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PubMed1986

Selective immunomodulation by the antineoplastic agent mitoxantrone. II. Nonspecific adherent suppressor cells derived from mitoxantrone-treated mice.

Mitoxantrone exerts a potent suppressive influence upon humoral immune responses. The B cell is a likely target for this inhibitory effect, and we have reported evidence supporting this possibility. The impact of mitoxantrone upon T lymphocyte reactivity was assessed as a second mode of action of this novel antineoplastic drug. TH and TS lymphocyte induction were tested in the in vitro anti-sheep erythrocyte response, and a surprising differential effect of mitoxantrone was observed. Helper activity was abrogated and suppressor function was enhanced. In apparent disagreement with this result, mitoxantrone inhibited the in vivo induction of TS cells using trinitrophenylated spleen cells. Macrophages were investigated as potential mediators of these effects upon immunoregulatory function. Replacement of macrophages in mitoxantrone-treated spleen cell preparations by normal adherent cells allowed the induction and complete expression of TH lymphocyte function. Conversely, replacement of mitoxantrone-treated macrophages with normal adherent cells before induction of TS cells failed to generate TS cell function. Thus, TH cells were resistant and TS cells were completely susceptible to mitoxantrone. Furthermore, supplementation of normal TH cell cultures with splenic macrophages from mitoxantrone-treated mice inhibited the induction of helper function. Production of the lymphokines IL 2 and TRF in mitoxantrone-treated mice was normal. This is consistent with the retention of functional TH cells in drug-treated spleens. Macrophages in the spleens of mitoxantrone-treated mice were responsible for the abrogated helper function and the enhanced suppressor activity. Although TS cell induction was directly inhibited by the drug, the effect upon TH cell function was secondary to the action of mitoxantrone-induced suppressor macrophages. Mitogen-stimulated lymphokine production was normal. Thus, mitoxantrone is a selective immunomodulator. The macrophage-mediated suppression of TH cell induction and humoral immunity investigated in spleens from mitoxantrone-treated mice is an intriguing finding that may have significant implications for immunotherapy.

Animals↗
PubMed1997

Comparison of the structural changes induced by doxorubicin and mitoxantrone in the heart, kidney and intestine and characterization of the Fe(III)-mitoxantrone complex.

Histologic, nick end labeling for apoptosis and electron microscopic studies were made of the heart, kidney and small intestine in spontaneously hypertensive rats (SHR) treated for 12 weeks with doxorubicin (1 mg/kg/week), mitoxantrone (0.5 or 0.25 mg/kg/week) or saline (controls). Semiquantitative scoring showed that the severity of the cardiac lesions produced by doxorubicin was comparable to that resulting from 0.5 mg/kg mitoxantrone, but greater than that induced by 0.25 mg/kg mitoxantrone (to which it is therapeutically equivalent). The nephropathy and the intestinal toxicity produced by doxorubicin were also more severe than those resulting from either dose of mitoxantrone. Apoptosis of cardiac myocytes was not induced by either drug, but involved cardiac dendritic cells in SHR given doxorubicin. Apoptosis in renal tubular epithelium was comparable in SHR given doxorubicin and the higher dose of mitoxantrone. Doxorubicin induced more frequent apoptosis in intestinal epithelium than did the higher dose of mitoxantrone. We also show that mitoxantrone and iron(III) form a strong 2:1 complex, in which the drug may be acting as a tridentate ligand. This complex, like the iron(III)-doxorubicin complex, may be capable of redox cycling and producing reactive oxygen intermediates (ROI) that damage tissue. Decreased formation of ROI by mitoxantrone may account for its reduced cardiotoxicity compared to that of doxorubicin.

Animals↗
PubMed2004

Improved liquid chromatographic method for mitoxantrone quantification in mouse plasma and tissues to study the pharmacokinetics of a liposome entrapped mitoxantrone formulation.

A simple, rapid HPLC method for quantification of mitoxantrone in mouse plasma and tissue homogenates in the presence of a liposome entrapped mitoxantrone formulation (LEM-ETU) is described. Sample preparation is achieved by protein precipitation of 100 microl plasma or 200 microl tissue homogenate with an equal volume of methanol containing 0.5 M hydrochloric acid:acetonitrile (90:10, v/v). Ametantrone is used as the internal standard (i.s.). Mitoxantrone and i.s. are separated on a C18 reversed phase HPLC column, and quantified by their absorbance at 655 nm. In plasma, the standard curve is linear from 5 to 1000 ng/ml, and the precision (%CV) and accuracy (percentage of nominal concentration) are within 10%. In mouse tissue (heart, kidney, liver, lung, and spleen) homogenates (5%, w/v), the standard curve is linear from 25 to 2000 ng/ml, with acceptable precision and accuracy. The method was used to successfully quantify mitoxantrone in mouse plasma and tissue samples to support a pharmacokinetic study of LEM-ETU in mice.

