Mitoxantrone In Multiple Sclerosis Research Articles

Mitoxantrone in Multiple Sclerosis: Malignancy Risk Higher Than Previously Appreciated

Several studies have found the incidence of acute myeloid leukemia (AML) after mitoxantrone use is about 0.8%. Mitoxantrone continues to be used as

Therapy-related acute leukaemia with mitoxantrone: Four years on, what is the risk and can it be limited?

Therapy-related acute leukaemia (TRAL) is a significant concern, when considering treatment with mitoxantrone for multiple sclerosis (MS). We re-evaluated the literature, identifying all case reports and series of > 50 patients reporting TRAL cases in MS. TRAL was diagnosed in 0.73% of the 12,896 patients identified. Median onset was 22 months following treatment. We calculated a number needed to harm of 137.5 exposed patients, significantly higher than our 2008 analysis. We found that 82.8% of patients were exposed to > 60 mg/m2 with a relative risk of 1.85 (p = 0.018) compared to < 60mg/m2, strongly suggesting a relationship to dose. MS treatment regimens which limit the mitoxantrone dose to < 60mg/m2 reduce the risk of TRAL.

THERAPY RELATED ACUTE LEUKAEMIA WITH MITOXANTRONE: 4 YEARS ON, WHAT IS THE RISK AND CAN IT BE LIMITED?

BackgroundTherapy related acute leukaemia (TRAL) is a concern for neurologists and patients when considering treatment with Mitoxantrone for Multiple Sclerosis (MS). In 2008 we performed a literature review to determine...

Mitoxantrone for multiple sclerosis

This is an updated Cochrane review of the previous published version.Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies. Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included. The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used. Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI -1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of patients with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX. MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (˜12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature.MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.

Long-Term Follow-Up of Pediatric Patients Treated with Mitoxantrone for Multiple Sclerosis

The chemotherapeutic agent mitoxantrone is approved for the treatment of aggressive multiple sclerosis (MS) in adults. Its use, however, is limited by the risk of severe adverse events including cardiotoxicity, myelosuppression, liver toxicity and secondary leukemia. The aim of this retrospective study is to present data on the safety, tolerability and efficacy of mitoxantrone in a small cohort of children with MS. 4 pediatric MS patients with a high relapse rate or severe, disabling relapses were treated with mitoxantrone and followed for 3.8-18 years. The cumulative dose of mitoxantrone was 36, 68, 84 and 120 mg/m (2), respectively. The frequency and severity of relapses as well as disability scores, decreased in the year after treatment onset. Short-term adverse events were transient in all cases. Cardiac monitoring by transthoracic echocardiography (TTE) showed asymptomatic left ventricular dysfunction during treatment in 1 patient, which was again normal at the next assessment. Long-term adverse events, including late-onset mitoxantrone-induced cardiotoxicity or secondary leukemia did not occur during the follow-up period. In our cohort of pediatric MS patients, mitoxantrone showed short-term reduction of disease activity and no long-term adverse events on follow-up. However, the risk of mitoxantrone-induced cardiotoxicity or toxic leukemia remains a life-long threat.

Immunotherapy and multiple sclerosis

The depiction of Judgment Day on the facade of the Cathedral of Notre Dame shows an angel weighing the good and evil of souls to determine whence they go. Hanging on one side are devils tilting the scale in the wrong direction. In making decisions about treating multiple sclerosis (MS) with immunotherapies, we weigh risks and benefits. For us, the devil is in the details of those risks and benefits. If we underestimate risks or overestimate benefits, the scales can tilt in the wrong direction. In 2000, the Food and Drug Administration (FDA) registered the chemotherapy drug, mitoxantrone, for the treatment of aggressive relapsing-remitting MS and secondary progressive MS (SPMS). The FDA based its decision largely on the results of a placebo-controlled trial conducted by the Mitoxantrone for Multiple Sclerosis (MIMS) Study Group. FDA approval came when the only published data from the trial were in abstracts.1,2 When the complete report of the MIMS trial was finally published in 2002,3 neurologists were already using mitoxantrone to treat SPMS. In 2003, the Therapeutics and Technology Assessment (TTA) Subcommittee of the American Academy of Neurology (AAN) reviewed the evidence on mitoxantrone for the treatment of MS.4 The TTA subcommittee noted that there were blinding problems with the MIMS trial, the study …

Cardiotoxicity and other adverse events associated with mitoxantrone treatment for MS

