Mitoxantrone, prednimustine, and vincristine for elderly patients with aggressive non-Hodgkin's lymphoma.

Elderly patients with intermediate- or high-grade non-Hodgkin's lymphoma have a worse outcome than those who are younger than 60 years. It has been shown that aggressive combination chemotherapy is poorly tolerated in older patients resulting in a subsequent decrease in dose intensity. A phase II trial was conducted with mitoxantrone, prednimustine, and vincristine (NSO) in this group of patients. NSO consists of mitoxantrone 12 mg/M2 intravenously on day one, vincristine 1.4 mg/M2 intravenously on day 1 (maximum dose of two mg), and prednimustine 100 mg/M2 orally once a day for four days. NSO was repeated every 21 days. Thirty-six patients were able to be evaluated. There were 18 males and 18 females with the median age of 71 (range 60-85). NSO was well tolerated and nonhematological toxicities were uncommon. More than 80% of the patients received 90% or greater of the intended dose. The complete response rate was 60.6% and partial response was 21.8%. At 60 months the Kaplan-Meier estimate of progression-free survival was 47.9% (standard error 8.6%) and actual survival was 40.6% (standard error 8.8%). There were no differences in outcome between those with performance status (PS) of zero or one and those with PS > 1. NSO is well tolerated by elderly patients including those with PS > 1. These results compare favorably with other combinations in elderly patients with aggressive non-Hodgkin's lymphoma.

Prednimustine and mitoxantrone (PmM) in patients with low-grade malignant non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and prolymphocytic leukemia (PLL).

Thirty-five patients with a mean age of 60.6 years (44-78 years, 22 male, 13 female) with advanced low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or prolymphocytic leukemia (PLL) were treated every 4 weeks with prednimustine 100 mg/m2 p.o. d 1-d 5 and mitoxantrone 8 mg/m2 i.v. d 1 and d 2. Seven patients had CLL, one lymphocytic NHL, two PLL, 13 immunocytoma, nine centroblastic/centrocytic NHL, and three centrocytic NHL. Twenty-five patients were pretreated. The subjective toxicity of the treatment was mild, with no WHO grade-3 alopecia, polyneuropathy, cardiotoxicity, mucositis, nausea, or vomiting. Hematologic side effects with WHO grade-4 granulopenia and thrombopenia were experienced by 26% and 23% of the patients, respectively. The overall response rate (CR+PR) was 72% for lymphoma patients and 37% for CLL patients, with a median remission duration of 14.6 months. The maximum response was achieved after a median of two treatment courses. Prednimustine with mitoxantrone is a subjectively well tolerated treatment for low-grade malignant NHL, to be further evaluated in phase-III studies. The regimen may shorten the duration of treatment, saving time-consuming out-patient visits and costs.

Long-term toxicology effects of prednimustine in comparison with chlorambucil, prednisolone, and chlorambucil plus prednisolone in Sprague-Dawley rats.

Chlorambucil was linked to prednisolone to improve the therapeutic and toxic properties of this potent alkylating agent, which is known to induce second tumors in humans. To compare the carcinogenic potency of the linked compound with that of the respective individual agents and of their unlinked mixture, prednimustine (I), chlorambucil (II), prednisolone (III), chlorambucil plus prednisolone (IV), or vehicle were administered to groups of 120 female Sprague-Dawley rats for 18 months. The following doses were administered nine, four, five, two times, or once a month per subgroup of 30 rats: I, 12 mg/kg; II, 3 mg/kg; III, 3 mg/kg; IV, 3 mg/kg. After natural death of animals, median survival times were analyzed, and percentages of malignant tumors were recorded. An increased tumor risk was found in the following organs compared with those of vehicle-treated controls: I, external auditory canal (EAC); II, mammary gland (MG), central and peripheral nervous tissue (CPNT), hematopoietic and lymphatic tissue (HLT), and EAC; III, none; and IV, MG, CPNT, and EAC. There is evidence of carcinogenic activity of prednimustine compared with untreated controls, but the cancer-inducing potential of the linked compound is distinctly lower than that of the unlinked mixture of chlorambucil plus prednisolone or that of chlorambucil.

Cytotoxicity and metabolism of prednimustine, chlorambucil and prednisolone in a Chinese hamster cell line.

Prednimustine and chlorambucil induce dose- and time-dependent cell death in V79 Chinese hamster cells in vitro. Prednimustine was found to be 3-4 times more potent than either chlorambucil or an equimolar mixture of its components chlorambucil and prednisolone after 24 h treatment. Prednimustine was hydrolyzed to prednisolone and chlorambucil in the system, and the concentration of prednimustine was reduced by one half within 15 h. Prednisolone was not further metabolized, but chlorambucil was rapidly inactivated by dechlorination, the half-life being 2.5 h. No dechlorinated prednimustine was formed during the experiments. The higher stability of prednimustine than chlorambucil is probably due to protective binding to different serum proteins from those that bind chlorambucil. Substitution of fetal calf serum by human serum albumin revealed that hydrolysis of prednimustine is catalyzed by esterases present in the serum. In similar substitution experiments cell survival studies indicated that prednimustine itself was not cytotoxic. Rather, cytotoxicity was found to correlate with hydrolysis to chlorambucil. Thus, it appears that the prolonged availability of chlorambucil is responsible for the increased potency of prednimustine in this system.

