Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 203-208, 15 February 2003

Mitoxantrone in progressive multiple sclerosis: when and how to treat?

  • R.E Gonsette

      Affiliations

    • Corresponding Author InformationTel.: +32-2-752-96-22; fax: +32-2-752-97-00.

National Center for MS, Melsbroek B 1820, Belgium

Article Outline

Abstract 

Mitoxantrone (MX) has been approved by the Food and Drug Administration (FDA) for the treatment of patients with worsening relapsing–remitting (RR) or secondary progressive (SP) multiple sclerosis (MS). However, indications should be refined and mitoxantrone reserved as a rescue therapy to: (1) patients in the relapsing–remitting phase with frequent and disabling exacerbations likely leading to permanent severe disability and (2) to patients in the secondary progressive phase whose disability progression rate increases by one EDSS point or more per year and who do not respond to other current therapies. 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 the most effective and safe treatment regimen, not exceeding the maximum cumulative dose of 140 mg/m2. Given the potent myelosuppressive activity of mitoxantrone, dosage should be carefully adapted to the body surface and hematological changes. Long-term toxicities (amenorrhoea and therapy-related leukemia) seem acceptable but a valid evaluation will need a longer follow-up in more patients. Cardiotoxicity, the major long-term toxicity, is clearly dose-dependent and is a strict treatment duration limiting factor. To reduce the risk of cardiac events, the drug should be administered by slow infusion (over 30 min). Analogs of mitoxantrone with a much lower cardiotoxicity are currently investigated in animal experimental models.

Keywords:  Mitoxantrone, Progressive multiple sclerosis, Immunosuppression

 

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1. Introduction 

Mitoxantrone (MX), a cytotoxic drug exhibiting very potent immunosuppressive properties, has been approved by the United States Food and Drug Administration (FDA) for the treatment of patients with progressive multiple sclerosis (MS).

According to the FDA recommendations, MX is indicated “for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary progressive (SP), progressive relapsing, or worsening relapsing–remitting (RR) MS (i.e. patients whose neurologic status is significantly abnormal between relapses)”. Based on the FDA recommendations, it has been estimated that half of 140000 patients with severe secondary progressive MS are eligible for MX therapy in the USA [1]. This is almost as many patients as for existing therapies. This evaluation seems overestimated and the FDA indications should be refined.

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2. Immunosuppressive therapies in progressive phase 

Immunosuppressors have been used in progressive MS since several decades, but their efficacy on progression is still debated. Comparing the therapeutic benefit (percentage of treated patients doing better than those from the placebo group) as demonstrated by treatment failure (EDSS+≥1 confirmed at 3 months) in placebo-controlled trials, it appears that cyclosporine A [2], methotrexate [3] and azathioprine [4] do not reach a clinically significant benefit as defined by Goodkin et al. [3]: 50% reduction in the treatment failure rate in the treated group (for example 40% vs. 80%). More potent immunosuppressive therapies provide a transient clinically significant benefit, which does not exceed 1 year. This was observed after short-term (2 months) total lymphoid irradiation [5] as well as with monthly administration of cyclophosphamide (CY) for 2 years [6].

Mitoxantrone, a recent anticancer drug, has unique pharmacokinetic and immune properties. Given its sequestration for an extended period of time in a deep tissue compartment and a slow release (about 1 month) [7], MX is a “long acting” immunosuppressor. Consequently, immunocompetent cells are exposed permanently to the drug for a long time. In addition to a downregulation of CD4 cells [8], MX has specific immune effects on lymphoid tissues [9] that are characterized by a marked suppressive effect on most B cell functions: antigen presentation, antibody-dependent demyelination and complement mediated myelinolysis [10], [11]. MX inhibits also the demyelinating activity of macrophages [12]. Compared with other immunosuppressors, MX exerts a specifically broad immunosuppression on the key players of immune reactions: T cells, B cells and macrophages. In addition, MX induces the proliferation of nonspecific suppressor cells [13].