Mitoxantrone is used for aggressive multiple sclerosis (MS), but concerns about safety, including cardiotoxicity and other laboratory measures, prevail. To evaluate the incidence and potential predictors of adverse events associated with mitoxantrone at the MS Clinic, University of British Columbia, Canada. Retrospective review of patients treated with mitoxantrone by standard protocol; maximum cumulative dose = 120 mg/m(2). Left ventricular ejection fraction (LVEF) was measured with regular multiple-gated acquisition (MUGA) scans; blood cell counts and biochemical liver tests were performed before infusions. Generalized estimating equations were used to examine potential predictors of adverse events (graded according to the Common Toxicity Criteria, version 4) in patients with normal baseline and > or =1 follow-up MUGA or laboratory assessment. All 163 patients (58% women) treated with mitoxantrone from 1999 to 2007 were reviewed. Mean baseline age was 41.9 (SD 10.8) years, cumulative dose was 59.7 (SD 26.0) mg/m(2), and median follow-up duration was 14 months (maximum 6.5 years). By study end, 14% developed de novo cardiotoxicity (grade > or =2) as measured by decreased LVEF, 27% neutropenia (grade > or =1), 15% anemia (grade > or =1), and 15% liver toxicity (grade > or =1). Possible predictors of adverse events included sex, age, disease duration, and cumulative dose; only women exposed to a higher cumulative dose were at a greater risk of anemia (adjusted odds ratio 1.26, 95% confidence interval 1.08-1.48 per 10 mg/m(2)). Based on cardiac and laboratory assessments, mitoxantrone was reasonably well tolerated. However, cardiotoxicity was evident after doses well below current maximum recommended levels. A dose-response effect was not apparent. Findings emphasize the importance of monitoring; the long-term effects of mitoxantrone in multiple sclerosis require investigation.

Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the FEMIMS study

Background Improved prognosis in women with multiple sclerosis (MS) undergoing immunosuppressive treatment with mitoxantrone (MITO) has led to an increased interest in the effect of such treatments on fertility. FErtility and Mitoxantrone In MS (FEMIMS) is a collaborative retrospective study aimed at evaluating the impact of MITO treatment on fertility in women with MS. Methods Occurrence of chemotherapy-induced amenorrhea (CIA) was evaluated in 189 women with MS treated with MITO before the age of 45. An “ad hoc” questionnaire, paying particular attention to onset of CIA either during or post-MITO treatment, was administered to each patient. The probability of CIA was calculated using a multivariate logistic regression analysis taking into account age at exposure, cumulative dose, and use of estroprogestinic (EP) drugs during treatment. Results Forty-eight (26%) patients presented CIA following MITO. The probability of CIA was increased by 2%/mg/m2 of cumulative dose and by 18% for each year of age, whereas it was reduced by administration of EP during treatment. Conclusions MITO treatment may affect reproductive capacity in women with MS. Patients of childbearing age should be properly counseled before MITO treatment and EP therapy should be administered to reduce the risk of CIA.

Acute promyelocytic leukemia after mitoxantrone therapy for multiple sclerosis

Mitoxantrone is a DNA-topoisomerase 2 inhibitor used as a single agent for treatment of relapsing–remitting or progressive multiple sclerosis (MS). We present here two patients treated with mitoxantrone for MS who subsequently developed acute promyelocytic leukemia (APL). These constitute, to our knowledge, the eighth and ninth reports of APL in patients treated with mitoxantrone for MS. Topoisomerase 2 inhibitors are associated with therapy-related acute myeloid leukemia (t-AML) with 11q23 abnormalities, but therapy-related APL (t-APL) is less common, and documentation of nine cases of t-APL after mitoxantrone therapy for MS suggests a specific association.

Pharmacokinetics and pharmacodynamics of the interferon-betas, glatiramer acetate, and mitoxantrone in multiple sclerosis

Five disease-modifying agents are currently approved for long-term treatment of multiple sclerosis (MS), namely three interferon-beta preparations, glatiramer acetate, and mitoxantrone 1 1 A sixth disease-modifying agent, natalizumab, has been approved for treatment of multiple sclerosis after acceptance of this manuscript. Its pharmacokinetics and pharmacodynamics are not subject of this review. . Pharmacokinetics describes the fate of drugs in the human body by studying their absorption, distribution, metabolism and excretion. Pharmacodynamics is dedicated to the mechanisms of action of drugs. The understanding of the pharmacokinetics and pharmacodynamics of the approved disease-modifying agents against MS is of importance as it might contribute to the development of future derivatives with a potentially higher efficacy and a more favourable safety profile. This article reviews data thus far present both on the pharmacokinetics as well as on the putative mechanisms of action of the interferon-betas, glatiramer acetate, and mitoxantrone in the immunopathogenesis of MS.

