Fatigue in multiple sclerosis
Jul. 21, 2023
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Mitoxantrone was first approved in 1986 for the treatment of acute myelogenous leukemia. In 1996 it was approved to treat pain in patients with advanced hormone-refractory prostate cancer in combination with corticosteroids. In 1997, results of clinical trials were published, describing the potential of mitoxantrone in treating patients with progressive multiple sclerosis; it was approved by the Food and Drug Administration for this indication in 2000.
Mitoxantrone is a novel anthracenedione antineoplastic agent that is similar in structure to doxorubicin but with a molecular change that produces less damage to the heart.
Pharmacodynamics. Mitoxantrone acts as an immunosuppressor agent in multiple sclerosis by suppressing the activity of T cells, B cells, and macrophages that are involved in an attack on the myelin sheath. Mitoxantrone inhibits both DNA and ribonucleic acid synthesis and has a cytocidal effect on both proliferating as well as nonproliferating cultured human cells. A possible mechanism for therapeutic efficacy of mitoxantrone in the treatment of multiple sclerosis is that it may inhibit the migration of inflammatory cells into and within the central nervous system.
Pharmacokinetics. Pharmacokinetics in humans receiving multiple daily intravenous doses has not been performed. Following an intravenous injection, pharmacokinetics of mitoxantrone is characterized by a 3-compartment model. The following are important features:
• The mean alpha half-life is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours, and the mean gamma (termination or elimination) half-life is 23 to 215 hours with a median of 75 hours.
• Steady-state volume of distribution in the tissues exceeds 1000/m2. Tissue concentrations exceed those in the blood except during the terminal elimination phase.
• In monkeys, distribution to the brain, spinal cord, eye, and spinal fluid is low.
• In patients administered with 15 to 90 mg/m2 intravenously, there is a linear relationship between the dose and the area under the curve.
• Mitoxantrone is 78% bound to plasma proteins.
• Metabolism and elimination have not been well characterized. Eleven percent or less of mitoxantrone is recovered in urine, and 25% or less is recovered in feces within 5 days after administration, with 65% of the recovered material being unchanged.
Pharmacogenetics. Based on earlier studies, single-nucleotide polymorphisms in ABC-transporter genes were associated with therapeutic response in relapsing/secondary progressive multiple sclerosis, but a multicenter, retrospective analysis found no association between genotype and treatment response (14). These data discourage the use of mitoxantrone in primary progressive multiple sclerosis regardless of pharmacogenetic response biomarkers previously described in relapsing/secondary progressive multiple sclerosis.
Clinical results have demonstrated that mitoxantrone had a statistically significant impact on reduction of relapse rate and delay in disability progression in multiple sclerosis patients. Earlier uncontrolled studies dating back to 1997 showed beneficial effects, both clinical and radiological, including a reduction in the number of gadolinium-enhanced lesions observed on T1-weighted MRIs. Some of the controlled clinical trials since 2007 are listed in Table 1.
A longitudinal, open-label, prospective study to evaluate the efficacy and toxicity of mitoxantrone over a 2-year treatment period with a further 3-year follow-up (02).
Delayed beneficial effect was observed after completion of mitoxantrone treatment and only a small number of patients showed progression of disability after discontinuation of the drug.
A prospective, single-arm, open-label study of secondary progressive multiple sclerosis patients to assess long-term effects of mitoxantrone on peripheral immune subsets of patients using flow cytometry (05).
Mitoxantrone, in addition to the previously known suppression of B cells, promoted natural killer cell maturation, which was seen only in patients that showed a clinical response to treatment.
In view of the potential for serious toxicity of mitoxantrone and modest benefit in multiple sclerosis, further controlled clinical studies on a larger number of patients were suggested. Long-term follow-up studies indicate sustained clinical benefits and an acceptable adverse events profile.
In an observational multicenter study of patients with catastrophic relapse or a quickly aggressive form of multiple sclerosis, mitoxantrone had a rapid and strong impact on the disease when treatment was instituted early (21).
In an open-label retrospective study, cognitive functions of patients with progressive multiple sclerosis undergoing mitoxantrone therapy remained stable (26).
