Deciphering the Prognostic Significance of MYD88 and CD79B Mutations in Diffuse Large B-Cell Lymphoma: Insights into Treatment Outcomes

Background The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different MYD88 and CD79B mutation status merit further investigation. Objective This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among MYD88-CD79B(co-mut), MYD88/CD79B(single-mut), and MYD88-CD79B(co-wt) DLBCL patients. Patients and Methods Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing MYD88-CD79B(co-mut), MYD88/CD79B(single-mut), and MYD88-CD79B(co-wt) treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology. Results In the MCD subtype, patients with MYD88-CD79B(co-mut) showed comparable progression-free survival (PFS) and overall survival (OS) compared to MYD88/CD79B(single-mut) or MYD88-CD79B(co-wt). However, in the non-MCD subtype, patients with MYD88-CD79B(co-mut) exhibited significantly inferior OS than MYD88/CD79B(single-mut) or MYD88-CD79B(co-wt), while there was no significant OS difference between MYD88/CD79B(single-mut) and MYD88-CD79B(co-wt) (median OS: 68.8 [95% CI 22-NA] vs NA [95% CI 112-NA] vs 177.7 [95% CI 159-NA] months; MYD88-CD79B(co-mut) vs MYD88/CD79B(single-mut): p = 0.02; MYD88-CD79B(co-mut) vs MYD88-CD79B(co-wt): p = 0.03; MYD88/CD79B(single-mut) vs MYD88-CD79B(co-wt): p = 0.33). Regarding patients with MYD88-CD79B(co-mut), there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the MYD88-CD79B(co-mut) group, patients with PIM1(mut) had better PFS than PIM1(wt) (median PFS: 8.34 [95% CI 5.56-NA] vs 43.8 [95% CI 26.4-NA] months; p = 0.02). Possible mechanisms contributing to the superior PFS of PIM1(mut) patients may include activated lymphocyte-mediated immunity and interferon response, a higher proportion of natural killer T cells and plasmacytoid dendritic cells, as well as suppressed angiogenesis and epithelial-mesenchymal transition, along with lower fibroblast and stromal score. Conclusions In the MCD subtype, patients with MYD88-CD79B(co-mut) showed comparable PFS and OS compared to MYD88/CD79B(single-mut) or MYD88-CD79B(co-wt), while in the non-MCD subtype, they exhibited significantly inferior OS. There was no significant disparity in PFS and OS of MYD88-CD79B(co-mut) between the MCD and non-MCD subtypes. The presence of PIM1(mut) within the MYD88-CD79B(co-mut) group correlated with better PFS, which may result from an intricate interplay of immune processes and tumor microenvironment alterations.