Animals↗
PubMed2001

Mitoxantrone and fludarabine in the treatment of patients with non-Hodgkin's lymphoma failing primary therapy with a doxorubicinor mitoxantrone-containing regimen.

Patients with recurrent lymphoma of any grade were treated with mitoxantrone (12 mg/m2 given intravenously (IV) over 15-30 minutes on day 1) followed by fludarabine at a dose of (25 mg/m 2 given IV over 30 minutes on days 1-3) every 28 days fludarabine at a dose of (25 mg/m2 given IV over 30 minutes on days 1-3) every 28 days. All patients had failed one prior chemotherapy regimen that contained either doxorubicin or mitoxantrone, total dose not exceeding 350 mg/m2 doxorubicin or 80 mg/m2 mitoxantrone. mitoxantrone. Thirty one patients (22 with intermediate- or high-grade and 9 with low-grade NHL) were enrolled. Median age was 63 years (range: 21 to 87). The objective response rate for patients with intermediate/high-grade NHL was 55% (27% with CR) and 89% (56% with CR) for patients with low-grade NHL. Median time to disease progression was 5.1 months for patients with intermediate/high-grade NHL and 10.8 months for patients with low-grade NHL. Median time to death for patients with intermediate/high-grade disease was 11.4 months. Median time to death for patients with low-grade NHL was not calculable as only one death (due to respiratory failure) occurred in this group 6.5 months after study start. The regimen was well tolerated. Grade 3/4 neutropenia was reported in 80% (24 of 30) of patients and Grade 3/4 thrombocytopenia in 19% (6 of 31) of patients. Nine hospitalizations for adverse events (primarily fever and neutropenia) occurred among eight patients, all with intermediate/high-grade NHL, during a total of 118 cycles of therapy. Further studies of this combination regimen in patients with intermediate/high-grade NHL and studies combined with monoclonal antibodies in low-grade NHL are warranted.

Adult↗
PubMed1989

[Mitoxantrone containing multi-drug chemotherapy in the management of malignancies. Collaborative Group for Clinical Trial of Mitoxantrone].

182 patients with various malignancies treated by mitoxantrone containing multi-drug chemotherapy are reported. Sixteen cancer patients treated with adriamycin or epirubicin combined with other drugs during the same period served as control. Of these 182 patients, there were 171 evaluable patients. Fourty-four had complete remission, 64 partial remission, 38 stable lesions, and 25 progressive lesions with response rate of 63.2%. Fifty-five breast cancer patients treated with mitoxantrone, methotrexate and 5-fluorouracil gave a response rate of 52.7%; 82 malignant lymphoma patients who received cyclophosphamide, mitoxantrone, vincristine and prednisone regimen gave a response rate of 81.7%; 29 patients with gastrointestinal carcinoma as treated by UFT, mitoxantrone, mitomycin C lead to a response rate of 31.0% and 5 patients with other malignancies gave a response rate of 60.0%. Of the control group, there were 15 evaluable patients. 10 of 12 malignant lymphoma patients responded, while no effect was observed in 2 breast cancer and 1 gastric cancer patients. Acute and subacute toxicities in the two groups were observed and the factors influencing the therapeutic effects were analysed.

Adult↗
PubMed1986

[A phase II study of mitoxantrone in refractory and relapsed malignant lymphomas. Cooperative Study Group of Mitoxantrone in Malignant Lymphomas].

A phase II clinical trial of mitoxantrone in refractory or relapsed malignant lymphomas was conducted by a cooperative study involving 17 institutions. Of 46 patients entered, 33 were evaluable for responses and toxicity. Thirty-one of the 33 had been previously exposed to adriamycin at a median dose of 220 mg/m2 (range 21-489 mg/m2), and two additional patients had each been given THP-adriamycin at a dose of 80 mg/m2 or 4'-epi adriamycin at a dose of 69 mg/m2. Mitoxantrone was administered in 3 different schedules: 8-12 mg/m2, every 3-4 weeks in 23 patients; 4-6 mg/m2, weekly, in 3 patients; and 2-4 mg/m2, for 5 days, in 7 patients. Summarizing the responses obtained in the 3 schedules, there were 2 partial responders among 5 with Hodgkin's disease, while there were 8 complete responders and 4 partial responders among 28 with non-Hodgkin's lymphoma. The overall response rate for all the evaluable patients was 42% with a complete response rate of 24%. The median response duration was 7+ weeks (range 4-27+ weeks) for complete responders and 7 weeks (range 4-46+ weeks) for partial responders. The major toxicity was myelosuppression: leukocytopenia less than 3,000/microliter occurred in 79% of patients, and thrombocytopenia less than 75,000/microliter in 35%. Other toxic effects were minimal, mild nausea and/or vomiting occurred in 39%, and diarrhea in 3%. Possible drug-related liver and renal dysfunctions were observed in 19% and 10%, respectively. The favorable response to mitoxantrone in patients with prior anthracycline antibiotic therapy suggests that the drug is not fully cross-resistant with anthracycline antibiotics, and that this drug is of value in combination with other drugs as a salvage therapy for patients with refractory or relapsed malignant lymphomas.

