In DLBCL, a Molecular Signature Predicts Primary Treatment Resistance
—These investigators assessed the potential benefit of a high-risk signature to evaluate the molecular drivers of primary treatment resistance in patients with DLBCL.
A recent study published in Hematological Oncology by Allison Bock, MD, and colleagues has identified key molecular features associated with primary treatment resistance (PTR) in diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma.1 Some patients do not fully respond to first-line immunotherapy, typically rituximab, cyclo-phosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The specific molecular profiles associated with PTR have not been determined.
“We wanted to evaluate the ability of this risk signature to identify patients with PTR and further characterize this specific subset of patients with poor outcomes,” the authors stated in the article.
.jpg)
The genomics of PTR
The study compared the molecular profiles of newly diagnosed patients with DLBCL who experienced PTR (n = 41; 9%) to those who achieved a response to frontline immunochemotherapy (n = 351; 91%). Median overall survival for patients with PTR was shorter than that for patients who did not experience PTR (12.7 months vs. 182 months, p < 0.001, respectively).
Frequency of Specific Mutations:
- Whole exome sequencing (WES) data was available for 38 patients with PTR. Mutations were most frequent in TP53 (34%, n=13/38) and KMT2D (32%, n=12/38), and 79% (n = 30/38) of cases harbored mutations in at least one of the top mutated chromatin modifiers.
- TP53 mutations and/or 17p13.1 deletions were observed in 55% (n = 20/36) of patients with available WES and copy number variation (CNV) data.
High-risk Molecular Signature:
- Compared to those without PTR, patients with PTR showed a significant enrichment of TP53 mutations (OR 2.98, 95% CI 1.3–6.5, p = 0.005) and ARID1A mutations (OR 3.62, 95% CI 1.3–9.3, p = 0.007), while losses of 19p13.2 and 15q15.3 were less frequent.
- TP53 or ARID1A mutations were able to identify PTR in 47% (n = 18/38) of cases.
- Pathway analysis revealed a downregulation of the TP53 pathway in patients with PTR.
The researchers had previously developed a novel high-risk signature based on the identified molecular features which accurately predicted PTR in 46% (n = 14/30) of patients at diagnosis as high‐risk and 53% as intermediate risk (n = 16/30).
Clinical Implications and Next Steps
Given the poor outcomes of this population of patients, these findings have several important implications for the clinical management of DLBCL. Dr. Bock and coauthors noted, “There is no effective strategy to predict which newly diagnosed DLBCL patients will have PTR…Notably in this study, we report an enrichment of TP53 mutations (34%) and ARID1A mutations (21%) in PTR compared to non‐PTR patients suggesting that these two mutations play a prominent role in primary chemoresistance.”
The high-risk signature may be used to identify patients at increased risk of PTR at diagnosis. However, further research is needed to validate these findings in larger cohorts.
Published:
References
.jpg)
