Craig H. Smith, MD, MS Hub Medical Group, Seattle, WA

Multiple sclerosis (MS) has not been cured, but in recent years several medications have become available that can slow its progression. Even so, many patients eventually enter a stage of progressive deterioration that has been very difficult to treat. Two years ago the Food and Drug Administration (FDA) approved the use of mitoxantrone (marketed by Serono and Pfizer under the name Novantrone®) to treat secondary and relapsing progressive forms of MS. Several studies have shown that mitoxantrone is a very effective medication that can temporarily arrest the progression of MS. However, since this immunomodulatory therapy is a potentially toxic agent that can cause heart disease and an increased risk of a certain type of leukemia, there are important restrictions on its use. This review will look at the evidence-based medicine supporting the appropriate uses, and potential pitfalls in the use of mitoxantrone.

Progress to Date

Cancer Treatment

Mitoxantrone is an anthracendione, structurally similar to the anthracyclines, that has been used for more than a decade to treat a variety of cancers (Shenkenberg & von Hoff, 1986). It works by binding the DNA in a variety of immune system cells, preventing them from being replicated for cell division or from being copied into RNA. In cancer treatments, this effect stops the rapid division of cancer cells.

It became clear that mitoxantrone was effective in killing tumor cells with relatively low side-effects. Researchers in the MS field became interested because other chemotherapy treatments had previously been shown to suppress an experimental form of MS in animals, and some were useful for treating human MS (Ridge et al., 1985).

Mitoxantrone in an Animal Model of MS

MS is an autoimmune disease, that is, a disease in which a person’s body is attacked by its own immune system. In MS, the immune system attacks thenervous system, destroying myelin, the fatty white sheath that surrounds nerve fibers. The attacks happen focally, causing small areas of destruction, called lesions. Since myelin is needed for nerve signals to be appropriately sent and received, the lesions prevent or degrade nervous system signals. In addition, the nerve fibers themselves can be damaged or destroyed where they pass through the lesions. Much MS research is aimed at finding medications that can prevent these lesions from forming.

In 1985, Ridge and colleagues (1985) studied the effects of mitoxantrone in an animal model of MS, called experimental allergic encephalitis (EAE). At a low dose of mitoxantrone, the onset of the disease was delayed, and at higher doses mitoxantrone suppressed the development of lesions.

Since EAE is triggered experimentally, researchers know how long it will take to develop and can give medications before the symptoms appear. In humans, physicians have to wait until MS develops before it can be diagnosed and treated. To more closely approximate the situation in humans, mitoxantrone was given to animals in which the symptoms of EAE had already appeared, and it significantly suppressed the development of new lesions.

In the animal model, EAE can be transferred from animal to animal by injecting healthy animals with immune cells from sick ones. In the study by Ridge et al. (1985), the authors found mitoxantrone treatment prevented the disease from being transferred in this way. This evidence suggested that mitoxantrone affected the properties of the immune cells themselves, preventing them from recognizing myelin and/or from going through the cellular changes required to orchestrate an MS-like attack.

More details about how mitoxantrone might work were provided in a study by Watson and colleagues (1991). First, they found that mitoxantrone blocked myelin degradation by immune cells of mice with EAE in laboratory cultures. Next, they tested the ability of mitoxantrone to prevent EAE from developing when it was given just before symptoms were expected to appear. This timing meant that immune cells had already crossed the blood-brain barrier into the central nervous system. At a high dose, mitoxantrone prevented the development of EAE, even in these mice, indicating that mitoxantrone apparently entered the nervous system from the bloodstream to stop immune reactions that were already in progress. Finally, the authors tested whether mitoxantrone could prevent relapses in mice with wellestablished disease and found that it provided nearly complete protection from relapse. These results provided support for testing mitoxantrone as a treatment for human MS.

Treatment of MS With Mitoxantrone in Humans

The first a study in which mitoxantrone was used to treat MS were pilot studies involving only small numbers of patients. Mauch and colleagues (1992) gave mitoxantrone to 10 patients with rapidly worsening relapsing forms of MS. Four patients showed improvement in their level of disability immediately after treatment started. At the end of a year, one patient had dropped out, but eight of the remaining patients showed improvement on a standard neurological exam. The MRI results were even more dramatic. At the start of the study, the patients had a total of 169lesions that showed enhancement with the agent gadolinium (which highlights lesions where there is active inflammation). At the end of the study, the nine remaining patients had a total of only 10gadolinium-enhancing lesions. Eight patients continued mitoxantrone treatment for another year, and after 2 years, there were only five such lesions (Krapf, Mauch, Fetzer, Laufen, &Kornhuber, 1995). The authors did not report any serious side-effects from mitoxantronein either paper in which their findings were published.

In 1997, a European group conducted the first randomized, multi-center study of mitoxantrone’s efficacy in MS (Edna et al., 1997). In this study, 42 patients were randomly assigned to receive either steroid(methylprednisolone) treatment alone, or steroid and mitoxantrone together. The patients all had active, relapsing forms of MS, as measured by MRI and a clinical examination.

