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PubMed2005

Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group.

BACKGROUND AND OBJECTIVES: Although bendamustine has been used for more than 30 years in the treatment of lymphoma, little is known about the optimal dosing schedule in relapsed or refractory B-cell chronic lymphocytic leukemia (CLL). Various dose and treatment schedules have been used empirically, and several phase II studies have shown impressive efficacy. To determine the maximal tolerated dose, dose-limiting toxicity and the optimal therapeutic dose of bendamustine for further phase III clinical trials the GCLLSG designed a phase I/II study for pre-treated CLL patients. DESIGN AND METHODS: Sixteen patients (median age 67 years) with relapsed or refractory CLL were enrolled. All patients had been pre-treated with a median of three different regimens. Bendamustine was given at a starting dose of 100 mg/m2 on day 1 and 2, repeated every 3-4 weeks. RESULTS: Major toxicities were leukocytopenia (CTC grade 3+4) in 8/16 and infections (CTC grade 3+4) in 7/16 patients. Six patients had dose-limiting toxicity which led to dose de-escalation from 100 to 70 mg/m2 in three patients. The maximum tolerated dose was 70 mg/m2. According to NCI-WG criteria, 9/16 patients (56%) responded to therapy, seven to doses <or=80 mg/m2. Two patients achieved complete remission. Five patients had a partial response and two patients stable disease. The median duration of response was 42.7 months. After a follow-up period of 53.2 months, five patients (31%) were still in remission. The median overall survival time for all patients was 45.6 months. INTERPRETATION AND CONCLUSIONS: The study confirms the excellent efficacy of bendamustine in heavily pre-treated and treatment-refractory patients, even at reduced doses of 140 mg/m2 per course. In pre-treated CLL patients, impaired bone marrow function is likely to enhance the myelotoxic side effects of bendamustine. Based on these results, the recommended optimal therapeutic dose of bendamustine in refractory CLL is 70 mg/m2 on days 1 and 2 every 4 weeks.

Aged↗
PubMed1991

[Pharmacokinetics of bendamustin (Cytostasan) in B6D2F1-mice].

The pharmacokinetics of bendamustine, (1; Cytostasan), an alkylating antineoplastic agent of the N-lost group, was investigated in B6D2F1 mice. After i.v. injection of the maximally tolerated dose of 50 mg/kg a rapid decrease of the unchanged drug in plasma (MRT 21.9 min) and slowly decreasing levels of mono-, dihydroxy and beta-hydroxy-1 were observed. Variations of the age of the animals as well as of the dose administered did not alter the short MRT of 1. 1 is excreted via the kidneys to a considerable extent showing a similar metabolite pattern in urine as in plasma. The absorption of the drug from the gastrointestinal tract is incomplete resulting in an absolute bioavailability of about 40%.

Administration, Oral↗
PubMed1991

Hepatobiliary elimination of bendamustin (Cytostasan) in rats.

Biliary excretion of bendamustin (Cytostasan, 5-[bis(2-chloroethyl)amino]-i-methylbenzimidazole-2-butyric acid; 1) and its metabolites was studied in rats after i.v. administration of 14C-1. The most significant finding was the rapid excretion of 1 related radioactivity in the bile occurring shortly after injection. While radioactivity eliminated by bile within 2 h was 41.8%, in the course of subsequent 22 h it amounted only to 3.2%. Bile samples analyzed by TLC indicated that the total amount of radioactivity was excreted in the form of conjugates and two hydroxy metabolites. A significant amount of radioactivity was excreted in urine. The diversion of bile by cannulation of the bile duct led to a significant decrease of elimination by feces.

Animals↗
PubMed1991

[Synthesis of a potential metabolite of the carcinostatic bendamustin (Cytostasen)].

The synthesis of the methylester of (5-[Bis(2-chlorethyl)amino]-1-methyl-benzimidazolyl-(2))ethanolic acid (4) has been described. The assumption that the butanoic acid group of the anticancer drug bendamustine (Cytostasan) will be biotransformed in patients to the ethanoic acid group as found for chlorambucil has been disproved by means of a comparison of the methylated metabolites and 4 by MS and HPLC.

Antineoplastic Agents↗
PubMed1989

[Therapeutic results and toxic side effects of the combination cytostasan, adriamycin and vincristine as second-line therapy of metastatic breast cancer].

Remission rate of 30-50% can be obtained by different cytostatic combinations in second-line-therapy of the metastasized breast cancer. The combination of adriamycin and vincristine with cytostasan reveals a remission rate of 52% in 50 CMF-pretreated female patients. Considerable toxic side effects led to a dose reduction of cytostasan and adriamycin in 31 female patients without clinical efficiency loss. The long remission periods of the total responders (5+ -23 months) are remarkable. Both 3 female patients with bone +/- soft tissue metastasis and 3 female patients with visceral metastasis benefited from a clinical total remission. The remission rates indicated no significant differences between the group of patients with soft tissue +/- bone metastasis (56.3%) and that with a predominantly visceral metastasis (50.0%). The CyAV-combination with a low dose provides an effective therapeutical scheme with acceptable side effects for CMF-pretreated female patients with breast cancer.