Adolescent↗
PubMed2005

Separation of liposome-entrapped mitoxantrone from nonliposomal mitoxantrone in plasma: pharmacokinetics in mice.

A method is described for quantification of the liposomal and nonliposomal forms of mitoxantrone (MTO) in mouse plasma after intravenous administration of liposome-entrapped MTO Easy-to-Use (LEM-ETU) formulation. This is based on the property of liposome-entrapped MTO (LEM) to pass through reversed-phase C(18) silica gel cartridges, while nonliposomal MTO or free MTO is retained with strong hydrophobicity and later is eluted with acidic methanol. Extraction of LEM and free MTO from plasma is performed in two steps. This technique is rapid and sensitive and can be used for a large series of sample preparation. The plasma samples are found stable after one freeze-thaw cycle. The recovery of MTO, as well as the precision, linearity, and accuracy of the method for both free and liposomal MTO, appears satisfactory for pharmacokinetic studies. The pharmacokinetic results in mice show a sustained release of MTO from LEM-ETU.

Animals↗
PubMed2001

Resistance to mitoxantrone in multidrug-resistant MCF7 breast cancer cells: evaluation of mitoxantrone transport and the role of multidrug resistance protein family proteins.

We examined the role of multidrug resistance protein (MRP) 1 (ABCC1) in the emergence of mitoxantrone (MX) cross-resistance in a MCF7 breast cancer cell line selected for resistance to etoposide. The resistant cell line, MCF7/VP, expresses high levels of MRP1, whereas the parental cell line, MCF7/WT, does not. MCF7/VP cells are 6-10-fold cross-resistant to MX when compared with MCF7/WT cells. Drug transport studies in intact MCF7/VP cells revealed that MX resistance is associated with reduced MX accumulation due to enhanced MX efflux. MX efflux is ATP dependent and inhibited by sulfinpyrazone and cyclosporin A. Inhibition of MX efflux with these agents sensitizes cells to MX cytotoxicity and partially reverses MX resistance in MCF7/VP cells. Whereas resistance is partially attributable to increased MX efflux in MRP1-expressing MCF7/VP cells, we found no evidence for glutathione or other conjugates of MX in these cells. Moreover, glutathione depletion with buthionine sulfoximine had no effect on MX transport or sensitivity in MCF7/VP cells. MRP1 substrates are generally amphiphilic anions such as glutathione conjugates or require the presence of physiological levels of glutathione for MRP1-mediated transport. Therefore we conclude that MRP1 overexpression is unlikely to be responsible for increased MX efflux and resistance in MCF7/VP cells. In considering the potential involvement of other MRP family isoforms, a 3-fold increase in the expression of MRP5 was observed in MCF7/VP cells. However, stable expression of a transduced MRP5 expression vector in MCF7/WT cells failed to confer MX resistance. Because other transporters known to be associated with MX resistance, including P-glycoprotein and BCRP/MXR (ABCG2), are not expressed in MCF7/VP cells, we conclude that increased MX efflux and resistance in MCF7/VP cells is attributable to a novel transport mechanism or that MX represents a novel class of cationic, glutathione-independent MRP1 substrates.

ATP-Binding Cassette Transporters↗
PubMed2004

Mitoxantrone: a review of its use in multiple sclerosis.