Cochrane review of randomized clinical trials showed only partial efficacy (20). The authors concluded that use of mitoxantrone should be limited to patients that have worsening progressive relapsing and secondary progressive forms of multiple sclerosis after assessment of the individual patient’s risk and benefit profile.
Mitoxantrone is indicated when the treatment goal is to slow the worsening of neurologic disability and to reduce the relapse rate in patients with clinically worsening forms of relapsing-remitting and secondary progressive multiple sclerosis. Mitoxantrone is not indicated in the treatment of patients with primary progressive multiple sclerosis. Mitoxantrone is included in the list of high-efficacy therapies (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) for multiple sclerosis, which are traditionally used after unsuccessful treatment with first-line disease-modifying therapies.
A systematic review has shown that mitoxantrone may be effective in reducing the frequency of relapses and slowing down the progression of disability in patients with neuromyelitis optica spectrum disorder (11).
Results of retrospective analysis suggest that methotrexate is a good candidate for treatment of children with worsening relapsing remitting multiple sclerosis, but further studies are needed to establish its safety and efficacy (12).
Mitoxantrone is contraindicated in patients who have demonstrated prior hypersensitivity to it. It is contraindicated in patients with a baseline left ventricular ejection fraction of less than 50%.
The goal is to control the progression of multiple sclerosis, and a long-term treatment is required. The limit of the total dose is reached in about 24 months, and the effect of mitoxantrone is maintained for another 6 to 12 months after discontinuation. Reported duration of clinical trial follow-up studies is 10 years. In patients with relapsing remitting multiple sclerosis, 3 or more relapses within 2 years preceding treatment and at least one Gd-enhancing lesion are predictors of a significant relative benefit of mitoxantrone therapy. Retrospective analysis of data in a study showed that most patients remained stable and the relapse rate of multiple sclerosis decreased with mitoxantrone initiation (28). Poor tolerability affected compliance in this study, but dose-limiting adverse events were rare.
Genetic biomarkers to predict side effects and therapeutic efficacy of mitoxantrone are being evaluated to enable its use for personalized treatment of multiple sclerosis (07).
A retrospective study has shown that methotrexate therapy enables stabilization of multiple sclerosis without causing any significant side effects in most patients with secondary progressive disease as compared to patients with primary progressive disease (17). Combination of induction therapy with mitoxantrone (6 monthly courses) followed by maintenance therapy with an immunomodulatory treatment, such as an interferon-β or glatiramer acetate, provides a rapid reduction in disease activity and sustained disease control up to at least 5 years in 60% of patients (18). Clinical follow-up of patients with relapsing and progressive multiple sclerosis 10 years after discontinuing mitoxantrone treatment showed that patients with the most active forms of the disease are the most likely to benefit from mitoxantrone in the long term (06). The Expanded Disability Status Score in patients with progressive multiple sclerosis increased from 5 to 6.5 by year 10. Analysis of prospective data from patients with relapsing-remitting and rapidly progressive multiple sclerosis treated with methoxantrone and followed-up over a 10-year period have shown that it is an effective disease-modifying treatment (13).
A retrospective, nonrandomized, observational study on multiple sclerosis patients during the mitoxantrone treatment period showed that patients with initial relapsing remitting multiple sclerosis who had discontinued immunomodulatory therapies because of lack of efficacy, suggesting the beginning of conversion to secondary progressive multiple sclerosis, were free of exacerbations with a decrease in gadolinium-enhancing lesions on MRI (27).
Data from a retrospective study have shown that high-efficacy therapy including mitoxantrone commenced within 2 years of disease onset is associated with less disability after 6 to 10 years than when commenced later in the disease course (15).
An induction phase with the monthly intravenous administration of 12 mg/m2 followed by a maintenance phase with 12 mg/m2 every 3 months for 2 years seems to be the most effective and safe treatment regimen.
Pediatric. Currently, mitoxantrone is approved only for use in adults with multiple sclerosis. Long-term follow-up of pediatric patients treated with mitoxantrone for multiple sclerosis showed reduction of disease activity and no significant adverse events on follow-up (16). Nevertheless, cardiotoxicity remains a potential threat of lifelong use of this drug.
Geriatric. Safety and effectiveness in geriatric patients have not been demonstrated.
