Safety of Prophylactic Use of Darbepoetin Alfa in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP 14 or R-CHOP21: Preliminary Results of the LNH03-6B Randomized GELA Study.

Introduction: Whether erythropoietin (Epo) has an impact on survival of patients (pts) with malignancies is debated. Since Dec 2003, the GELA has conducted a prospective randomized study to evaluate the safety and efficacy of Darbepoetin alfa (DA) in elderly pts with DLBCL treated by immunochemotherapy. In 2005, new recommendations about the use of Epo for patients with chemotherapy induced anemia have been published. Following these recommendations, the protocol was temporarily stopped and a first safety analysis was performed. Here we report the preliminary results on the first 130 enrolled patients.

Patients and methods: pts between 66 and 80 years old with DLBCL and aaIPI ≥1 have been enrolled from Dec 2003 to Aug 2005. Pts were firstly randomised between two regimens combining Rituximab and the classical CHOP (Coiffier and al. NEJM 2002) delivered every 2 (R-CHOP14) or 3 weeks (R-CHOP21) for 8 cycles and were subsequently randomised between an investigational arm with DA (Arm 1) given in order to maintain hemoglobin (Hb) level between 13 and 15 g/dL and a conventional arm (Arm 2) with usual treatment of chemotherapy induced anemia, including transfusions and Epo according to usual practices. G-CSF was given according to physicians’decision.

Results: 63 pts were randomised in Arm 1 and 67 in Arm 2. Median age is 71 y (66 – 80). Patients’characteristics were similar between arms and the percentage of patients with aaIPI 2–3 is 59%. Mean Hb level at randomisation is 12.2 g/dL (7.1 – 15.6). There rate of deaths during the treatment period is similar between arms (8% and 10%) and mainly related to treatment toxicity or lymphoma progression. The number of serious adverse events of any cause is lower in Arm 1 (96 events) compared to Arm 2 (153 events). Grade 3–4 Hb toxicity is higher in Arm 2 (39% versus 22%, p = NS). 18/63 (29%) patients received red blood cells transfusions in Arm 1 compared to 37/67 (55%) in Arm 2 (p=0.01). The number of patients with at least one episode of febrile neutropenia is lower in Arm 1 as compared to in Arm 2 (23% vs 36%, p = NS). There is no increase of cardiac and vascular events (respectively 9% and 9% in Arm 1 compared to 8% and 10% in Arm 2). The median level of Hb in Arm 1 during treatment is 12.05 g/dL and 10.65 g/dL in Arm 2. Sixteen percent of patients in Arm 1 have had at least one episode of Hb > 15 g/dL during treatment compared to 5% in Arm 2. The rate of thromboembolic events is similar in these patients (2/10) and in those who never have reached this Hb level (7/53). One year after completion of treatment, overall survival (OS) of the entire population is estimated at 74% and event free survival (EFS) at 67%. OS (78% in Arm 1 versus 70% in Arm 2 at 1 year) and EFS (73% in Arm 1 versus 64% in Arm 2 at 1 year) are similar between the two arms.

Conclusions: these preliminary results provide encouraging results about the safety of a prophylactic use of Darbepoetin alfa and support the continuation of accrual to draw definite conclusions about safety and also efficacy.