A RANDOMIZED MULTICENTRE PHASE III STUDY FOR FIRST LINE TREATMENT OF YOUNG PATIENTS WITH HIGH RISK (AAIPI 2-3) DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL): RITUXIMAB (R) PLUS DOSE-DENSE CHEMOTHERAPY CHOP14/MEGACHOP14 WITH OR WITHOUT INTENSIFIED HIGH-DOSE CHEMOTHERAPY (HDC) AND AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT). RESULTS OF DLCL04 TRIAL OF ITALIAN LYMPHOMA FOUNDATION (FIL)

Background: The outcome of young DLBCL patients at high risk is not satisfactory with RCHOP. FIL conducted a multicenter randomized phase III trial, with a 2x2 factorial design, to compare two R-dose-dense chemotherapies, RCHOP14 (RC14) vs RMegaCHOP14 (RMC14), followed or not by HDC+ASCT (HDT). Patients and Methods: The main hypothesis was to test an increase of 2-year Progression-Free-Survival (PFS) from 50% in the standard arm (no-HDT) to 65% in the experimental arm (HDT); secondary comparison was between the two dose-dense regimens. Inclusion criteria were: age 18-65; untreated DLBC; aaIPI 2-3. Patients were stratified according aaIPI and randomized at diagnosis to receive: RC14 x 8; RMC14 x 6 (1200 mg/m2 Cyclophosphamide, 70 mg/m2 Doxorubicin, standard Vincristine/Prednisone); RC14 x 4 + HDT (R + high dose Cytarabine + Mitoxantrone + Dexamethasone + BEAM and ASCT); RMC14 x 4 + the same HDT. Results: From June 2005 to September 2010, 412 patients were enrolled and 399 were eligible: median age 49 (18-63); stage II/III/IV 6/29/65%; LDH >normal 89%, PS >1 43%, aaIPI 2/3 score 74/26%. At the time of this analysis, 375 are evaluable: 195 no-HDT and 180 HDT arm. Response rates were: CR 74%, PR 6%, NR 12%, toxic deaths 3% and 5% dropped out. Treatment-related deaths in no-HDT and HDT arm were: 2.6% and 3.3%. With a median follow-up of 23 months, 2-year PFS was 65% (95%CI:59-70). Two-year PFS for no-HDT vs HDT was: 59% (95%CI:51-57) vs 72% (95%CI:64-78), p .008 (Fig.1). Two-year PFS rates for RC14 vs RMC14 were superimposable. Two-year OS was 83% (95%CI: 78-87) with no differences between no-HDT and HDT. In a Cox-model, including the four arms, assuming RC14 as reference, the risk of relapse was significantly reduced mainly in RCHOP14+HDT arm (HR=0.47, 95%CI=0.27-0.81, p .007) with minor effect in RMegaCHOP14+HDT (HR=0.69, p .15) arm. Conclusions: this randomized trial showed that HDT, as first line treatment in young high risk DLBCL, significantly reduced the relapse rate in comparison to standard RCHOP14. A more aggressive dose-dense chemotherapy does not seem to play a significant role. So far, this advantage in PFS does not translate in overall survival differences. A longer follow-up will further clarify the role of HDT as first line treatment in this poor-prognosis DLBCL patients. 072 Figure 1. 2-year PFS for no-HDT vs HDT