Pregnancy. Mitoxantrone may cause fetal harm when administered to pregnant women. There are no adequate and well-controlled studies in pregnant women. If the drug is used during pregnancy or the patient becomes pregnant during treatment, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant. The only documented case of mitoxantrone therapy in the first trimester of pregnancy resulted in an underweight baby at full term who was delivered by cesarian section but without congenital malformations (09).
Nursing mothers. Mitoxantrone is excreted in human milk in significant concentrations for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breast feeding should be discontinued before starting the treatment.
Anesthesia. No contraindication is noted.
Hepatic impairment. Mitoxantrone clearance is reduced by hepatic impairment. Patients with severe hepatic impairment have an area under the curve more than 3-fold that of patients with normal hepatic function receiving the same dose. No laboratory measurement allows for dose adjustment.
Renal impairment. Mitoxantrone pharmacokinetics in patients with renal impairment is unknown.
Pharmacokinetic studies of the interaction of mitoxantrone with concomitantly administered medications have not been performed. Interaction with the human P450 system has not been investigated. There is no interaction with concomitantly administered corticosteroids.
During clinical trials, treatment with mitoxantrone resulted in generally manageable side effects that were primarily mild to moderate. During the 2-year trial, the most frequent side effects reported by patients treated with 12 mg/m2 were nausea, alopecia, upper respiratory tract infection, urinary tract infection, menstrual disorder, and transient neutropenia.
Dose-related cardiotoxicity has been reported in patients receiving mitoxantrone. Reports of cardiac adverse effects and leukemia led the United States Food and Drug Administration to institute a "black box" warning in 2005. According to a 2010 report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, the risk of cardiotoxicity and leukemia in patients treated with mitoxantrone is higher than that suggested at the time of the 2003 report (19). A study suggests a significantly increased risk for cardiovascular comorbidity and toxicity in multiple sclerosis patients treated with methotrexate (24). Heart involvement is dependent on the dose and the duration of methotrexate exposure but not on age or disease duration. A retrospective observational cohort study on mitoxantrone-treated patients with multiple sclerosis with a median follow-up of 8.7 years showed an increased risk of leukemia and colorectal cancer (03).
Multiple sclerosis patients of childbearing age are at risk of developing mitoxantrone-induced amenorrhea, and this risk can be reduced by estroprogestinic treatment (08).
There are several case reports of acute myeloid leukemia as an adverse event associated with mitoxantrone treatment in multiple sclerosis (25). One patient developed acute myeloid leukemia 11 months after mitoxantrone had been discontinued but recovered completely with stabilization of the neurologic disease following treatment with chemotherapy and autologous bone marrow transplantation (04). There is one report of death in a case of childhood-onset multiple sclerosis due to acute myeloid leukemia with 11q23 MLL gene rearrangement following mitoxantrone treatment (22). Because of an increasing number of reports of acute myeloid leukemia after mitoxantrone therapy in multiple sclerosis patients, hematological monitoring is recommended for at least 5 years after the last dose of mitoxantrone. Multiple sclerosis treatment regimens, which limit the mitoxantrone dose to less than 60 mg/m2, reduce the risk of therapy-related acute leukemia (10).
Management. Cardiac assessment prior to start of therapy with mitoxantrone is recommended because reduction in cardiac high-energy phosphates in some patients with multiple sclerosis causes a subclinical involvement of the heart. It is recommended that patients receiving mitoxantrone should have cardiac monitoring because subclinical reductions in left ventricular ejection fraction may occur with serial doses. The myocardial performance index may be an adjunctive parameter to conventional echocardiography for detecting subclinical cardiotoxicity of mitoxantrone in the clinical management of multiple sclerosis patients (23). The lifetime cumulative dose should not exceed 140 mg/m2. An open-label study on patients treated with mitoxantrone showed that those receiving concomitant dexrazoxane, a cardioprotective agent, exhibited a significantly lesser decline in left ventricular ejection fraction (01).
Taking the risks into consideration, mitoxantrone is still a reasonable option for patients with relapsing-remitting or secondary progressive multiple sclerosis who are progressing despite current disease-modifying therapies. The risks of substantial myelosuppressive and cardiotoxic effects can be reduced by careful patient selection, drug administration, and monitoring. Nevertheless, it is recommended that all potential serious adverse events be carefully weighed against the potential benefits in an individual patient before starting mitoxantrone therapy.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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