Efficacy and Safety of Prophylactic Use of Darbepoetin Alfa in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Immunochemotherapy: Results of the Interim Analysis of the LNH03-6B GELA Study.

There are still controversies about the impact of erythropoiesis stimulating agents (ESA) on survival of patients with malignancies. The Groupe d'Etude des Lymphomes de l'Adulte (GELA) has conducted a multicentric prospective randomized phase III study to evaluate efficacy and safety of Darbepoetin alfa (DA) in elderly patients with DLBCL treated by immunochemotherapy. Here, we report the results of the planned interim analysis, held after the inclusion of the first 202 patients, with a median follow-up of 24 months.

Patients and methods: Patients between 60 and 80 years old with DLBCL and aaIPI ≥ 1 were eligible. They were firstly randomized between two immunochemotherapy regimens combining Rituximab and CHOP given every 2 (R-CHOP14) or 3 weeks (R-CHOP21) for 8 cycles. They were subsequently randomized between an investigational arm with DA (Arm 1) given in order to maintain hemoglobin level between 13 and 15 g/dL and a conventional arm (Arm 2) with usual management of chemotherapy-induced anemia, including red blood cell transfusions and ESA according to usual practices. The objective was to evaluate the efficacy of DA in association with chemotherapy (R-CHOP) as measured by the EFS at 2 years, events being defined as death from any cause, relapse for complete responders and unconfirmed complete responders, progression during or after treatment and changes of therapy during allocated treatment. Secondary objectives were OS, PFS, DFS, response rate and analysis of toxicity.

202 patients were included and 201 received study treatment ; 90 patients were randomized in DA group and 111 in conventional treatment group. Median age was 72 years. Patients' characteristics were similar in both arms with a slightly higher proportion of patients with aaIPI 2-3 in conventional arm : 68% compared to 56% (p=NS). Median hemoglobin (Hb) level at randomization was 12.2 g/dL. The median Hb level during treatment in DA arm was 11.9 g/dL and 10.7 g/dL in conventional arm respectively. Overall, 41 patients in conventional group received at least one dose of ESA during treatment. Eighteen percent of patients in DA group had at least one episode of Hb > 15 g/dL during treatment compared to 6% in conventional treatment group. Response rate (CR+CRu) after treatment was similar in both groups (69% in DA arm, 72% in conventional arm). Two-year EFS was 59% in DA arm compared with 49% in conventional arm (p=NS). A similar trend was observed for 2-year PFS (61% vs 51%), 2-year DFS (71% vs 56%) and 2-year OS (74% vs 63%) (p=NS for all). Grade 3-4 hematological toxicity was similar in the two groups. In contrast, proportion of patients receiving at least 1 red cell transfusion was higher in conventional arm (49% versus 36%). A total of 288 AEs were reported as serious (130 in DA group and 158 in symptomatic treatment group), concerning 122 patients (61%). Most SAEs were related to infectious complications. The rate of thromboembolic SAEs (composite criteria with pulmonary embolism, venous thrombosis from any site, coronary disease including myocardial infarction and cerebrovascular event) is slightly higher in DA group (13 SAEs) than in conventional arm (9 SAEs). Finally, the number of patients who died because of treatment toxicity was comparable in DA group (6 patients, 7%) and in conventional treatment group (7 patients, 6%).

The results of interim analysis of the LNH 03-6B provide encouraging results about efficacy and safety of a prophylactic use of DA in this population. It should be confirmed by the final analysis of the LNH03-6B trial which is planned in 2010.

No relevant conflicts of interest to declare.