Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial.

The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re-evaluated after a median observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow-up, investigator-assessed complete response (CR) rate (21·0% vs 10·8%), median progression-free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non-responders. However, patients with objective response or a CR experienced a significantly longer OS than non-responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first-line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.

Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia.

PURPOSE: This randomized, open-label, parallel-group, multicenter study was designed to compare the efficacy and safety of bendamustine and chlorambucil in previously untreated patients with advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Patients (

A phase I study of bendamustine hydrochloride administered once every 3 weeks in patients with solid tumors.

The present phase I trial was planned to assess the maximum tolerated dose, the dose-limiting toxicity and the pharmacokinetics of bendamustine hydrochloride in a once every 3 weeks schedule, and to recommend a safe dose for future phase II studies. Included were patients with refractory solid tumors. Bendamustine hydrochloride was administered as a short intravenous infusion over 30 min. The starting dose was defined at 160 mg/m2 and dose escalation used increments of 20 mg/m2. Plasma and urine samples were analyzed using validated high-pressure liquid chromatography/fluorescence assays. Twenty-six patients (14 men, 12 women) were enrolled for the study. At 280 mg/m2, one out of four patients developed a thrombocytopenia grade 4, two experienced grade 3 fatigue and three experienced cardiac toxicity (grade 2). The latter toxicity was considered dose limiting also and further dose escalation was stopped. Plasma pharmacokinetics parameters of bendamustine hydrochloride and its metabolites were assessed in 15 patients. Mean pharmacokinetic parameters of bendamustine hydrochloride were a tmax of 32.3 min, a t1/2 of 37.8 min, a volume of distribution of 14.2 l/m and a clearance of 287.8 ml/min/m2. No dose dependency of bendamustine hydrochloride was observed within the used dose range. The metabolites comprised only 23% of the overall area under the concentration-time curve. The maximum tolerated dose of bendamustine hydrochloride on day 1 q 3 weeks is 280 mg/m2. Fatigue and cardiac toxicity were dose limiting. The plasma pharmacokinetics data of bendamustine and its metabolites were in accordance with previous reports. The recommended dose for future trials is 260 mg/m2 every 3 weeks.

Synthesis and characterization of some new phase II metabolites of the alkylator bendamustine and their identification in human bile, urine, and plasma from patients with cholangiocarcinoma.

The alkylating agent bendamustine is currently in phase III clinical trials for the treatment of hematological malignancies and breast, lung, and gastrointestinal tumors. Renal elimination mainly as the parent compound is thought to be the primary route of excretion. Because polar biliary conjugates were expected metabolites of bendamustine, three cysteine S-conjugates were synthesized, purified by quantitative high-performance liquid chromatography (HPLC), and characterized by NMR spectroscopy and mass spectrometry (MS). HPLC assays with MS, as well as fluorescence detection of bile, urine, and plasma after single-dose intravenous infusion of 140 mg/m(2) bendamustine in five subjects with cholangiocarcinoma, indicated the existence of these phase II metabolites, which were identified as cysteine S-conjugates by comparison with the previously characterized synthetic reference standards. The sum of the three cysteine S-conjugates of bendamustine was determined in human bile and urine to be 95.8 and 26.0%, respectively, expressed as mean percentage of the sum of the parent compound and identified metabolites. The percentage of administered dose recovered in urine as cysteine S-conjugates ranged from 0.9 to 4.1%, whereas the total percentage of the administered dose excreted in urine as the parent drug and seven metabolites ranged from 3.8 to 16.3%. The identification of cysteine S-conjugates provide evidence that a major route of bendamustine metabolism in humans involves conjugation with glutathione. Results indicate the importance of phase II conjugation in the elimination of bendamustine, besides phase I metabolism and hydrolytic degradation, and require further investigation.