title: Prespecified candidate biomarkers identify follicular lymphoma patients who achieved longer progression-free survival with bortezomib-rituximab versus rituximab.
abstract: OBJECTIVE
  Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib-rituximab versus rituximab in the phase III LYM-3001 study.
  
  
  METHODS
  A total of 676 patients were randomized to five 5-week cycles of bortezomib-rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes.
  
  
  RESULTS
  In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib-rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib-rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib-rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets.
  
  
  CONCLUSIONS
  Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib-rituximab versus rituximab.
authors.affiliation: Hématologie, Hospices Civils de Lyon and University Lyon 1, Lyon, France. bertrand.coiffier@univ-lyon1.fr
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
authors.forename: Erin D
authors.initials: ED
authors.lastname: Henitz
authors.forename: Jayaprakash D
authors.initials: JD
authors.lastname: Karkera
authors.forename: Reyna
authors.initials: R
authors.lastname: Favis
authors.forename: Dana
authors.initials: D
authors.lastname: Gaffney
authors.forename: Alice
authors.initials: A
authors.lastname: Shapiro
authors.forename: Panteli
authors.initials: P
authors.lastname: Theocharous
authors.forename: Yusri A
authors.initials: YA
authors.lastname: Elsayed
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.forename: Michael E
authors.initials: ME
authors.lastname: Schaffer
authors.forename: Evgenii A
authors.initials: EA
authors.lastname: Osmanov
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Hong
authors.forename: Adriana
authors.initials: A
authors.lastname: Scheliga
authors.forename: Jiri
authors.initials: J
authors.lastname: Mayer
authors.forename: Fritz
authors.initials: F
authors.lastname: Offner
authors.forename: Simon
authors.initials: S
authors.lastname: Rule
authors.forename: Adriana
authors.initials: A
authors.lastname: Teixeira
authors.forename: Joanna
authors.initials: J
authors.lastname: Romejko-Jarosinska
authors.forename: Sven
authors.initials: S
authors.lastname: de Vos
authors.forename: Michael
authors.initials: M
authors.lastname: Crump
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Zinzani
authors.forename: Andrew
authors.initials: A
authors.lastname: Cakana
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: George
authors.initials: G
authors.lastname: Mulligan
authors.forename: Deborah
authors.initials: D
authors.lastname: Ricci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D005260:Female; D006579:Heterozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D011719:Pyrazines / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D000069283:Rituximab; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D055815:Young Adult; D000097382:CD68 Molecule
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines; D000069283:Rituximab; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C577981:PSMB1 protein, human