Experiments in experimental allergic encephalomyelitis (EAE), the animal model of MS, having confirmed that MX was definitely more potent than other immunosuppressors, in particular than CY [14], [15], [16], [17], this new compound was proposed as a substitute for the treatment of acute progressing MS [18]. Several pilot studies strongly suggested a beneficial effect of MX on relapse rate and disability progression [19], [20], as well as on active brain lesions as demonstrated by magnetic resonance imaging (MRI) [21], [22], [23]. In further clinical trials, monthly administration of MX for 6 or 12 months provided a highly significant benefit (≈80%) on progression within 1 year in acute progressive MS [24] or in RR MS [25].

The recent approval of MX by the FDA was based on the results of the randomized placebo-controlled trial “Mitoxantrone in multiple sclerosis (MIMS) study”, recently presented at several meetings [26], [27], and the data of the randomized multicenter study in active MS [24]. As the results of the MIMS study are still in press [28], the most important data are summarized in Table 1. In this trial, after trimonthly administration of MX for 2 years in patients with SP MS (with or without superimposed exacerbations), the therapeutic benefit on progression is clinically significant (>60%) and persists for 1 year after cessation of therapy. MX seems thus more effective than other immunosuppressors on progression of disability and provides a longer benefit.

Table 1. Mitoxantrone in multiple sclerosis (MIMS) study (12 mg/m2 every third month for 2 years)
Placebo (n=6)Mitoxantrone (n=60)p=(Chi-square test)
Effects on relapses
Relapses: n=/patient/year (mean)1.010.400.0002a
Treated relapses (n=)76.824.10.0002
Time to 1st treated relapse (median, months)14.2not reached0.0004

Effects on disability
Ambulation index changes (mean)+0.77+0.300.03
Treatment failure (% patients) (EDSS+≥1 confirmed at 3 m)21.98.30.03

a Wilcoxon–Mann–Whitney test.

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3. When to treat with mitoxantrone 

Initially, MX has been proposed as a rescue therapy for patients with a rapidly progressing MS who fail to respond to currently available treatments [29]. The recent recommendations of the FDA are somewhat indefinite and should be refined. Given the rather limited experience with this new immunosuppressor in MS and potential long-term toxicity, MX should be reserved to two main categories of patients. A first group concerns RR patients experiencing frequent, disabling relapses likely leading to permanent severe disability. They have been coined “rapidly or early transitional MS”. Patients included in the Edan et al.'s study [24] are a good example. A second indication concerns patients in the progressive phase who suddenly deviate from the natural evolution of the disease. According to Weinshenker et al. [30], the mean rate of deterioration in patients with progressive disease is 0.5 EDSS point per year. We thus suggest to limit MX indications to patients whose disability progression rate increases by one EDSS point or more per year. It would be unwise to propose MX in patients whose disability progression does not deviate from the natural history of MS. Most of them will respond to the treatment, but after cessation of MX therapy, they will certainly progress again and, at the present time, treatments able to maintain the benefit of MX are still under investigation.

Interestingly, data from the MIMS study indicate that MX seems more effective in patients in the early phases of the disease and with a low disability. The higher therapeutic benefit in RR MS [25] and in acute progressive MS [24], including mainly young patients with a low EDSS, also supports this assumption. Of note however that, in those two trials, MX was administered on a monthly basis.

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4. How to treat 

The treatment regimen with immunosuppressors is an important issue. Most studies with MX were performed with the intermittent administration schedule every 3 or 4 weeks used in cancer therapy. With this treatment regimen, however, administration of MX is restricted to 1 year maximum.

In preliminary studies [18], we found that MX produced a marked immunosuppression (leukopenia≤2000/ml, lymphopenia≤1000/ml) similar to that obtained with cyclophosphamide, after three or four monthly infusions and that this important immunosuppressive state was maintained for 2 years with a subsequent trimonthly administration. A striking decrease in B-cell count (≤35/ml) specific to MX was also observed. Magnetic resonance imaging studies demonstrated later that gadolinium-enhancing lesions disappeared within 3 to 4 months after monthly administration [22], [24]. It does not seem necessary therefore to prolong monthly administration for more than 3 months.

An induction phase with three monthly administrations of 12 mg/m2, followed by a maintenance phase every 3 months, seems a good compromise allowing a treatment for 2 years with a reasonable cumulative dose. The rationale for an induction phase is based on the presence of very active inflammatory reactions and the need to control rapidly disease progression. The rationale for maintenance therapy is obvious. MS is a chronic disease and it has been observed that effects of a short-term treatment with MX are limited in time [31].

Several observations substantiate the use of an induction phase to improve the efficacy of immunosuppression in MS. It has been shown that bimonthly administration of CY is effective only when preceded by an induction phase [32], and MRI studies demonstrate that the abrogation of Gd enhancing lesions occurs earlier with monthly administration of MX (at 3rd month) [24] than with administration every 3 months (at 6th month) [23].

After 2 years, the maximum cumulative dose is 120 mg/m2 but, due to dosage adjustments to hematological changes, the actual cumulative dose rarely exceeds 105 mg/m2. Given the marked acute myelotoxicity of MX and the linear association of the total area under the serum concentration–time curve (AVC) and absolute dose [7], the use of body surface area to individualize dosing seems more appropriate than a fixed dose. The dosage must be carefully adapted to the decrease in leukocyte, granulocyte and thrombocyte counts. To keep a steady treatment schedule, we prefer to adjust the dosage regimen rather than to delay infusions. The guidelines (Table 2) adopted in an open clinical trial [29] and in the MIMS study [26] were found useful and safe.

Table 2. Mitoxantrone dosage adjustment
Hematological resultsDose to be administered
100%90%75%Stop
IF
Leucocytes (×103/ml)≥43–3.992–2.99<2
Granulocytes (×103/ml)≥21.5–1.991–1.49<1
Platelets (×103/ml)≥10075–9950–74<50

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5. The benefit/risk ratio 

The main advantages of MX compared with CY are a better immediate tolerance (mild alopecia and gastrointestinal discomfort, no sustained myelotoxicity) and a lower long-term toxicity. In contrast with CY, MX has in theory less negative effects on reproductive organs and a weak carcigenocity.

Even though one case of amenorrhoea only was reported in cancer therapy [33], menstrual disorders are observed more frequently than expected in MS patients treated with MX. Amenorrhoea seems related to the perfusion dosage schedule rather than to the cumulative dose (5 mg/m2: 7%; 12 mg/m2: 28% [28]; 14 mg/m2: 33% [29]). Usually observed soon after initiating therapy, amenorrhoea is transient in almost all cases and is successfully treated with hormonal substitution.

A first case of therapy-related acute leukemia (t-AL) was diagnosed in a patient with MS treated with MX 5 years after initiating therapy [34]. In cancer therapy, t-AL following treatments with topoisomerase II inhibitors are observed in 2% to 12% of patients [35] and tends to respond to standard antileukemic therapy. In a recent paper concerning the risk of t-AL in 1122 patients with MS treated with MX [36], no case of t-AL was reported. In contrast, in a review of 802 patients with MS treated with MX in France, two cases of t-AL were observed (0.25%), an incidence deemed higher than that of de novo AML by the authors [37]. A valid appraising of the risk of t-AL incidence in MS patients treated with MX will require a longer follow-up in more patients. However, this incidence seems definitely lower than that observed in patients with malignancies receiving MX therapy and hopefully in the same range as de novo acute myeloid leukemia.

The major drawback of MX remains the cardiotoxicity. It soon became evident indeed that, even though the risk of cardiotoxicity was lower with this new compound in cancer patients, this anthraquinone specific toxicity also concerned MX and prevented its long-term administration [29]. The duration of the maintenance phase is thus strictly limited by the maximum cumulative dose (140 mg/m2). Patients with MS seem more vulnerable to cardiotoxic drugs than cancer patients. It is increasingly clear indeed that a nonnegligible number of MS patients have impaired cardiac function. Subclinical ventricular dysfunction and particularly a decrease in the ventricular ejection fraction is observed in about 25% of MS patients, making them more susceptible to the cardiotoxicity of immunosuppressive agents [38], [39], [40], [41], [42].