In vivo Effects of Mitoxantrone on the Production of Pro- and Anti-Inflammatory Cytokines by Peripheral Blood Mononuclear Cells of Secondary Progressive Multiple Sclerosis Patients

Objective: Mitoxantrone is an antineoplastic agent also used for the treatment of multiple sclerosis (MS). However, despite its efficacy, few data are available on its mechanism of action.The current study was designed to evaluate the short-term (1 month) and long-term (12 months) in vivo effects of mitoxantrone on pro- and anti-inflammatory cytokine production by the peripheral blood mononuclear cells (PBMC) of secondary progressive MS patients. Methods: Eighteen patients with secondary progressive MS underwent mitoxantrone therapy (at a dose of 12 mg/m² once every 3 months) over a 1-year period. Blood samples were obtained at baseline, after 1 month and after 12 months of treatment. The production of cytokines in the PBMC was measured by enzyme-linked immunosorbent assay. Results: There were no significant effects of mitoxantrone on proinflammatory cytokines [interleukin (IL) 6 and IL-12p40] and anti-inflammatory cytokines (IL-10 and transforming growth factor-β) in our patients. Patients who showed no signs of therapeutic response were characterized by a higher basal PBMC production of IL-6 compared with that of the responding patients (p < 0.05) and mitoxantrone reduced this production after 12 months of treatment (p < 0.05). In the responding patients, IL-10 was significantly increased by mitoxantrone after 12 months of treatment (p < 0.05). Conclusion: These findings provide additional information useful in the selection of the patient population suitable for mitoxantrone treatment and suggest that most probably the therapeutic action of mitoxantrone in MS is not entirely mediated by its immunosuppressant effects.

Efficacy and safety of mitoxantrone in multiple sclerosis: a retrospective analysis of 105 patients

Efficacy and safety of mitoxantrone in multiple sclerosis: a retrospective analysis of 105 patients

Multiple sclerosis: Mitoxantrone promotes differential effects on immunocompetent cells in vitro

Mitoxantrone is an anti-neoplastic anthracenedione derivative that, based on its immunosuppressive properties, is approved for the treatment of severe forms of relapsing–remitting or secondary progressive multiple sclerosis (MS). Whether the beneficial clinical effects of mitoxantrone in MS are due to a broad immunosuppression, or whether there is a specific mechanism of action remains unknown. Peripheral blood mononuclear cells (PBMCs) from untreated or interferon-β-treated patients with MS or from healthy donors were stimulated in the presence or absence of mitoxantrone. Irrespective of the source of the cells and the cellular phenotype, mitoxantrone inhibited proliferation of activated PBMCs, B lymphocytes, or antigen-specific T-cell lines (TCLs) stimulated on antigen-presenting cells (APCs) in a dose-dependent manner. For functional analysis, TCLs or APCs were incubated separately with mitoxantrone. Pre-incubation of APC more effectively impaired TCL proliferation than pre-incubation of TCLs. Production of cytokines, expression of activation markers, matrix metalloproteinases, and chemokine receptors were not influenced substantially by mitoxantrone. In contrast, in dendritic cells (DCs), mitoxantrone interfered with the antigen-presenting capabilities. For evaluation of apoptotic cell death of target cells, annexin-V-conjugates and a DNA fragmentation assay were applied. Mitoxantrone induced apoptosis of PBMCs, monocytes and DCs at low concentrations, whereas higher doses caused cell lysis. Our observations suggest that the beneficial effects of mitoxantrone in MS result (i) from its immunosuppressive action based on nonspecific cytotoxic effects on lymphocytes, (ii) by inducing programmed cell death of professional APCs, such as DCs.

Mitoxantrone for multiple sclerosis in clinical practice

Patients with worsening relapsing-remitting multiple sclerosis (MS), secondary progressive MS, and progressive relapsing MS are potential candidates for treatment with mitoxantrone. Early identification of these patients is essential because there is emerging evidence that early and aggressive treatment might delay or limit long-term disability. Treatment with mitoxantrone is associated with certain adverse events, such as cardiotoxicity. However, the possible benefits of treatment (e.g., reduction in disease progression) outweigh the risks for patients with aggressive or worsening disease. With the selection of appropriate patients and careful monitoring for adverse events, mitoxantrone can be safely administered.