Mitoxantrone (Novantrone), a synthetic anthracenedione derivative, is an antineoplastic, immunomodulatory agent. Its presumed mechanism of action in patients with multiple sclerosis (MS) is via immunomodulatory mechanisms, although these remain to be fully elucidated. Intravenous mitoxantrone treatment improved neurological disability and delayed progression of MS in patients with worsening relapsing-remitting (RR) [also termed progressive-relapsing (PR) MS] or secondary-progressive (SP) disease. In a pivotal randomised, double-blind, multicentre trial, mitoxantrone 12 mg/m(2) administered once every 3 months for 2 years provided significant improvements in neurological disability ratings, including Kurtzke Expanded Disability Status Scale (EDSS), Ambulatory Index (AI) and Standardised Neurological Status (SNS) scores, compared with placebo. The drug also significantly reduced the mean number of corticosteroid-treated relapses and prolonged the time to the first treated relapse, with the beneficial effects on disease progression supported by magnetic resonance imaging. Post hoc analyses suggest that the benefits associated with mitoxantrone treatment may be sustained for at least 12 months after cessation of treatment, mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo. Concomitant intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g once every month for 6 months was more effective than intravenous methylprednisolone monotherapy in preventing the development of new gadolinium-enhanced lesions in patients with very active RRMS or SPMS. The drug was generally well tolerated in patients with MS. Adverse events were generally mild to moderate in severity and usually resolved upon discontinuation of treatment or with appropriate pharmacotherapy. At the recommended dosage, mitoxantrone appears to have a low potential to cause cardiotoxicity. In conclusion, intravenous mitoxantrone reduces the relapse rate and slows progression of the disease in patients with worsening RRMS, PRMS or SPMS; thus providing a new option for the management of these patients. The drug was generally well tolerated at the recommended dosage, although potential cardiotoxicity limits the total cumulative dose to 140 mg/m(2). Further studies are warranted to determine which patients with worsening RRMS, PRMS or SPMS are most likely to benefit from mitoxantrone treatment and to more fully define the long-term safety and tolerability of mitoxantrone, including the use of concomitant cardioprotectants to extend the therapeutic lifespan of the drug. Pharmacodynamic Profile. Mitoxantrone, a synthetic anthracenedione derivative, is an established cytotoxic, antineoplastic agent. Its presumed mechanism of action in multiple sclerosis (MS) is immunosuppression. In antineoplastic studies, the drug showed several immunomodulatory effects, inducing macrophage-mediated suppression of B-cell, T-helper and T-cytotoxic lymphocyte function. Currently, the pharmacodynamic properties of mitoxantrone have not been investigated to any extent in patients with MS. In one study, 6 months' treatment with intravenous mitoxantrone generally had no effect on the distribution of cytokine-positive peripheral blood monocyte cells in patients with MS. In an animal model of the disease, mitoxantrone suppressed the development and progression of both actively and passively induced acute experimental allergic encephalomyelitis (EAE). It appeared to be 10-20 times more effective than cyclophosphamide in the suppression of EAE. Moreover, mitoxantrone approximately doubled the mean time to onset of EAE versus control animals (279 vs 148 days after immunisation; p < 0.00005). In vitro, mitoxantrone 10 and 100 micro g/L inhibited myelin degradation by leucocytes and peritoneal macrophages derived from mice with acute EAE by approximately 60% and 100%. Pharmacokinetic Profile. Currently, there are no published pharmacokinetic data for intravenous mitoxantrone in pitoxantrone in patients with MS, paediatric patients or in those with renal impairment. All studies, to date, have been in patients with cancer receiving a single, approximately 30-minute intravenous infusion of mitoxantrone 5-14 mg/m(2). The drug exhibits triexponential pharmacokinetics, with a rapid initial distribution (alpha) phase, an intermediate distribution (beta) phase and a much slower elimination (gamma) phase. The mean half-life of the alpha phase appears to be 6-12 minutes and that of the beta phase 1.1-3.1 hours. Mitoxantrone has a high affinity for tissue, with a volume of distribution of up to 2248 L/m(2). Mitoxantrone persists for prolonged periods in tissues and was detectable in autopsy tissue from patients who last received the drug up to 272 days before death. At concentrations of 10-10000 ng/mL, the drug was 70-80 % bound to plasma proteins in dogs. Elimination of mitoxantrone occurs predominantly through biliary excretion and may be impaired in patients with hepatic dysfunction or third space abnormalities (e.g. ascites). The mean terminal elimination half-life of mitoxantrone ranged from 23 hours to 215 hours. Renal clearance accounts for 10 % of the total clearance of the drug. Total clearance of mitoxantrone ranged from 13 to 34.2 L/h/m(2) and renal clearance from 0.9 to 2.7 L/h/m(2). The drug appears to have a low potential for interaction with other concomitantly administered agents. Therapeutic Efficacy. Intravenous mitoxantrone (infusion of > or = 5 minutes), either as monotherapy or in combination with intravenous methylprednisolone, delayed the progression of the disease in patients with secondary-progressive (SP) or worsening relapsing-remitting (RR) MS (the latter is also termed progressive-relapsing MS) in comparative, randomised, multicentre trials. In a double-blind, monotherapy trial (Mitoxantrone In Multiple Sclerosis [MIMS] trial), mitoxantrone 12 mg/m(2) (n = 60) once every 3 months for 2 years significantly improved neurological disability relative to placebo (n = 64), as assessed by changes in mean Kurtzke Expanded Disability Status Scale (EDSS) score, mean Ambulatory Index (AI) score and mean Standardised Neurological Status (SNS) score. The drug also significantly reduced the mean number of corticosteroid-treated relapses per patient and prolonged the time to the first treated relapse. A Wei-Lachin multivariate analysis of these five efficacy variables indicated that the global difference between the two treatment groups was 0.30 (p < 0.0001). Mitroxantrone was also more effective than placebo according to secondary endpoints in this study, with fewer mitoxantrone recipients experiencing a relapse, a deterioration of > or =1 EDSS point or a confirmed deterioration in EDSS score over a 3-month period. Mitoxantrone recipients also showed less deterioration in quality-of-life ratings and had fewer hospital admissions, whereas more placebo recipients had new gadolinium-enhanced lesions at study end (the latter parameter was assessed using magnetic resonance imaging [MRI] in a subgroup of 110 patients, including 40 patients who received an exploratory 5 mg/m(2) dose). Furthermore, post hoc analyses indicated that the beneficial effects of mitoxantrone treatment on EDSS, SNS and AI scores were sustained for at least 12 months after cessation of treatment, with mean changes from baseline at 36 months in EDSS, AI and SNS scores of 0.10, 0.61 and 0.19, respectively, in the mitoxantrone group versus 0.46, 1.13 and 3.38 with placebo. Preliminary data from a cost-minimisation analysis based on results from the MIMS trial indicated that approximately half of the cost of mitoxantrone was offset by cost savings in other areas associated with the treatment of MS (direct and indirect major costs), with a total annual incremental cost for mitoxantrone of dollar 1661 per patient. Combination therapy once-monthly with intravenous mitoxantrone 20mg plus intravenous methylprednisolone 1g was more effective than intravenous methylprednisolone 1g once every month in preventing the development of gadolinium-enhanced lesions in patients with very active RRMS or SPMS (double-blind assessment using MRI scans). After 6 months, significantly more combination therapy recipients had no new gadolinium-enhanced lesions (90.5% vs 31.3% with monotherapy; p < 0.001) [primary endpoint]. There were also significant reductions in both the mean number of new enhancing lesions and the total number of gadolinium-enhanced lesions in patients receiving combination therapy versus methylprednisolone monotherapy.Tolerability. Mitoxantrone was generally well tolerated in patients with MS. Treatment-emergent adverse events occurring significantly more frequently with mitoxantrone (12 mg/m(2) once every 3 months for 2 years) than placebo were nausea, alopecia, menstrual disorders, urinary tract infection, amenorrhoea, leucopenia and elevated gamma-glutamyltranspeptidase levels. Adverse events were usually mild to moderate in severity and generally resolved with discontinuation of treatment or when treated with appropriate pharmacotherapy. Eight percent of patients discontinued treatment in the mitoxantrone 12 mg/m(2) group due to an adverse event versus 3% of placebo recipients. The incidence of drug-related acute myelogenous leukaemia was very low (0.12%) in a cohort of 802 patients with MS receiving mitoxantrone. Evidence suggests that the risk of cardiotoxicity is low in patients with MS. After 1 year of monotherapy, 3.4% of mitoxantrone recipients had a reduction in left ventricular ejection fraction (LVEF) to < or =50% compared with 0% of placebo recipients; at the end of the second year, respective incidences were 1.9% and 2.9% (total cumulative dose of mitoxantrone per patient was 96 mg/m(2) after 2 years' treatment). (ABSTRACT TRUNCATED)

