Genetic landscape and prognostic value of IRF4 alterations in Diffuse large B-cell lymphoma patients

Abstract

Abstract Objective: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell NHL with high heterogeneity. Patients with IRF4 alterations in various hematologic malignancies have a different prognosis. Methods: From January 1st, 2006 to December 31st, 2022, all enrolled novel DLBCL patients treated with R-CHOP or R-CHOP-like regimens underwent high-resolution sequencing based on probe capture, immunohistochemistry and fluorescence in situ hybridization. Publicity datasets were used to validate. Differential expression gene and connectivity map (CMap) analysis were used to screen the potential drugs to improve the clinical outcome. Results: By April 28th, 2023, 324 patients were enrolled, 164 had disease progressed or recurrence, while 160 hadn’t. The number of patients in each group who had mutations in TP53, MYD88, BCL2, IRF4, STAT3, BCOR, ID3, and CD79A varied significantly. TP53 and IRF4 mutations (mPFS of mutation vs. wildtype: 33.93 vs. 11.17 months, p=0.018, HR:0.60, 95%CI:0.35-1.01) were found to be significantly associated with poor survival, according to univariate and multivariable analysis. Subgroup analysis showed that for IRF4mut GCB/nonGCB and IRF4wt GCB/nonGCB patients had significantly different PFS (p=0.002, HR:2.92, 95%CI: 1.05-8.10). Pairwise comparisons analysis show that the IRF4mutnonGCB subtype is significantly associated with shorter PFS in both our cohort and validation cohort (p=0.001). According to CMap , IRF4mut patients may benefit from regimens containing lenalidomide, ibrutinib, or mitoxantrone as first- and subsequent-line treatment options. Conclusions: This study comprehensively described the genetic landscape of novel DLBCL. IRF4 mutation is an independent prognostic factor in DLBCL patients, and PFS is significantly shortened in IRF4mut nonGCB DLBCL subtype.