Rationale for the use of mitoxantrone in multiple sclerosis

Mitoxantrone is a member of the anthracendione family developed to treat malignancies and increasingly used to treat multiple sclerosis (MS). It has been studied as a treatment for MS since the late 1980s, and is licensed in a number of countries for progressive and worsening MS. Review of the published earlier open-label, and more recently of controlled trials suggests that mitoxantrone is efficacious in cases of worsening MS that have an inflammatory component as evidenced by progression with or without superimposed relapses and/or gadolinium (Gd) enhancing magnetic resonance (MR) lesions. Today there is no robust evidence of efficacy in primary progressive MS or in later stages of secondary progressive MS beyond an EDSS score of 6. Relevant immunomodulatory mechanisms act both on T- and B-cell function, and mitoxantrone has selective immune effects in MS by decreasing levels of TNF-alpha, IL-2, IL-2R-β1, IL-10 and IFN-gamma. Adverse events include nausea, alopecia, infections, menstrual disorders, risk of cardiotoxicity and malignancy. Different regimens are used according to different regulatory demands in different countries. The two most commonly used regimens are every 3 months intravenous (i.v.) 12 mg/m 2 for 2 years or 20 mg mitoxantrone (i.v.) combined with 1 g methylprednisolone (i.v.) every 4 weeks for 6 months. The cumulative life dose in MS patients is 140 mg/m 2. Mitoxantrone is currently used as a second line drug in MS patients whose disease is not controlled by β-interferon or glatiramer acetate. In this review, we will discuss the clinical disease patterns of MS patients who are most likely to benefit from mitoxantrone, its magnitude of clinical effect, and limitations of using mitoxantrone in MS. Mitoxantrone as a second line therapy in non-responders of β-interferon and glatiramer acetate will be assessed. Recent strategies of combination therapy, and the optimal dose regimen will also be discussed.

Mechanisms of mitoxantrone in multiple sclerosis–what is known?

The recent publication of the MIMS-study (Mitoxantrone In Multiple Sclerosis) and the approval of several health authorities support the use of mitoxantrone in patients with active relapsing–remitting or secondary progressive multiple sclerosis. This review provides information on data thus far present on the putative mechanisms of action of mitoxantrone in the immunopathogenesis of this disabling disease.

Heart transplantation in a patient with multiple sclerosis and mitoxantrone-induced cardiomyopathy

We describe a 30-year-old man with end-stage heart failure after therapy with mitoxantrone for multiple sclerosis. A successful orthotopic heart transplantation was performed when intensified medical therapy failed to improve the patient's hemodynamics. In spite of the severe underlying disease he did well on dual immunosuppression with methylprednisone and cyclosporine. Neurologic symptoms remained stable throughout the procedure and, after 2 months, he resumed preoperative ambulatory status. Eight years after the operation, the patient is now in New York Heart Association (NYHA) Class I status. Using canes, he is able to walk short distances. Repeated urinary tract infections caused by Escherichia coli became a problem, but have been controlled by long-term oral antibiotic prophylaxis with trimethoprim.

Mitoxantrone: a review of its use in multiple sclerosis.

Mitoxantrone: a review of its use in multiple sclerosis.

Mitoxanthrone in the therapy of multiple sclerosis

The recent publication of the MIMS study (Mitoxantrone in multiple sclerosis), approval by local health authorities, and the recommendation by the MS Therapy Consensus Group (MSTCG) support the use of mitoxantrone in patients with active multiple sclerosis. This review provides an outline of relevant preclinical and clinical studies, discusses relevant side effects of the compound, and compares its use with other therapeutic approaches to this crippling disorder.

The case for mitoxantrone in multiple sclerosis

Mitoxantrone [‘Novantrone’] is an antineoplastic agent that exerts potent immunomodulatory effects, including suppression of B cell immunity and reduction of T cell numbers. As a consequence, researchers have long since recognised mitoxantrone as a potential research candidate for autoimmune diseases such as multiple sclerosis (MS). A long-term, phase III, European trial demonstrating a mitoxantrone-associated delay in disease progression in patients with progressive MS has recently been highlighted. * These results were further elaborated upon and discussed at the 51st Annual Meeting of the American Academy of Neurology [ Toronto, Canada; April 1999 ].