title: Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial.
abstract: BACKGROUND
  Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become the standard of care for elderly patients with diffuse large B-cell lymphoma. We aimed to ascertain if a dose-dense R-CHOP regimen administered every 2 weeks (R-CHOP14) was superior to the standard 3-week schedule (R-CHOP21).
  
  
  METHODS
  We did a randomised phase 3 trial at 83 centres in four countries. 602 patients aged 60-80 years with untreated diffuse large B-cell lymphoma and at least one adverse prognostic factor (age-adjusted international prognostic index ≥ 1) were eligible for the study. We randomly allocated individuals to R-CHOP-ie, rituximab (375 mg/m(2)), cyclophosphamide (750 mg/m(2)), doxorubicin (50 mg/m(2)), vincristine (1.4 mg/m(2), up to 2 mg) all on day 1, and prednisone 40 mg/m(2) daily for 5 days-administered every 14 days (n=304) or every 21 days (n=298) for eight cycles. We did permuted-block randomisation (block size four, allocation ratio 1:1) stratified by centre and number of adverse prognostic factors. The primary endpoint was event-free survival. Our analysis was of the intention-to-treat population, and we present the final analysis. This study is registered with ClinicalTrials.gov, number NCT00144755.
  
  
  RESULTS
  Two patients allocated R-CHOP21 were ineligible for the study and were excluded from analyses. After median follow-up of 56 months (IQR 27-60), 3-year event-free survival was 56% (95% CI 50-62) in the R-CHOP14 group and 60% (55-66) in the R-CHOP21 group (hazard ratio 1.04, 95% CI 0.82-1.31; p=0.7614). Grade 3-4 neutropenia occurred in 224 (74%) of 304 patients allocated R-CHOP14 and 189 (64%) of 296 assigned R-CHOP21, despite increased use of granulocyte colony-stimulating factor in the R-CHOP14 group compared with the R-CHOP21 group. 143 (47%) patients in the R-CHOP14 group received at least one red-blood-cell transfusion versus 93 (31%) in the R-CHOP21 group (p=0.0001). 35 (12%) patients allocated R-CHOP14 received at least one platelet transfusion versus 25 (8%) assigned R-CHOP21 (p=0.2156). 155 (51%) patients who were assigned R-CHOP14 had at least one serious adverse event compared with 140 (47%) who were allocated R-CHOP21.
  
  
  CONCLUSIONS
  In elderly patients with untreated diffuse large B-cell lymphoma and at least one adverse prognostic factor, a 2-week dose-dense R-CHOP regimen did not improve efficacy compared with the 3-week standard schedule. The frequency of toxic side-effects was similar between regimens, but R-CHOP14 was associated with increased need for red-blood-cell transfusion.
  
  
  BACKGROUND
  Groupe d'Etude des Lymphomes de l'Adulte (GELA), Amgen.
authors.affiliation: Service d'Hématologie Adultes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France. richard.delarue@nck.aphp.fr
authors.forename: Richard
authors.initials: R
authors.lastname: Delarue
authors.forename: Hervé
authors.initials: H
authors.lastname: Tilly
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mounier
authors.forename: Tony
authors.initials: T
authors.lastname: Petrella
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.forename: Catherine
authors.initials: C
authors.lastname: Thieblemont
authors.forename: Serge
authors.initials: S
authors.lastname: Bologna
authors.forename: Hervé
authors.initials: H
authors.lastname: Ghesquières
authors.forename: Maya
authors.initials: M
authors.lastname: Hacini
authors.forename: Christophe
authors.initials: C
authors.lastname: Fruchart
authors.forename: Loïc
authors.initials: L
authors.lastname: Ysebaert
authors.forename: Christophe
authors.initials: C
authors.lastname: Fermé
authors.forename: Olivier
authors.initials: O
authors.lastname: Casasnovas
authors.forename: Achiel
authors.initials: A
authors.lastname: Van Hoof
authors.forename: Antoine
authors.initials: A
authors.lastname: Thyss
authors.forename: Alain
authors.initials: A
authors.lastname: Delmer
authors.forename: Olivier
authors.initials: O
authors.lastname: Fitoussi
authors.forename: Thierry Jo
authors.initials: TJ
authors.lastname: Molina
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.forename: André
authors.initials: A
authors.lastname: Bosly
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone