Biological signatures of International Prognostic Index in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive subtype of lymphoma with clinical and biological heterogeneity. The International Prognostic Index (IPI) shows great prognostic capability in the era of rituximab, but the biological signatures of IPI remains to be discovered. In this study, we analyzed the clinical data in a large cohort of 2592 newly diagnosed patients with DLBCL. Among them, 1233 underwent DNA sequencing for oncogenic mutations, and 487 patients underwent RNA sequencing for lymphoma microenvironment (LME) alterations. Based on IPI scores, patients were categorized into four distinct groups, with 5-year overall survival were 41.6%, 55.3%, 71.7%, and 89.7%, respectively. MCD-like subtype was associated with age > 60 years, multiple extra-nodal involvement, elevated serum lactate dehydrogenase (LDH), and IPI scores 2-5, while ST2-like subtype showed opposite trend. Patients with EZB-like-MYC+ and TP53Mut subtypes exhibited poor clinical outcome independent of IPI, integrating TP53Mut into IPI could better distinguish patients with dismal survival. The EZB-like-MYC-, BN2-like, N1-like, and MCD-like subtypes had inferior prognosis in patients with IPI scores ≥ 2, indicating necessity for enhanced treatment. Regarding LME categories, the germinal center-like LME was more prevalent in patients with normal LDH and IPI 0-1. The mesenchymal LME served as an independent protective factor, while the germinal center-like, inflammatory, and depleted LME categories correlated with inferior prognosis for IPI scores 2-5. In summary, our work explored the biological signatures of IPI, thus providing useful rationale for future optimization of the IPI-based treatment strategies with multi-omics information in DLBCL.