title: Assessment of CD37 B-cell antigen and cell of origin significantly improves risk prediction in diffuse large B-cell lymphoma.
abstract: 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.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.affiliation: Department of Oncology, The First Affiliated Hospital Zhengzhou University, Zhengzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Hematology and Oncology, The Ohio State University, Columbus, OH.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Kausar J
authors.initials: KJ
authors.lastname: Jabbar
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Ganiraju C
authors.initials: GC
authors.lastname: Manyam
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Maria de Winde
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van den Brand
authors.affiliation: University Hospital, Basel, Switzerland.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: San Bortolo Hospital, Vicenza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Visco
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkaer
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: April
authors.initials: A
authors.lastname: Chiu
authors.affiliation: Department of Pathology, Weill Medical College of Cornell University, New York, NY.
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.affiliation: Department of Pathology, The Methodist Hospital, Houston, TX.
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
authors.affiliation: Department of Pathology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Department of Hematology and Oncology, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Richards
authors.affiliation: Cleveland Clinic, Cleveland, OH.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.affiliation: Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: William W L
authors.initials: WW
authors.lastname: Choi
authors.affiliation: Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea.
authors.forename: Jooryung
authors.initials: J
authors.lastname: Huh
authors.affiliation: San Raffaele H. Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: San Raffaele H. Scientific Institute, Milan, Italy.
authors.forename: Andrés J M
authors.initials: AJ
authors.lastname: Ferreri
authors.affiliation: Odense University Hospital, Odense, Denmark.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Møller
authors.affiliation: Gundersen Lutheran Health System, La Crosse, WI.
authors.forename: Ben M
authors.initials: BM
authors.lastname: Parsons
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Jane N
authors.initials: JN
authors.lastname: Winter
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Frederick B
authors.initials: FB
authors.lastname: Hagemeister
authors.affiliation: Hospital Universitario Marqués de Valdecilla, Santander, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Han van Krieken
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Annemiek B
authors.initials: AB
authors.lastname: van Spriel
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Graduate School of Biomedical Sciences, The University of Texas School of Medicine, Houston, TX.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
mesh_terms: D018951:Antigens, CD20 / Q000235:genetics / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000473:pathology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018951:Antigens, CD20; D000951:Antigens, Neoplasm; C059071:CD37 protein, human; D016328:NF-kappa B; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D059470:Tetraspanins; D016159:Tumor Suppressor Protein p53