Animals↗
PubMed2006

Management of worsening multiple sclerosis with mitoxantrone: a review.

BACKGROUND: Mitoxantrone, an intravenously administered immunosuppressant that inhibits T-cell, B-cell, and macrophage proliferation, is indicated for reducing neurologic disability and relapse frequency in patients with secondary progressive multiple sclerosis (SPMS), progressive relapsing MS, or worsening relapsing-remitting MS (RRMS). OBJECTIVE: This article reviews the pathogenesis and natural history of MS and examines the available treatment options for patients with RRMS, worsening RRMS, or SPMS, with a focus on mitoxantrone. METHODS: MEDLINE (1966-present) and the Cochrane Central Register of Controlled Trials (1994-present) were searched for relevant randomized, blinded, controlled clinical trials using the terms mitoxantrone, Novantrone, and multiple sclerosis. RESULTS: Five randomized, blinded, controlled trials and an ongoing open-label Phase IV safety study were identified and included in this review. In one randomized, double-blind trial (N=25), patients with RRMS who received mitoxantrone 8 mg/m2 monthly had significantly reduced relapse rates at 1 year compared with those who received placebo (P=0.014). In a 2-year, randomized, partially blinded trial (N=51), patients with active RRMS who received mitoxantrone 8 mg/m2 monthly had significantly fewer relapses compared with those who received placebo (P<0.001), and significantly fewer patients had confirmed progression of disability (1-point increase in Expanded Disability Status Scale [EDSS] score) (P=0.02). In a randomized, double-blind trial (N=49), patients with relapsing SPMS who received mitoxantrone 12 mg/m2 monthly for 3 months followed by 12 mg/m2 g3mo for up to 32 months had significant improvements in EDSS scores compared with those who received methylprednisolone 1 g IV monthly for 3 months followed by 1 g IV g3mo (P=0.002 at 1 year, P=0.045 at 2 years) and significant reductions in the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) (P=0.002 at 1 and 2 years, P=0.03 at 3 years). In a randomized, partially blinded Phase II trial in 42 patients with active RRMS or SPMS, patients who received mitoxantrone 20 mg IV monthly and methylprednisolone 1 g IV monthly had significantly fewer new gadolinium-enhancing lesions on MRI (P<0.001) and significantly fewer relapses (P<0.01) at 6 months compared with those who received methylprednisolone alone. In a pivotal Phase III trial (N=194), patients with worsening RRMS or SPMS who received mitoxantrone 12 mg/m2 g3mo for 2 years had significantly fewer relapses (P<0.001) and significantly less deterioration in disability, as measured by change in EDSS score (P=0.019), compared with those who received placebo. In a nonrandomized subgroup of patients from this study (n=110), those who received mitoxantrone 12 mg/m2 g3mo had a significant reduction in the number of T2-weighted MRI lesions at 24 months (P=0.027). The most common adverse events in these studies included nausea and/or vomiting (18%-85%), alopecia (33%-61%), amenorrhea (8%-53%), urinary tract infections (6%-32%), and upper respiratory tract infections (4%-53%). Leukopenia was reported in 10% to 19% of patients. Use of mitoxantrone can lead to serious adverse effects, particularly cardiotoxicity, myelosuppression, and, rarely, leukemia. Long-term use of mitoxantrone may compromise left ventricular function. Limited cardiotoxicity was reported in the clinical studies; in the pivotal clinical trial, 2 patients who received mitoxantrone 12 mg/m2 had decreases in left ventricular ejection fraction to <50% of baseline. CONCLUSIONS: In the available clinical trials, mitoxantrone provided effective treatment for worsening RRMS or SPMS. When mitoxantrone is used as recommended, the risks of substantial myelosuppressive and cardiotoxic effects can be reduced by careful patient selection, drug administration, and monitoring. The lifetime cumulative dose should be strictly limited to 140 mg/m2, or 2 to 3 years of therapy.

