title: The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study.
abstract: OBJECTIVE
  To evaluate the prognostic value of the cell of origin (COO) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBLC), prospectively treated by rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) versus rituximab, ifosfamide, carboplatin, and etoposide and followed by intensive therapy plus autologous stem-cell transplantation on the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) trial.
  
  
  METHODS
  Among the 396 patients included on the trial, histologic material was available for a total of 249 patients at diagnosis (n = 189 patients) and/or at relapse (n = 147 patients), which included 87 matched pairs. The patient data were analyzed by immunochemistry for CD10, BCL6, MUM1, FOXP1, and BCL2 expression and by fluorescent in situ hybridization for BCL2, BCL6 and c-MYC breakpoints. The correlation with survival data was performed by using the log-rank test and the Cox model.
  
  
  RESULTS
  Characteristics of immunophenotype and chromosomal abnormalities were statistically highly concordant in the matched biopsies. In univariate analysis, the presence of c-MYC gene rearrangement was the only parameter to be significantly correlated with a worse progression-free survival (PFS; P = .02) and a worse overall survival (P = .04). When treatment interaction was tested, the germinal center B (GCB) -like DLBCL that was based on the algorithm by Hans was significantly associated with a better PFS in the R-DHAP arm. In multivariate analysis, independent prognostic relevance was found for the GCB/non-GCB the Hans phenotype interaction treatment (P = .04), prior rituximab exposure (P = .0052), secondary age-adjusted International Prognostic Index (P = .039), and FoxP1 expression (P = .047). Confirmation was obtained by gene expression profiling in a subset of 39 patients.
  
  
  CONCLUSIONS
  COO remains a major and independent factor in relapsed/refractory DLBCL, with a better response to R-DHAP in GCB-like DLBCL. This needs confirmation by a prospective study.
authors.affiliation: Hematology, APHP, Hôpital Saint Louis, INSERM U728, IUH, Paris, France. catherine.thieblemont@sls.aphp.fr
authors.forename: Catherine
authors.initials: C
authors.lastname: Thieblemont
authors.forename: Josette
authors.initials: J
authors.lastname: Briere
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mounier
authors.forename: Hans-Ullrich
authors.initials: HU
authors.lastname: Voelker
authors.forename: Wendy
authors.initials: W
authors.lastname: Cuccuini
authors.forename: Edouard
authors.initials: E
authors.lastname: Hirchaud
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Andrew
authors.initials: A
authors.lastname: Jack
authors.forename: Christer
authors.initials: C
authors.lastname: Sundstrom
authors.forename: Sergio
authors.initials: S
authors.lastname: Cogliatti
authors.forename: Philippe
authors.initials: P
authors.lastname: Trougouboff
authors.forename: Ludmila
authors.initials: L
authors.lastname: Boudova
authors.forename: Loic
authors.initials: L
authors.lastname: Ysebaert
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Catherine
authors.initials: C
authors.lastname: Chevalier
authors.forename: Dominique
authors.initials: D
authors.lastname: Bron
authors.forename: Norbert
authors.initials: N
authors.lastname: Schmitz
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
authors.forename: Remi
authors.initials: R
authors.lastname: Houlgatte
authors.forename: Christian
authors.initials: C
authors.lastname: Gisselbrecht
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D018951:Antigens, CD20 / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000473:pathology*; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics; D018365:Neoplasm, Residual / Q000188:drug therapy*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D012307:Risk Factors; D000069283:Rituximab; D016879:Salvage Therapy / Q000379:methods
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D003561:Cytarabine; D000069283:Rituximab; D005047:Etoposide; D003907:Dexamethasone; D016190:Carboplatin; D002945:Cisplatin; D007069:Ifosfamide