center between April 2016 and April 2021, including axicabtagene ciloleucel in 50%, tisagenlecleucel in 32%, and lisocabtagene maraleucel in 18%. Targeted next-generation sequencing (NGS) was performed on pre–CAR-T tumor samples in 82 patients.
Median follow-up after CAR T-cell infusion was 21.1 months (interquartile range = 10.7–30.7 months).
In the entire cohort, outcomes were similar to those observed in pivotal trials: complete response was achieved in 54% of patients, median overall survival was 21.1 months (95% confidence interval [CI] = 14.8 months–not reached), and median progression-free survival was 6 months (95% CI = 3.4–9.7 months); at 1 year, overall survival was 65% and progression-free survival was 38%. No significant associations of histologic or cytogenetic features with complete response were observed.
Complete response rates (P = .9775) and overall survival (P = .83) did not differ between the 82 patients with NGS profiling vs those without. Among the patients with NGS profiling, 37% had TP53 mutations or copy number alterations.
In the NGS cohort, compete response by 90 days was observed in 33 (65%) of 51 patents with wild-type TP53 vs 10 (29%) of 29 with a TP53 alteration (P = .009). In multivariate analysis adjusting for age, Karnofsky performance status, primary refractory disease, lactate dehydrogenase level, and CAR T-cell costimulatory domain, TP53 status was an independent predictor of response (odds ratio for wild-type vs altered TP53 = 3.61, 95% CI = 1.31–10.7, P = .016).
Overall survival at 1 year was 76% (95% CI = 65%–89%) among patients with wild-type TP53 vs 44% (95% CI = 29%–67%) among those with TP53 alterations (P = .012). On multivariate analysis, TP53 alteration was an independent predictor of poorer survival (hazard ratio = 2.03, 95% CI = 1.02–4.03, P = .044).
Transcriptomic profiling in a cohort of 562 patients with newly diagnosed lymphoma showed that TP53 alterations were associated with dysregulation of pathways related to CAR T-cell cytotoxicity, including interferon and death receptor signaling pathways, and reduced CD8-positive T-cell tumor infiltration.
The investigators concluded, “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.”
Roni Shouval, MD, PhD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, and a grant from the Long Island Sound Chapter, Swim Across America. For full disclosures of the study authors, visit ascopubs.org.
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