Anti-Inflammatory Agents↗
PubMed1989

Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer.

Three hundred twenty-five women with metastatic adenocarcinoma of the breast who had failed one prior chemotherapeutic regimen for advanced disease were randomized to receive 14 mg/m2 of mitoxantrone or 75 mg/m2 of doxorubicin intravenously (IV) every 3 weeks. Enrollment was closed on October 31, 1984, after 165 patients were randomized to mitoxantrone and 160 patients to doxorubicin. Patients randomized to the two treatment groups were compared for response rate, duration of response, time to progression or death, time to treatment failure (TTF), and survival. The response rate to mitoxantrone was 20.6%, to doxorubicin 29.3% (P = .07). The median response duration was 151 days for the mitoxantrone group and 126 days for the doxorubicin group (P = .16). The median TTF was 70 days in the mitoxantrone group and 104 days in the doxorubicin group (P = .36). The median survival of patients initially randomized to receive mitoxantrone was 273 days; for doxorubicin 268 days (P = .40). There were three responses among 77 patients crossed over to mitoxantrone after initial treatment with doxorubicin. The major dose-limiting toxicity for both drugs was leukopenia. There was significantly less severe and less frequent toxicity with mitoxantrone administration. Severe nausea and vomiting occurred in 9.5% of mitoxantrone patients and 25.3% of doxorubicin patients (P less than .001). The incidence of severe stomatitis and mucositis was 0.6% in the mitoxantrone group and 8.4% in the doxorubicin group (P = .001). Severe alopecia occurred in 5.1% of mitoxantrone patients and 61.0% of doxorubicin patients (P less than .001). A life-table comparison of the cumulative dose to the development of a cardiac event showed that mitoxantrone had significantly less cardiotoxicity than doxorubicin (P = .0005). This study demonstrates that mitoxantrone is active as a single agent in the treatment of metastatic breast cancer. Compared with doxorubicin it appears to be marginally less active and significantly less toxic. We conclude that mitoxantrone can be used alone or with other standard drugs to palliate the symptoms of metastatic breast cancer, especially in settings where drug toxicity is an important consideration.

Adenocarcinoma↗
PubMed1986

Human autopsy tissue concentrations of mitoxantrone.

A sensitive high-performance liquid chromatography method was used to measure mitoxantrone in autopsy tissue samples of 11 patients who had received the drug iv 10-272 days antemortem. Mitoxantrone was readily detectable in tissues from all patients. Tissue concentrations were proportional to lifetime cumulative dose of mitoxantrone, and decreased very slowly with time. The thyroid and the liver had the highest mitoxantrone concentrations, followed by the heart. These high cardiac concentrations of mitoxantrone could be partially responsible for the occasional case of cardiotoxicity seen with mitoxantrone. The brain had the lowest mitoxantrone concentrations. Organ mitoxantrone concentrations did not conform to a flow-limited model. Tumor mitoxantrone concentrations varied quite markedly from one site to another in the same patient. Tumors generally had lower mitoxantrone concentrations than did surrounding normal tissues. Mitoxantrone concentrations were consistently highest in intrahepatic tumors and lowest in intracerebral tumors. It is unclear whether the low concentrations in brain tumors were due to a partially intact blood-brain barrier or to the fact that most brain tumors had been irradiated prior to mitoxantrone administration. Further studies are warranted to more fully explore the relationship between human tissue mitoxantrone concentrations and efficacy and toxicity.