Adult↗
PubMed1989

[Experiences with intra-arterial tumor chemotherapy of malignant liver tumors via totally implantable catheter systems].

Locoregional chemotherapy was applied to 30 patients for isolated, surgically not removable liver tumours (13 colorectal carcinomas, 17 carcinomas on different sites). Ten patients were in Stage I, 16 in Stage II, and four in Stage III. Cytostatics were administered through totally implantable catheter systems. The following therapeutic protocol was mainly used: 5-flourouracil 800-1,000 mg/m2/3hr/die X 5 in 22 days, adriamycin 30 mg/m2/3 hr/die X 2 in 22 days. The average time of treatment amounted to ten months. Cytotoxis side effects were of minor importance. Hepatic side effects, such as chemical hepatitis or sclerosing cholangitis, were not recordable. Reduction of tumour size by 50 percent or more was recorded by computed tomography from 14 cases (46.6 percent). The objectivated rate of responsiveness in patients with colorectal carcinoma was 61.5 percent. The average period up to progression amounted to 12.1 months. Premortal spreading of the disease beyond the liver was recorded from six patients.

Antineoplastic Agents↗
PubMed1988

Stability studies of 14C-Cytostasan solutions and its extraction using dicarbolide of cobalt.

In this study the stability of 14C-Cytostasan (1, bendamustine), in water solutions was investigated. In distilled water a rapid degradation of carrier-free 14C-1 occurred. The degradation products of 14C-1 are 14C-monohydroxy-1 and 14C-dihydroxy-1 (evidence with the TLC). The degradation rate of 14C-1 was reduced by addition of nonlabelled 1 to the 14C-1 stock solution. The possibility of using distribution coefficient as a stability indicator of 14C-1 solutions was investigated. A number of organic solvents ranging from polar to nonpolar were used for extraction of 14C-1 from water solution. Only ethyl acetate was slightly effective. The distribution coefficient of 14C-1 was dramatically enhanced in presence of dicarbolide of cobalt (DC-H+) in benzene at extraction from HClO4 (0.5 mol.l-1).

Bendamustine Hydrochloride↗
PubMed1988

[Renal actions of bendamustin (Cytostasan) in rats].

In adult rats influences of single doses of bendamustin (0.5, 1 or 5 mg/100 g b.wt. i.p.) on kidney function were measured (time of experimentation 8 d following administration). Bendamustin administration is followed by an increase of kidney weight caused by a higher water content of kidney tissue. An increase of plasma concentrations of creatinine and of urea following bendamustin (1 or 5 mg/100 g b.wt. i.p.) indicates a reduced excretion capacity of kidney. Bendamustin administration is not connected with a distinct proteinuria. The highest administered does (5 mg bendamustin/100 g b.wt. i.p.) caused an oliguric effect connected with a distinctly reduced renal excretion of osmotically active substances. There is a distinct diminution of renal excretion of sodium following bendamustin administration and a decrease of renal excretion of PAH can be stated. It is most likely that bendamustin can reduce the glomerular function: Following administration of 1 mg bendamustin/100 g b. wt. i.p. CIn is reduced whereas a statistically significant increase of tubular transport capacity for organic anions can be measured (TmPAH).

Animals↗
PubMed1985

[The pharmacokinetics of bendamustine (Cytostasane) in humans].

The pharmacokinetics of bendamustine (Cytostasane) was determined in plasma on seven patients after its intravenously and oral application, respectively. Cytostasane was given in a dosis of 4.2-5.5 mg . kg-1 as an intravenous infusion over 3 min and as gelatine capsules in a 7-d intervall. Its elimination from the plasma is fast, monoexponentially and two-phasic after intravenous application (t1/2 alpha = 9.6 min, t1/2 beta = 36.1 min). The AUC was 11.17 micrograms . ml-1 . h, the central distribution volume 11.15 l and the distribution volume in steady state 20.51 l. The mean total clearance was 528.9 ml . min-1. After oral application maximal plasma levels of Cytostasane were detectable before 1 h. The mean oral bioavailability was 0.57, ranged from 0.25 to 0.94. Cytostasane undergoes metabolism. Its hydrolysis in plasma is slow (t1/2 = 1.67 h). After Cytostasane the depression of leucocytes was mild.

Bendamustine Hydrochloride↗
PubMed1983

[Animal experimental examination of a phase III study on the effect of the combination therapy of bruneomycin, cytostasan and prednisone].

The effectivity of a combined application of Bruneomycin, Cytostasane and Prednisone has been tested in five qualitatively different experimental animal test models. The selected dose levels and the treatment schedule were based on an instruction given in a phase III-study. No effectivity was demonstrable in any of the tumor systems selected neither with the single components, nor with their combination, though the toxicity clearly revealed a dose dependence.

Animals↗
PubMed1982

The effect of ZIMET 3164 and ZIMET 3393 on phagocytosis in Tetrahymena pyriformis GL.

