Two previous studies conducted in the prerituximab era have demonstrated the superiority of the intensive chemotherapy regimen ACVBP over standard CHOP in DLBCL (Tilly H et al. Blood 2003;102:4284; Reyes F et al. N Eng J Med 2005;352:1197). In order to investigate the role of intensive chemotherapy associated with rituximab, the GELA initiated in 2003 a multicenter, phase III open-label, randomized trial comparing efficacy and safety of R-ACVBP vs R-CHOP in younger DLBCL patients with an age-adjusted IPI (aaIPI) of 1.
Patients between 18 and 59y with DLBCL and aaIPI=1 were eligible. R-ACVBP consisted of 4 induction courses given every 2 weeks: rituximab (375 mg/m2) on d1, doxorubicin (75 mg/m2) on d1, cyclophosphamide (1200 mg/m2) on d1, vindesine (2mg/m2) on d1 and 5, bleomycin (10 mg) on d 1 and 5, prednisone (60 mg/m2) from d1 to d5, and intrathecal methotrexate (IT) (15 mg) on d2, G-CSF from d6 to d13. Patients then received a sequential consolidation therapy: 2 courses of methotrexate (3 g/m2) plus leucovorin rescue, 4 courses of rituximab (375 mg/m2), etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on d1, and 2 courses of cytosine-arabinoside (100 mg/m2, SC) for 4 days, each consolidation course being administered at a 14-day interval. Standard R-CHOP was delivered every 3 weeks for 8 cycles along with IT methotrexate at d1 of the first 4 cycles. The primary objective was to evaluate the efficacy of R-ACVBP compared to R-CHOP as measured by the event-free survival (EFS). Secondary endpoints were response rate, progression free survival (PFS), disease-free survival (DFS) for complete responders, overall survival, neuro-meningeal relapse rate and toxicities. Results are presented on an intend-to-treat basis. Response to treatment was evaluated according to 1999 Cheson criteria.
From December 2003 to December 2008, 380 patients were randomized in 73 hematology/oncology departments of the GELA. One patient withdrew his consent the day of randomization and 379 received at least one day of study treatment, 196 with R-ACVBP and 183 with R-CHOP. Median age was 47y (18-59). Patient characteristics were well-balanced in terms of demography and baseline disease status: male gender, 59%; stage III-IV, 55%; elevated LDH, 44%; mass>10 cm, 22%; B symptoms, 28%; number of extra-nodal sites >1, 26%; bone marrow involvement, 13%. Overall response rate was 90.3% in the R-ACVBP group and 88.5% in the R-CHOP group (p=0.57). Complete remission rate (CR+CRu), was 82.7% for R-ACVBP and 80.3% for R-CHOP (p=0.56). At the time of this final analysis, in June 2010, the median follow-up was 44 months. The 3-year EFS was 80.9% (95% confidence interval (CI) 74.5–85.9) in the R-ACVBP group and 66.7% (CI 59.2–73.2) in the R-CHOP group (p=0.0035, hazard ratio (HR) 0.559). Significant differences were also observed for PFS (86.8% at 3 years (CI 80.9–91.0) vs 73.4% (CI 66.1–79.3), p=0.0015, HR 0.482), DFS (91.3% at 3 years (CI 85.1–95.0) vs 80.3% (CI 72.8–85.9), p=0.0019, HR 0.393) and overall survival (92.2% at 3 years (CI 87.1–95.3) vs 83.8% (CI 77.2–88.6), p=0.0071, HR 0.439). Patients in the R-ACVBP group experienced more frequently a serious adverse event (42% vs 15% in the R-CHOP group). Grade 3–4 hematological toxicity was more frequent in the R-ACVBP group, with a higher proportion of patients receiving red cell (51% vs 7% for R-CHOP) or platelet transfusions (13% vs 1%) and/or experiencing febrile neutropenia (39% vs 9%). There were 3 deaths (1.5%) attributed to toxicity of study treatment in the R-ACVBP group and 2 (1.1%) in the R-CHOP group.
Compared to standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves EFS, PFS, DFS and overall survival with increased but manageable hematological toxicity in younger patients with DLBCL.
Coiffier:Roche: Honoraria, Research Funding; Genentech: Research Funding. Gisselbrecht:Roche: Research Funding. Bosly:Roche: Membership on an entity's Board of Directors or advisory committees. Tilly:Amgen: Honoraria.
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