Autopsy↗
PubMed1990

Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Lederle Cooperative Group.

This phase III, randomized trial in previously untreated adults with ANLL compared mitoxantrone plus cytosine arabinoside with the CALGB "7 + 3" daunorubicin-based regimen. Two hundred evaluable patients (98 treated with the mitoxantrone-based regimen and 102 with the daunorubicin-based regimen) were included in the analysis of efficacy. The median age of the patients was 60 years. The induction regimen comprised cytosine arabinoside 100 mg/m2 by infusion daily for 7 days and mitoxantrone 12 mg/m2 or daunorubicin 45 mg/m2 daily for days 1-3. If needed, a second induction course was administered: cytosine arabinoside for 5 days and mitoxantrone or daunorubicin for 2 days. Postremission therapy consisted of two consolidation courses, identical to the second induction course. Sixty-three percent (62 of 98) of patients treated with mitoxantrone achieved complete remission (CR), compared to 53% (54 of 102) treated with daunorubicin. The median time to CR was 35 days in patients treated with mitoxantrone and 43 days for those treated with daunorubicin. Eighty-nine percent (55 of 62) of patients treated with mitoxantrone who entered complete remission achieved CR following one induction course, compared to 68% (37 of 54) of patients treated with daunorubicin who entered CR. The median duration of CR was 240 days in patients treated with mitoxantrone and 198 days in those treated with daunorubicin; the median length of survival was 328 days in patients who received mitoxantrone and 247 days in those who received daunorubicin. The toxicity profiles in patients treated with either of the two regimens were comparable in incidence and in severity. Patients treated with mitoxantrone required fewer median platelet units and were treated with fewer median days of intravenous antibiotics, compared to those who received daunorubicin. Mitoxantrone in combination with cytosine arabinoside is effective in previously untreated ANLL. complete remissions occur more frequently after a single induction course of the mitoxantrone-based regimen, compared to the standard Cancer and Acute Leukemia Group B regimen. This should be explored in further trials.

Adult↗
PubMed1989

Excretion and metabolism of mitoxantrone in rabbits.

The hepatic clearance of mitoxantrone was evaluated in rabbits using both bile-duct cannulated animals and freshly isolated hepatocytes in suspension or in primary culture. Mitoxantrone metabolic behavior was assessed by high-performance liquid chromatography using a method which specifically resolved mitoxantrone from its mono- and dicarboxylic acid derivatives. Excretion of mitoxantrone in bile and urine was studied over a 6-h period of observation following i.v. bolus injection of 0.04, 0.20, and 1.0 mg [14C]mitoxantrone/kg. Bile route represented the main excretion pathway for mitoxantrone and its metabolites--mainly the monocarboxylic acid derivative. Biliary excretion was very rapid (maximum biliary concentration achieved 9 to 18 min following drug administration) and amounted to 29.5 +/- 9.3%, 27.6 +/- 7.9%, and 28.3 +/- 3.8% of administered drug, respectively. Urinary excretion amounted to 7.3 +/- 0.2%, 7.1 +/- 4.6%, and 6.0 +/- 1.5%, respectively. Both biliary and urinary excretions of mitoxantrone and its metabolites remained linear over the range of concentrations routinely used in clinic. Metabolism of mitoxantrone was first studied using rabbit hepatocytes in suspension. Since metabolic rate was slow under these incubation conditions (observation period, 1 h), mitoxantrone metabolism was investigated in primary cultures of rabbit hepatocytes. Mitoxantrone was rapidly accumulated within the cells and metabolized to its various metabolites which rapidly effluxed in the extracellular medium. After a 48-h exposure of hepatocytes to a broad range of mitoxantrone concentrations (1 to 20 microM), it could be seen that (a) drug accumulation and metabolism did not exhibit saturation processes, (b) mitoxantrone was the main intracellular form, while (c) metabolites rapidly effluxed in the extracellular compartment and (d) the monocarboxylic acid derivative represented the main extracellular metabolite. This data demonstrates the important role played by the liver in the pharmacokinetic behavior of mitoxantrone and suggests a careful drug monitoring in patients with severe liver dysfunction.

Animals↗
PubMed1993

Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies.

PURPOSE: To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF. PATIENTS AND METHODS: Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m2 on day 1; GM-CSF (5 micrograms/kg once or twice daily) was administered on days 2 to 14. Therapy was repeated every 3 weeks. Dose escalation continued in sets of three patients until the dose limiting toxicity (DLT) was observed. The DLT was based on hematologic, non-hematologic, and cardiac toxicity, and delay of therapy by more than 1 week due to toxicity. Plasma samples were assayed for mitoxantrone concentrations using high performance liquid chromatography (HPLC). RESULTS: Twelve patients required either mitoxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m2/day. Therefore, we conclude the MTD was 37 mg/m2/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone levels increased linearly with dose; triexponential elimination of mitoxantrone was observed. No statistically significant correlation was observed between either peak mitoxantrone level or AUC and duration of absolute neutrophil count (ANC) < 500/mm3. CONCLUSION: The use of GM-CSF allows administration of mitoxantrone at a dose greater than three times that given in standard therapy; treatment is well tolerated. Further studies are needed to determine whether mitoxantrone has cumulative cardiac or hematologic toxicity.

