title: Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial.
abstract: BACKGROUND
  The randomized phase 3 LYM3001 trial in relapsed follicular lymphoma (FL) demonstrated higher overall (ORR) and complete response (CR) rates and prolonged progression-free survival (PFS) with bortezomib-rituximab versus rituximab. We report findings in high-risk patients (FL International Prognostic Index [FLIPI] score ≥3, and high tumor burden by modified Groupe d'Etude des Lymphomas Folliculaires [GELF] criteria).
  
  
  METHODS
  Patients aged ≥18 years with grade 1/2 FL, ≥1 measurable lesion, and documented relapse or progression following prior therapy, rituximab-naïve or rituximab-sensitive, were enrolled at 164 centers in 29 countries across Europe, the Americas, and Asia-Pacific. Patients were randomized (1:1) to five 5-week cycles of bortezomib-rituximab (bortezomib 1.6 mg/m2, days 1, 8, 15, and 22, all cycles; rituximab 375 mg/m2, days 1, 8, 15, and 22, cycle 1, and day 1, cycles 2-5; N=336) or rituximab alone (N=340). Randomization was stratified by FLIPI score, prior rituximab, time since last dose of anti-lymphoma therapy, and geographical region. The primary endpoint of the study was PFS.
  
  
  RESULTS
  103 bortezomib-rituximab and 98 rituximab patients had high-risk FL. The ORR was 59% versus 37% (p=0.002), the CR/CRu rate was 13% versus 6% (p=0.145), and the durable response rate was 45% versus 26% (p=0.008) with bortezomib-rituximab versus rituximab. Median PFS was 9.5 versus 6.7 months (hazard ratio [HR] 0.667, p=0.012) with bortezomib-rituximab versus rituximab; median time to progression was 10.9 versus 6.8 months (HR 0.656, p=0.009); median time to next anti-lymphoma treatment was 14.8 versus 9.1 months (HR 0.762, p=0.103); and the 1-year Overall Survival rate was 83.1% versus 76.6%. Overall, 51% of bortezomib-rituximab and 32% of rituximab patients reported grade ≥3 adverse events, including neutropenia (18%, 6%), anemia (4%, 5%), diarrhea (8%, 0%), thrombocytopenia (5%, 2%), and sensory neuropathy (1%, 0%).
  
  
  CONCLUSIONS
  High-risk FL patients treated with bortezomib-rituximab had significantly higher ORR and longer PFS than patients receiving rituximab alone, with greater clinical benefit than in the overall study population; additional toxicity was acceptable and did not affect treatment feasibility.
  
  
  BACKGROUND
  The phase 3 LYM3001 trial is registered with ClinicalTrials.gov, with the identifier NCT00312845.
authors.affiliation: Institute of Hematology and Medical Oncology 'L, & A, Seràgnoli', University of Bologna, Bologna, Italy. pierluigi.zinzani@unibo.it
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Zinzani
authors.forename: Nuriet K
authors.initials: NK
authors.lastname: Khuageva
authors.forename: Huaqing
authors.initials: H
authors.lastname: Wang
authors.forename: Bernardo
authors.initials: B
authors.lastname: Garicochea
authors.forename: Jan
authors.initials: J
authors.lastname: Walewski
authors.forename: Achiel
authors.initials: A
authors.lastname: Van Hoof
authors.forename: Pierre
authors.initials: P
authors.lastname: Soubeyran
authors.forename: Dolores
authors.initials: D
authors.lastname: Caballero
authors.forename: Rena
authors.initials: R
authors.lastname: Buckstein
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: Panteli
authors.initials: P
authors.lastname: Theocharous
authors.forename: Christopher
authors.initials: C
authors.lastname: Enny
authors.forename: Eugene
authors.initials: E
authors.lastname: Zhu
authors.forename: Yusri A
authors.initials: YA
authors.lastname: Elsayed
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coiffier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001897:Boronic Acids; D011719:Pyrazines; D000069283:Rituximab; D000069286:Bortezomib