In a study reported in the Journal of Clinical Oncology, Uppal et al identified factors associated with poorer outcomes in patients with TP53-mutated diffuse large B-cell lymphoma (DLBCL).
Study Details
The analysis included clinical and molecular data from 3,091 individuals which was derived from 10 cohorts of patients with newly diagnosed DLBCL treated with front-line rituximab-based immunochemotherapy regimens; data from the Phoenix trial cohort, assessing R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) vs R-CHOP plus ibrutinib, were also analyzed separately. The primary outcome measures were progression-free survival and overall survival.
Key Findings
TP53-mutant DLBCL differed from wild-type disease in numerous ways, including pattern and number of genetic lesions, malignant B-cell expression states, and tumor microenvironment composition. TP53 mutations were six times more common than MYC/BCL2/BCL6 double-/triple-hit status, but were associated with similar adverse prognostic risk.
Among patients with TP53-mutant disease, risk for outcome was also stratified by variant allele frequency (VAF), with patients having VAF ≥ 75% showing significantly poorer progression-free and overall survival. Downregulation of interferon signaling and lower macrophage content were found in TP53-mutant samples from patients with poor outcomes or VAF ≥ 75%.
TP53 mutations were also associated with adverse prognosis among patients with DLBCL assigned to specific LymphGen subtypes (EZB, MCD), malignant B-cell states (S1), and ecotypes (LE4, LE7, LE8); outcomes in patients with other molecular subtypes were similar to those in patients with wild-type disease.
In specific evaluation of Phoenix trial cohort data, the addition of ibrutinib to R-CHOP improved progression-free survival in patients with TP53-mutant DLBCL, overcoming the deleterious impact of high VAF, irrespective of patient age.
The investigators concluded: “The poor prognosis of TP53-mutant DLBCL is dependent on intrinsic features, such as VAF, and modulated by co-occurring genomic lesions or lymphoma cell-intrinsic or microenvironmental expression patterns.”
Gilles Salles, MD, PhD, of Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