Adult↗
PubMed1996

Pharmacokinetics and antitumor effects of mitoxantrone after intratumoral or intraarterial hepatic administration in rabbits.

The intratumoral (i.t.) delivery of anticancer drugs aims at controlling tumor growth and thereby provides palliative treatment for liver neoplasms. Mitoxantrone is a good candidate for local or regional administration because (1) its metabolism is mainly hepatic, (2) it has a steep dose-response curve for multiple solid tumors, and (3) its fixation in tissues is sustained without vesicant effects after extravasation. We compared the tolerance, pharmacokinetics, and antitumor effects of mitoxantrone on hepatic VX2 tumors in rabbits treated with i.t. intraarterial hepatic (i.a.h.) or i.v. mitoxantrone, i.t. ethanol; or i.t. 0.9% NaCl and in control animals. Tumor growth rates (TGRs) were evaluated at 9 days after treatment. Myelosuppression was the limiting toxicity of i.v. mitoxantrone at 1.5 mg/kg (maximal tolerated dose, MTD), but neither i.t. nor i.a.h. administration led to hematologic toxicity at the same dose. The mitoxantrone retained in tumors after i.t. administration was seen as blue-stained areas of complete necrosis according to histologic analysis. Pharmacokinetic parameters showed a significantly decreased systemic exposure to the drug after both regional treatments, although the i.a.h. route appeared to have an edge over the i.t. route. TGRs were significantly reduced after i.t. mitoxantrone (81 +/- 62%), i.a.h. mitoxantrone (337 +/- 110%), and i.t. ethanol treatments (287 +/- 117%) as compared with control values (886 +/- 223%; p < 0.01). Treatment with i.v. mitoxantrone (816 +/- 132%) had no antitumor effect, nor did NaCl injections (868 +/- 116%). Mitoxantrone given i.t. induced the highest antitumor effects, resulting in a 3.5-fold reduction in TGRs as compared with i.a.h. mitoxantrone and i.t. ethanol treatments (p < 0.02). Treatment with i.t. mitoxantrone provided efficient antitumor therapy without producing major side effects. This method should be considered as palliative treatment for nonresectable liver tumors and other localized malignancies.

Animals↗
PubMed2000

Dose-escalation study of single dose mitoxantrone in combination with timed sequential chemotherapy in patients with refractory or relapsing acute myelogenous leukemia.

A dose-escalation study was realized in order to assess the maximally tolerated dose (MTD) of high-dose mitoxantrone in a single injection combined with cytarabine and etoposide (EMA regimen) in refractory or relapsed acute myelogenous leukemia (AML). Between July 1997 and June 1998, 24 patients with relapsed or refractory AML entered the study. All but one patient had normal left ventricular ejection fraction (LVEF) at baseline. Performance status according to World Health Organization (WHO) criteria was less than two in all cases. All patients have been previously treated by mitoxantrone or anthracyclines. Four cohort of ten patients were scheduled with the following doses: (1) mitoxantrone 36 mg/m2 on day 1; (2) mitoxantrone 45 mg/m2 on day 1; (3) mitoxantrone 60 mg/m2 on day 1; (4) mitoxantrone 75 mg/m2 on day 1 in combination with cytarabine 500 mg/m2 per day (days 1-3, and days 8-10), and etoposide 200 mg/m2 per day (days 8-10). All patients received the full doses of the three drugs. The limiting toxicity was defined as WHO grade 4 nonhematologic toxicity and for impairment of cardiac function by Alexander's criteria (moderate or severe toxicity). The occurrence of limiting toxicity in at least three patients from the same dose level determined the MDT. No limiting toxicity was observed in mitoxantrone dose level 1. Two limiting toxicities were observed in mitoxantrone dose level 2 (one mucositis, one moderate cardiac toxicity), and three limiting toxicities in mitoxantrone dose level 3 (1 high transaminase levels, two moderate cardiac toxicities) ending the assay. Overall, 16 patients (67%) achieved complete remission (CR). One drug-addict patient died from cerebral hemorrhage due to severe aspergillosis and was not considered as a limiting toxicity. After EMA chemotherapy, 13 patients received subsequent chemotherapy courses involving anthracyclines or their derivatives. Six patients underwent allogeneic bone marrow transplantation. No late toxicity occurred. The median survival of the entire cohort was 41.4 weeks. We conclude that (i) EMA chemotherapy using a single injection of mitoxantrone is effective in the treatment of refractory or relapsing AML; (ii) the recommended phase II dose of mitoxantrone is 45 mg/m2 administered over 30 min as a single dose in combination with cytarabine and etoposide.

Adolescent↗