Assessment of CD37 B-cell antigen and cell-of-origin significantly improves risk prediction in diffuse large B-cell lymphoma

CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B-cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. In this study, we assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab-CHOP and 231 patients treated with CHOP chemotherapy. We found CD37 loss (CD37(-)) in ~60% of DLBCL predicted significantly decreased survival rates in R-CHOP-treated patients, independent of the International Prognostic Index (IPI), germinal-center-B-cell-like (GCB)/activated-B-cell-like (ABC) cell-of-origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37(-), including TP53 mutation, NF-κB(high), Myc(high), p-STAT3(high), survivin(high), p63(-), and BCL6 translocation. Conversely, CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining CD37(-) status and ABC cell-of-origin risk scores with the IPI, defined as M-IPI-R (molecularly-adjusted-IPI-for-R-CHOP), or IPI-plus-immunohistochemistry for CD37, Myc, and Bcl-2 (defined as IPI+IHC), significantly improved risk prediction over IPI alone. Gene expression profiling suggested that decreased CD20 and increased PD-1 levels in CD37(-) DLBCL, ICOSLG upregulation in CD37(+) GCB-DLBCL, and CD37 functions during rituximab-CHOP treatment, underlie the pivotal role of CD37 signaling to clinical outcomes. In conclusion, CD37 is a critical determinant of rituximab-CHOP outcome in DLBCL especially in GCB-DLBCL, representing its importance for optimal rituximab action and sustained immune responses. The combined molecular and clinical prognostic indices, M-IPI-R and IPI+IHC, have remarkable predictive values in rituximab-CHOP-treated DLBCL.