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

• Published in: Blood Vol. 128; no. 26; pp. 3083 - 3100
• Main Authors: Xu-Monette, Zijun Y., Li, Ling, Byrd, John C., Jabbar, Kausar J., Manyam, Ganiraju C., Maria de Winde, Charlotte, van den Brand, Michiel, Tzankov, Alexandar, Visco, Carlo, Wang, Jing, Dybkaer, Karen, Chiu, April, Orazi, Attilio, Zu, Youli, Bhagat, Govind, Richards, Kristy L., Hsi, Eric D., Choi, William W.L., Huh, Jooryung, Ponzoni, Maurilio, Ferreri, Andrés J.M., Møller, Michael B., Parsons, Ben M., Winter, Jane N., Wang, Michael, Hagemeister, Frederick B., Piris, Miguel A., Han van Krieken, J., Medeiros, L.Jeffrey, Li, Yong, van Spriel, Annemiek B., Young, Ken H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.12.2016; American Society of Hematology
• Subjects: Antigens, CD20 - genetics; Antigens, CD20 - metabolism; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B-Lymphocytes - metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Germinal Center - pathology; Humans; Lymphoid Neoplasia; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Middle Aged; Models, Biological; Multivariate Analysis; Mutation - genetics; NF-kappa B - metabolism; Prognosis; Programmed Cell Death 1 Receptor - metabolism; Protein Transport; Proto-Oncogene Proteins c-myc - metabolism; Risk Factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Survival Analysis; Tetraspanins - genetics; Tetraspanins - metabolism; Treatment Outcome; Tumor Suppressor Protein p53 - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2016-05-715094

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. 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 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 231 patients treated with CHOP. We found that CD37 loss (CD37−) in ∼60% of DLBCL patients showed significantly decreased survival after R-CHOP treatment, 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-κBhigh, Mychigh, phosphorylated STAT3high, survivinhigh, p63−, and BCL6 translocation. CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining risk scores for CD37− status and ABC cell of origin with the IPI, defined as molecularly adjusted IPI for R-CHOP (M-IPI-R), or IPI plus immunohistochemistry (IHC; IPI+IHC) for CD37, Myc, and Bcl-2, 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 R-CHOP treatment underlie the pivotal role of CD37 status in clinical outcomes. In conclusion, CD37 is a critical determinant of R-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 R-CHOP–treated DLBCL. •CD37 positivity predicts significantly better survival for DLBCL, and is superior to other prognostic factors in GCB-DLBCL.•CD37 loss is an important risk factor for R-CHOP resistance in both GCB- and ABC-DLBCL.