336MO - Genetic landscape and prognostic value of IRF4 alterations in diffuse large B cell lymphoma patients

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma with high heterogeneity. The prognosis of patients with IRF4 alterations in various hematologic malignancies showed an opposite prognosis. After removing patients with poor prognostic factors, this study aims to investigate the relationship between the DLBCL genetic landscape and the efficacy of first-line R-CHOP or R-CHOP-like regimens. Further explore the prognostic significance of IRF4 alterations in DLBCL patients.

Methods

High-resolution sequencing based on probe capture and immunohistochemistry were performed on all enrolled patients diagnosed with novel DLBCL in our hospital from January 1^st， 2006 to December 31^st，2022. Publicity datasets were used to validated the survival results. Drug candidates to enhance the treatment effect of IRF4 mutation (IRF4mut) patients were screened through implementing differential expression gene and connectivity map (CMap) analysis.

Results

Among 324 patients enrolled, 164 patients had disease progressed or recurrence, while 160 patients hadn't, with a median follow-up time of 23.6 months at the data cutoff date of April 28^th, 2023. Between groups, patients with progressed or recurrence disease had statistically different numbers of mutations such as TP53, IRF4 etc. Both univariate and multivariable analyses showed that mutations in TP53 and IRF4 (mPFS of mutation vs. wildtype: 33.93 vs. 11.17 months, p=0.018, HR:0.60, 95% CI: 0.35-1.01) were significantly associated with poor survival between the two groups. Subgroup analysis demonstrated a significant difference in PFS between IRF4mut GCB/nonGCB and IRF4 wildtype (IRF4wt) GCB/nonGCB patients (p=0.002, HR:2.92, 95%CI: 1.05-8.10). Both in our cohort and validation cohort IRF4mutnonGCB subtype are significantly connected to shorter PFS in pairwise comparisons (p=0.001). According to CMap, IRF4mutpatients may benefit from lenalidomide, ibrutinib, or mitoxantrone contained regimens.

Conclusions

The presence of IRF4 mutation is an independent predictor of prognosis in DLBCL patients, and nonGCB subtypes in this population are significantly associated with shorter PFS. While IRF4mut GCB patients tends to have better clinical outcome.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

China National Major Project for New Drug Innovation (2017ZX09304015).

Disclosure

All authors have declared no conflicts of interest.