The generation of free radicals seems to be the most likely mechanism responsible for the cardiotoxicity of anthraquinones. Dexrazoxane (DRZ), a cardioprotectant, which hydrolyzes to an EDTA analog (ADR-925), reduces significantly clinical cardiotoxicity of some anthraquinones in particular doxorubicin [43]. The DRZ metabolite acts as a chelator and removes iron from iron/anthracycline complexes and reduces free radical formation by these complexes [44].

Dexrazoxane has been proposed in association with MX in MS patients [45]. However, MX lacking an alpha-ketol side chain, produces less hydroxyl radicals [46]. It seems thus likely that MX acts by different mechanisms to cause cardiotoxicity. Preliminary in vitro and animal experiments did not demonstrate a protective effect of DRZ against MX-induced cardiac damages [47], [48] but more recently it has been reported that DRZ attenuates the cardiotoxicity of MX in spontaneous hypertensive rats [49]. No specific clinical studies have been done so far concerning cardioprotective effects of DRZ after administration of MX as a single agent in cancer patients. A clinical trial in MS patients treated with MX seems thus warranted especially as DRZ originally studied as an antineoplastic agent inhibits topoisomerase II, demonstrates additive or synergistic cytotoxic effects [50] and was found effective in preventing EAE [51] probably by chelating iron and decreasing reactive oxygen species formation.

Waiting for more information about cardioprotective effect of DZR in MS patients treated with MX, a simple and effective way to reduce the risk ratio for cardiac events is to decrease peak drug levels with a slow infusion (over 30 min). It has been demonstrated indeed that the cardiotoxicity of anthracyclines is related to the peak of plasma concentrations rather than to the total systemic exposure or the tissue concentration over time [52], [53].

Echocardiography is the most widely available and cost-efficient technique for the early detection of cardiomyopathy and should be performed every 6 months during treatment and 1 year after cessation of administration. Anthracyclines can induce early onset chronic progressive cardiotoxicity persisting or progressing after discontinuation of therapy, and late onset cardiotoxicity has been reported years after chemotherapy has been completed [52]. Discontinuation is required if left ventricular ejection fraction is decreased by 10% or more compared to baseline, confirmed at 3 months (before the next infusion) or in any case if the measured value is below 50%. Measurements should be done in the same echocardiographic unit and in the same technical conditions.

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6. Conclusions 

Mitoxantrone has been found effective on relapse rate and progression of disability in several open studies and in three prospective, randomized, controlled clinical trials. A recent report on disease modifying therapies in MS [54] classifies MX as “possibly” effective but the evidence of beneficial effects of MX will likely become stronger after the publication of the last phase III trial [26]. Of note that several observations have demonstrated a marked decrease in MRI activity during MX therapy. In the MIMS study, MX was found to alter disease activity with a quarterly administration schedule. However, both clinical and radiological observations favor a treatment regimen with an induction phase (12 mg/m2 MX every month for 3 months) followed by a maintenance phase (MX 12 mg/m2 every 3 months). Given the potent myelosuppressive activity of MX, dosage must be carefully adapted to myelotoxic effects and a slow infusion reduces the risks of cardiac events.

Indications are limited to patients with a “rapidly disabling MS”, i.e. “rapidly or early transitional MS” and “acute, secondary progressive MS”. The treatment must be applied as soon as possible since patients with an EDSS below 5 respond better.

When properly used, MX appears an effective and safe treatment in selected cases of rapidly progressive MS. However, the treatment duration is strictly limited by its cardiotoxicity. Analogues of MX with a lower myocardial toxicity have already been synthesized. One of them (BBR2778) has similar cytotoxic effects and histological studies have shown that it produces definitely less cardiac lesions than MX [55]. This new compound has been tested in the acute EAE model in mice, and has the same immunosuppressive activity as MX at equiactive doses, providing a clearly dose-dependent protection [56]. If further experiments confirm the potent immunosuppressive activity of this new compound, BBR2778 might be an interesting substitute for mitoxantrone in patients with multiple sclerosis.

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PII: S0022-510X(02)00335-0

Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 203-208, 15 February 2003

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