Intensified chemoimmunotherapy with R-ACVBP (rituximab [Rituxan] plus doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) significantly improved event-free survival, progression-free survival, disease-free survival, and overall survival compared with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in younger patients with diffuse large B-cell lymphoma (DLBCL), as reported in the multicenter, phase III, open-label, randomized LNH03-2B trial conducted by the GELA (Groupe d'Etude Des Lymphomes De l'Adulte).¹ However, the more intensified ACVBP regimen did incur greater hematologic toxicity.

Despite a high rate of febrile neutropenia (seen in almost 40% of patients) and greater need for transfusion in the R-ACVBP arm, the toxicity was manageable, said lead author Christian Recher, MD, PhD, CHU Toulouse, France, who presented results of the trial at the 52nd Annual Meeting of the American Society of Hematology (ASH), held December 4-7 in Orlando.

Study Data

The study enrolled 380 patients at 73 different centers in France with DLBCL and International Prognostic Index score of 1 from December 2003 through December 2008. Patients were randomly assigned to receive either intensified chemotherapy with R-ACVBP or R-CHOP. R-ACVBP was given in four induction courses given every 2 weeks; rituximab 375 mg/m²) on day 1, doxorubicin 75 mg/m² on day 1, cyclophosphamide 1,200 mg/m² on day 1, vindesine 2 mg/m² on days 1 and 5, bleomycin 10 mg on days 1 and 5, prednisone 60 mg/m² from day 1 to day 5, intrathecal methotrexate 15 mg on day 2, and G-CSF from day 6 to day 13. Patients then received several cycles of an intensive consolidation therapy. Standard R-CHOP was given every 3 weeks for eight cycles along with intrathecal methotrexate on day 1 of the first four cycles. No radiotherapy was given in either arm.

The primary endpoint was event-free survival, with secondary endpoints of response rate at end of treatment, and progression-free, disease-free, and overall survival. Mean follow-up was 44 months. At baseline, both groups were well balanced for age, stage, and disease characteristics. Approximately 59% were male; 55% had stage III or IV disease; 44% had elevated LDH; 22% had a tumor mass greater than 10 cm; 28% had B symptoms; 26% had more than one extranodal disease site, and 13% had bone marrow involvement.

Results

At a mean follow-up of 44 months, no difference was observed between treatment arms for response. Overall response rate was 92% for R-ACVBP and 88% for R-CHOP. Complete remission and complete remission-unconfirmed rates were 82.7% and 80.3%, respectively. The 3-year event-free survival rate (the primary endpoint) was 81% (95% CI = 74%-86%) vs 67% (95% CI = 59%-73%), which was significantly superior for the experimental arm (P = .0035). Progression-free, disease-free, and overall survival were also significantly better for the R-ACVBP arm:

• The 3-year progression-free survival rate was 87% (95% CI = 81%-91%) vs 73% (95% CI = 66%-79%) (P = .0015)
• The 3-year disease-free survival rate was 91% (95% CI = 85%-95%) vs 80% (95% CI = 73%-86%)
  (P = .0019)
• The 3-year median overall survival rate was 92% (95% CI = 87%-95%) vs 84% (95% CI = 77%-89%), respectively (P = .0071)

This is the first study to show an improvement in overall survival in patients with DLBCL in the rituximab era.

Toxicity and Other Concerns

Serious adverse events occurred more frequently in the R-ACVBP arm (42% vs 15%). Grade 3 or 4 hematologic toxicity was increased in that arm, as was grade 3 mucositis. A higher percentage in the R-ACVBP arm experienced febrile neutropenia (39% vs 9%), and a higher percentage of patients in that arm required red blood cell (51% vs 7%) or platelet (13% vs 1%) transfusions. Five toxic deaths occurred in the R-ACVBP arm (2.6%) and three occurred in the R-CHOP arm (1.6%).

In response to a question from the audience, Dr. Recher said that the GELA investigators did not evaluate quality of life, but it is clear that R-ACVBP could not be safely delivered to patients over 60 years old. He suspected that quality of life would be worse on the experimental treatment, given the side effects, but only in the first 2 months of treatment, because consolidation with high-dose methotrexate, followed by rituximab/ifosfamide and etoposide, is very well tolerated. ■

Reference

1. Recher C, Coiffier B, Haioun C, et al: A prospective, randomized study comparing dose intensive immunochemotherapy with R-ACVBP vs. standard R-CHOP in younger patients with diffuse large B-cell lymphoma (DLBCL). Groupe d'Etude Des Lymphomes De l'Adulte (GELA) study LNH03-2B. 52nd ASH Annual Meeting. Abstract 109. Presented December 5, 2010.