Tetrahymena pyriformis GL is a suitable model to study the influence on phagocytotic activity of two membrane-stabilizing benzimidazole nitrogen mustard derivative, ZIMET 3164 and ZIMET 3393 (cytostasan). Treatment by both compounds causes a gradual inhibition of food vacuole formation dependent on the concentrations used. Complete cessation of phagocytosis is observed by 5 micrograms/ml ZIMET 3164 and 50 micrograms/ml ZIMET 3393. Additionally, disturbances of ciliary movement including immobilization and changes of cell shape are induced. The cells resume food vacuole formation and ciliary movement after being rinsed with control solution. The results correspond well with those described recently in mammalian mononuclear phagocytes.

Animals↗
PubMed1980

[Stereologic studies on the mechanism of action of two 1,2-substituted 5-bis-(beta-chlorethyl)aminobenzimidazole derivatives].

The effects of two 1,2-substituted 5-bis-(beta-chloroethyl)-amino-benzimidazole derivatives on the course of phagocytosis in murine peritoneal macrophages after intraperitoneal injection of bovine fibrin has been investigated by means of quantitative ultrastructural stereologic methods. One of the compounds, IMET 3164, is a strong immunosuppressive agent with membrane-stabilizing effects while the other one, IMET 3393 (Cytostasan) is an effective cytostatic drug with weak immunological effects. From the results the following conclusions can be drawn. After stimulation by intraperitoneal injection of fibrin, macrophages of untreated animals show a rapid antigen uptake and digestion as well as a formation of new lysosomes. Simultaneously, an immigration into the peritoneal cavity of monocytes and an emigration of strongly storing macrophages takes place. After treatment with either benzimidazole-N-mustard derivative, most pronounced after IMET 3164, a delayed antigen phagocytosis and digestion and an inhibition of formation of new lysosomes can be observed. Likewise, the intraperitoneal cell fluctuation is strongly reduced after IMET 3164. The findings lend support to the hypothesis that immunosuppression may be induced, among other mechanisms, by an inhibition of phagocytosis and antigen processing by means of membrane-stabilizing compounds.

Animals↗
PubMed1996

Selective uptake of the anticancer drug bendamustine by liver and kidney tissues following its intravenous administration to mice.

Distribution of 14C-bendamustine following intravenous (i.v.) administration to mice was examined by whole body autoradiographic (WBAR) and quantitative techniques. The WBAR study showed that 14C-bendamustine-derived radioactivity was distributed extremely unevenly at each time interval investigated. After 5 min of administration the highest density of radioactive material was found in the liver and in the kidney. At all time intervals investigated the brain remained free of the label. In a detailed quantitative distribution study it was found that 14C-bendamustine-derived radioactivity was also unevenly distributed throughout the mouse tissues. At 5 min postdosing the level of 14C was by one order higher in the liver and in the kidney in comparison to the lungs, heart, spleen, and muscle. The results of both WBAR and quantitative tissue distribution studies suggest that bendamustine was selectively taken up from the blood by liver and kidney tissues. Because of this pharmacokinetic property, dose modification should be taken into consideration when administering the drug to patients suffering from hepatobiliary and kidney disorders.

Animals↗
PubMed1998

[Chemotherapy of advanced non-small-cell and small-cell bronchial carcinoma with bendamustine--a phase II study].

In the palliative treatment of advanced SCLC and NSCLC there is a big need for effective and well tolerable drugs. Bendamustin is an alcylatic agent which had shown activity in the treatment of Non Hodgkin- and Hodgkin-Lymphoma as well as in the treatment of solid tumors like Mamma-Carcinoma and Colorectal-Carcinoma. We treated 21 patients with NSCLC (5 pat. Stad. III b, 16 pat. Stad. IV) and 22 pat. with Extensive Disease SCLC with Bendamustin 70 mg/m2 i.v., day 1-4 (q.28 days). We observed a response rate of 40.9% in the patients with SCLC (9 PR/40.9%), (0 CR) and no response in the patients with NSCLC. Hematologic toxicity in both groups was mild (Leucopenia WHO 1 + 2: 13 pat./30.2%, WHO 3: 2 pat./4.6%; Anemia WHO 1 + 2: 13 pat./30.2%, WHO 3: 1 pat./2.4%; Thrombopenia WHO 1 + 2: 4 pat./9.6%, WHO 3: 1/2.4%). Non Hematologic toxicity consisting of Nausea/Vomiting (WHO 2 + 3:13 pat./30.2%), Diarrhea (WHO 2 + 3:3 pat./7%), Obstipation (WHO 1 + 2: 2 pat./4.6%), Fever (WHO 1 + 2: 9 pat./20.9%) and Alopecia (WHO 1 + 2: 13 pat./31.7%, WHO 3: 1 pat./2.4%) was well tolerable. Cardiac Arrhythmias occurred in 7 pat./16.3% and PNP in 2 pat./4.6%. Treatment had to be stopped in one patient because of an allergic skin reaction. Bendamustin is a well tolerable cytostatic drug with a remarkable activity in advanced SCLC which is comparable to other well known agents in the treatment of this disease. Because of the good toxicity profile a combination with other compounds might be feasible. In advanced NSCLC Bendamustin showed no activity.

Aged↗