Comparative carcinogenic activity of prednimustine, chlorambucil, prednisolone and chlorambucil plus prednisolone in Sprague-Dawley rats.

This study compares long term toxic effects of equivalent doses of prednimustine (12 mg/kg) chlorambucil (3 mg/kg), prednisolone (3 mg/kg) and chlorambucil plus prednisolone (3 mg/kg each) in comparison to vehicle treated controls after regular administration over a period of 18 months to 600 female Sprague Dawley rats. Frequency of administration to subgroups (30 rats each) varied between 9 (a), 4.5 (b), 2 (c) times or once (d) a month. When comparing organ specific, age-adjusted expected versus observed incidences after natural death of animals an increased tumor risk was found in organ systems of all treatment modalities but prednisolone. Prednimustine-administration was related to an elevated risk of developing squamous-cell carcinomas of the external auditory canal only (alpha = 0.013), whereas simultaneous application of chlorambucil plus prednisolone induced significantly higher rates of adenocarcinomas of the mammary gland, of malignant tumors of the central and peripheral nervous tissue and of squamous cell carcinomas of the external auditory canal (alpha less than 0.01 for each tissue). Chlorambucil alone caused a significantly higher rate of malignancies of the hematopoietic and lymphatic tissue (alpha less than 0.01) additionally to effects observed after the unlinked mixture of chlorambucil plus prednisolone. There is evidence of carcinogenic activity of prednimustine compared to untreated controls, but the cancer-inducing potential of the linked compound is distinctly lower than that of the unlinked mixture of chlorambucil plus prednisolone or of chlorambucilalone.

Comparison of the cytotoxic effect of prednimustine in cultured cells with high or low levels of metallothionein.

The purpose of this investigation was to evaluate the ability of the cysteinyl-rich protein metallothionein (MT) to protect cells against the cytotoxic effects of prednimustine, an ester of chlorambucil and prednisolone. The cells studied were MT-rich substrains of murine fibroblasts (C1 1D100) and human epithelial cells (HE100), both demonstrated in an earlier report to exhibit an approximate 3-fold increase in resistance to chlorambucil compared to their parent lines (C1 1D and HE) (Endresen et al. 1983). Both in cloning and in growth rate studies the MT-rich strains proved to be significantly more resistant also to prednimustine. E.g. in cloning studies D0 for C1 1D cells (D0 = the dose of drug reducing survival to 1/e) was 8.7 micrograms/ml prednimustine, whereas D0 for C1 1D100 was 12.4 micrograms/ml, representing an approximate 1.5-fold increase in resistance, P less than 0.001, t-test. Other cloning studies revealed that prednimustine had a significantly higher cell killing activity in the resistant cells than equimolar concentrations of its components, single or in combination. Following treatment with 3H, 14C-prednimustine (3H in the prednisolone moiety, 14C in the chlorambucil moiety) and subsequent gel filtration, about 40% of the cytosolic chlorambucil eluted with MT. However, no intact prednimustine was recovered in the MT fractions. The data indicate that the MT-rich cells possess increased resistance to prednimustine due to a sequestration by MT of the alkylating moiety. Since the interaction probably does not take place until after hydrolysis, it is possible that the intact conjugate may bypass this cellular defence mechanism.

The pharmacokinetics of prednimustine and chlorambucil in the rat.

In the rat prednimustine, the prednisolone ester of chlorambucil, is much less toxic than equimolar doses of chlorambucil, when administered subcutaneously (SC). This is due to differences in alkylating agent pharmacokinetics. Prednimustine injected SC produced low plasma concentrations (less than 5 microM) of the alkylating metabolites chlorambucil and phenyl acetic mustard, which were maintained for 48 h. No unhydrolysed prednimustine could be detected. Chlorambucil, in contrast, was rapidly absorbed, peak levels (40 microM) occurring within 2 h, after which chlorambucil and phenyl acetic mustard plasma levels decreased with half-lives of 2.4 h and 2.9 h respectively. The toxicity of chlorambucil could be similarly reduced by administering either the methyl ester of chlorambucil or by giving chlorambucil in a multiple-treatment low-dose schedule. Neither of these treatments inhibited the Yoshida alkylating agent-resistant tumour, however, whereas prednimustine or a combination of chlorambucil and prednisolone produced significant tumour growth inhibition. Prednisolone did not alter chlorambucil pharmacokinetics. Thus the reduced toxicity of prednimustine is due to chlorambucil esterification and the subsequent alteration in pharmacokinetics, whilst inhibition of alkylating agent-resistant tumours results from the combination of chlorambucil and prednisolone.