title: Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study.
abstract: Diffuse large B-cell lymphoma can be classified by gene expression profiling into germinal center and activated B-cell subtypes with different prognoses after rituximab-CHOP. The importance of previously recognized prognostic markers, such as Bcl-2 protein expression and BCL2 gene abnormalities, has been questioned in the new therapeutic era. We analyzed Bcl-2 protein expression, and BCL2 and MYC gene abnormalities by interphase fluorescence in situ hybridization in 327 patients with de novo disease treated with rituximab-CHOP. Isolated BCL2 and MYC rearrangements were not predictive of outcome in our patients as a whole, but only in those with the germinal center subtype of lymphoma. The prognostic relevance of isolated MYC rearrangements was weaker than that of BCL2 isolated translocations, but was probably limited by the rarity of the rearrangements. Seven of eight patients with double hit lymphoma had the germinal center subtype with poor outcome. The germinal center subtype patients with isolated BCL2 translocations had significantly worse outcome than the patients without BCL2 rearrangements (P=0.0002), and their outcome was similar to that of patients with the activated B-cell subtype (P=0.30), but not as bad as the outcome of patients with double hit lymphoma (P<0.0001). Bcl-2 protein overexpression was associated with inferior outcome in patients with germinal center subtype lymphoma, but multivariate analysis showed that this was dependent on BCL2 translocations. The gene expression profiling of patients with BCL2 rearrangements was unique, showing activation of pathways that were silent in the negative counterpart. BCL2 translocated germinal center subtype patients have worse prognosis after rituximab-CHOP, irrespective of MYC status, but the presence of combined gene breaks significantly overcomes the prognostic relevance of isolated lesions.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Visco
authors.forename: Alexander
authors.initials: A
authors.lastname: Tzankov
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.forename: Roberto N
authors.initials: RN
authors.lastname: Miranda
authors.forename: Yu Chuan
authors.initials: YC
authors.lastname: Tai
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Wei-min
authors.initials: WM
authors.lastname: Liu
authors.forename: Emanuele S G
authors.initials: ES
authors.lastname: d'Amore
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Santiago
authors.initials: S
authors.lastname: Montes-Moreno
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkær
authors.forename: April
authors.initials: A
authors.lastname: Chiu
authors.forename: Attilio
authors.initials: A
authors.lastname: Orazi
authors.forename: Youli
authors.initials: Y
authors.lastname: Zu
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Huan-You
authors.initials: HY
authors.lastname: Wang
authors.forename: Cherie H
authors.initials: CH
authors.lastname: Dunphy
authors.forename: Eric D
authors.initials: ED
authors.lastname: His
authors.forename: X Frank
authors.initials: XF
authors.lastname: Zhao
authors.forename: William W L
authors.initials: WW
authors.lastname: Choi
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhao
authors.forename: J Han
authors.initials: JH
authors.lastname: van Krieken
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
authors.forename: Weiyun
authors.initials: W
authors.lastname: Ai
authors.forename: Stacey
authors.initials: S
authors.lastname: O'Neill
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Andres J M
authors.initials: AJ
authors.lastname: Ferreri
authors.forename: Brad S
authors.initials: BS
authors.lastname: Kahl
authors.forename: Jane N
authors.initials: JN
authors.lastname: Winter
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Go
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.forename: Michael B
authors.initials: MB
authors.lastname: Møller
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D020869:Gene Expression Profiling; D016259:Genes, myc; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D000069283:Rituximab; D014178:Translocation, Genetic; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D019253:Proto-Oncogene Proteins c-bcl-2; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone