title: Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL.
abstract: Dual expression of MYC and BCL2 by immunohistochemistry (IHC) is associated with poor outcome in diffuse large B-cell lymphoma (DLBCL). Dual translocation of MYC and BCL2, so-called "double-hit lymphoma," has been associated with a high risk of central nervous system (CNS) relapse; however, the impact of dual expression of MYC and BCL2 (dual expressers) on the risk of CNS relapse remains unknown. Pretreatment formalin-fixed paraffin-embedded DLBCL biopsies derived from patients subsequently treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were assembled on tissue microarrays from 2 studies and were evaluated for expression of MYC and BCL2 by IHC. In addition, cell of origin was determined by IHC and the Lymph2Cx gene expression assay in a subset of patients. We identified 428 patients who met the inclusion criteria. By the recently described CNS risk score (CNS-International Prognostic Index [CNS-IPI]), 34% were low risk (0 to 1), 45% were intermediate risk (2 to 3), and 21% were high risk (4 or greater). With a median follow-up of 6.8 years, the risk of CNS relapse was higher in dual expressers compared with non-dual expressers (2-year risk, 9.7% vs 2.2%; P = .001). Patients with activated B-cell or non-germinal center B-cell type DLBCL also had an increased risk of CNS relapse. However, in multivariate analysis, only dual expresser status and CNS-IPI were associated with CNS relapse. Dual expresser MYC(+) BCL2(+) DLBCL defines a group at high risk of CNS relapse, independent of CNS-IPI score and cell of origin. Dual expresser status may help to identify a high-risk group who should undergo CNS-directed evaluation and consideration of prophylactic strategies.
authors.affiliation: Department of Medical Oncology and.
authors.forename: Kerry J
authors.identifier: 0000-0002-5835-9863
authors.initials: KJ
authors.lastname: Savage
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Graham W
authors.initials: GW
authors.lastname: Slack
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Department of Medical Oncology and.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Sehn
authors.affiliation: Department of Medical Oncology and.
authors.forename: Diego
authors.initials: D
authors.lastname: Villa
authors.affiliation: Section of Medical Oncology/Hematology, Cancer Care Manitoba, Winnipeg, MB, Canada; and.
authors.forename: Roopesh
authors.initials: R
authors.lastname: Kansara
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Robert
authors.initials: R
authors.lastname: Kridel
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ennishi
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: King L
authors.initials: KL
authors.lastname: Tan
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Susana
authors.initials: S
authors.lastname: Ben-Neriah
authors.affiliation: Division of Hematology, Sir Mortimer B. Davids-Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Johnson
authors.affiliation: Department of Medical Oncology and.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Pedro
authors.initials: P
authors.lastname: Farinha
authors.affiliation: Department of Medical Oncology and.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D019070:Cell Lineage; D002490:Central Nervous System / Q000473:pathology*; D003520:Cyclophosphamide / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D015999:Multivariate Analysis; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis*; D012008:Recurrence; D012306:Risk; D000069283:Rituximab / Q000008:administration & dosage; D046888:Tissue Array Analysis; D014178:Translocation, Genetic; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D003561:Cytarabine; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone; D008727:Methotrexate