Bendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity profile, when used as first-line therapy in patients with advanced CLL.

Introduction: Bendamustine (BEN) is a purine analog / alkylator hybrid agent with a particular mechanisms of action that provides effective treatment for a number of hematologic and non-hematologic malignancies. It is used primarily for chemo-naïve, relapsed or refractory B-CLL as well as for other types of non-Hodgkin’s lymphomas. The aim of this randomized phase III, open-label, multicenter study was to compare the efficacy and safety of BEN versus chlorambucil (CLB) in treatment-naïve patients (pts) with B-CLL Binet stage B/C. Patients and Methods: Pts with untreated B-CLL were randomized to receive BEN (100 mg/m2 on days 1+2) or CLB (0.8 mg/kg on days 1+15) for up to 6 treatment cycles. Primary endpoints were overall remission rate (ORR), defined as complete response (CR), nodular partial response (nPR) and partial response (PR), confirmed after 8 weeks, and progression-free survival (PFS). Secondary endpoints were duration of remission, overall survival (OS), safety, and quality of life (QoL). Follow-up was for ≥12 months after completion of treatment of the last patient, or until progression for pts with CR, nPR or PR and stable disease, or until death or lost to follow-up. A 5-stage, adaptive-group, sequential procedure was used with planned interim analyses to adjust the number of pts. Safety and efficacy were assessed by an Independent Data Monitoring Committee. Results: 305 pts were randomized to receive BEN (n=156) or CLB (n=149). As 7 pts did not receive study medication, 298 pts were included in the safety analysis. At the time of this analysis, 264 pts (139 BEN; 125 CLB) were available for the efficacy analysis. For both treatment groups: median age was 64 years; 70% had Binet stage B and 30% Binet stage C disease; median number of cycles/patient was 6; median follow-up was 18.5 months. ORR was significantly higher with BEN than with CLB (68% vs 39%; p<0.0001), with a CR of 30% vs 2%, respectively. Among the subgroups with Binet stage B and C disease, ORR was 70% and 61%, respectively, with BEN, vs 47% and 22%, respectively, with CLB. Median PFS (Kaplan-Meier estimate) was 21.7 months with BEN and 9.3 months with CLB (p<0.0001), and median duration of remission was 18.9 months with BEN and 6.1 months with CLB (p<0.0001). No difference in OS was seen between groups. Toxicity of BEN was manageable and did not impair QoL when compared with CLB. Infection rates (common toxicity criteria grades III+IV) were low in both groups (5.8% BEN; 3.5% CLB). Conclusions: BEN was significantly more effective than CLB in achieving remissions in treatment-naïve pts with B-CLL Binet stage B/C; median PFS and duration of remission were also significantly longer. Furthermore, safety data indicate that BEN toxicities are manageable and the drug is well tolerated. On the basis of these results, BEN should be considered as first-line chemotherapy for patients with B-CLL Binet stage B or C.

Objectives The objective of the present study was two fold: first, to determine the pharmacokinetic (PK) profile of the plasma-derived FIX concentrate AlphaNine® in patients with congenital severe haemophilia B (FIX:C 2%). To do this, two PK studies were carried out one six months after the first. The second objective was a comparison of the Alphanine® PK profile with the recombinant Factor IX, BeneFIX®. Patients and methods The first study was a prospective, five-center, open-label, comparative, PK study carried out in 25 severe hemophilia B patients who received 2 single doses of 65–75 IU/kg of AlphaNine® within 6 months (t=0 and t=6). The following parameters were assessed: in vivo recovery, half-life, AUC, mean residence time and clearance. As an extension of the study, a single dose of 65–75 IU/kg of BeneFIX® was administered in 9 out of 25 patients, after a wash-out period of 7–15 days. Results Table 1 summarizes the results obtained when comparing AlphaNine® within a period of time of 6 months (PK1 vs PK2) in 25 patients. Table 2 shows the results obtained when comparing the in vivo recovery of AlphaNine ® vs BeneFIX ® in the 9 patients studied. Conclusions These results confirm that AlphaNine® PK has similar profile as other plasma derived FIX products presently available to treat Hemophilia B patients. In addition, our results show that the recombinant FIX studied, BeneFIX® has a reduced in vivo recovery when is compared to AlphaNine®. Table 1 Parameter AlphaNine® (PK1) t=0 m AlphaNine® (PK2) t=6 m Results are expressed as Mean (SD) In vivo recovery (IU/dl:IU/kg) 1.0 (0.2) 1.2 (0.4) Half-life (h) 34.5 (6.2) 33.7 (5.4) Clearance (ml/min) 0.07 (0.01) 0.07 (0.01) AUC0-inf (IUxh/dl) 1602 (312) 1644 (360) MRT0-inf (h) 35.8 (5.4) 34.6 (5.2) Table 2 Parameter AlphaNine® (PK2) BeneFIX® Results are expressed as Mean (SD); * p<0.05 for the comparison of the in vivo recovery for the BeneFIX® group with the AlphaNine® PK2 In vivo recovery (IU/dl:IU/kg) 1.3 (0.5) 0.8 (0.2)*