Treatments were given intravenously once a month for 6 months. MRI scans, obtained monthly, were performed by researchers who did not know what treatment each patient received. The patients were also evaluated clinically every month, and relapses were evaluated by a neurological examination. These examiners did not have access to the MRI data, but they did know what treatment each patient was receiving.

The MRI results showed a significant effect following treatment with mitoxantrone. At the beginning of the study, all but 4.8% of patients in the steroid-alone group had gadolinium-enhancing lesions, as did all but 10% of patients in the mitoxantrone group. By the end of the study, 90.5% of the subjects treated with mitoxantrone were free of enhancing lesions, compared with 31.3% of the steroid-alone group. Another kind of lesion that is visible on certain MRI scans, called “T2-weighted”scans, represents damage with little or no inflammation. These “T2 lesions” were also significantly fewer in the mitoxantrone group than the steroid-alone group.

The patients’ disabilities improved in the mitoxantrone group compared with the steroid-only group. In themitoxantrone group, 12 patients (of 21) improved and one got31worse. In the steroid-only group, five dropped out because of severe relapses, six became more disabled, and three improved. Similarly, the relapse rate was much lower in the mitoxantrone group. The most frequent side-effects in this study were temporary hair loss and nausea, and about half of the women stopped menstruating, which was temporary in all but one woman, who was 44.

This study showed very promising effects of mitoxantrone. The study, however, had limitations because the examiners knew the treatment status of the patients and because the patients were given a steroid with themitoxantrone, instead of a placebo. This made it impossible to know whether it was themitoxantrone or the combination treatment that was so effective.

The first placebo-controlled, double blind, randomized, multi-center trial of mitoxantrone’s effectiveness in treating MS (“MIMS” Trial)was published in 2002 (Hartunget al.). This study, which meets the gold standard for clinical study design, involved 194patients with worsening relapsing-remitting MS (RRMS)or secondary progressive MS (SPMS). The patients were randomly assigned to three groups: a placebo group, allow-dose mitoxantrone group(5 mg/m2), and a higher-dose mitoxantrone group (12 mg/m2)for 2 years, (the highest dose was much lower than the normal mitoxantrone dosage used to treat cancers). There were striking differences between the placebo group and the higher-dose mitoxantrone group. The mitoxantrone group was significantly better in terms of change in disability score, ability to walk, number of relapses that required steroid treatment, and the length of time to the first relapse after the start of the study. They also scored much better than the placebo group on a standardized neurological test. The lower-dose group generally showed effects that were intermediate between placebo and the higher-dose group.

For the MRI segment of this study, a subgroup of 110 patients(36 from the placebo group, 40from the low-dose mitoxantrone group, and 34 from the high-dose mitoxantrone group)was scanned, each at 12 and 24months. At 24 months, none of the patients who were treated with the higher dose of mitoxantrone had gadolinium enhancing lesions compared with 16% of those given a placebo. There were also more new T2 lesions in the placebo group than in the higher-dosemitoxantrone group.

On the basis of the results of the MIMS Trial, the Edan et al. (1997) study, and other data provided by Edan’s group, the FDA approved mitoxantrone for use in patients with progressive relapsing MS, SPMS, and worsening RRMS. Primary progressive MS (PPMS) was not included, as there are no data to indicate mitoxantrone is effective for treating it.

Current Studies

Cardiac Toxicity

Mitoxantrone is known to cause heart disease, particularly a cardiomyopathy, which may lead to congestive heart failure (CHF).CHF is when the heart gradually loses its ability to pump the adequate volume of blood necessary to feed oxygen to all the body’s tissues. It has long been clear that the risk of heart damage increases with a person’s lifetime dose of mitoxantrone. This was first observed inpatients with cancer, however, little was known about the risk of heart damage in patients with MS who are treated with a much lower dose than patients with cancer. One study (De Castro etal., 1995) found no evidence of heart damage in 20 patients with MS who were given a cumulative dose of 96 mg/m2 mitoxantrone.No heart damage was seen in the studies by Edan et al. (1997), and four patients were found to have mild to moderate heart effects in the study by Hartung etal. (2002). More recently, Ghalie et al. (2002) examined the records from 1,378 patients with MS from three clinical trials to evaluate the danger of heart damage and found that of these patients, only two (0.15%)developed CHF, indicating a fairly low risk of this complication.

Mitoxantrone had a greater effect on another measure of heart function called left ventricular ejection fraction (LVEF). This is the percentage of the blood ejected from the left ventricle of the heart during a heartbeat. In a healthy heart, a large percentage of the blood(55% or greater) is ejected with each heartbeat. The LVEF can drop, though, before there is measurable damage to the heart muscle. Of the 1,378 patients in the Ghalie (2002) study, 17 patients (1.2%) developed an LVEF of less than 50%. When the data were examined from the perspective of cumulative dose, it appeared that a cumulative dose of greater than 100 mg/m2 was associated with an increased risk of lowered LVEF. This study shows that when the cumulative lifetime mitoxantrone dose is kept low enough, there is very little risk of heart damage. Unfortunately, this also means that while mitoxantrone can be used to stop the progression of MS, it cannot be used over the long term to prevent later progression.

One possibility for increasing the safe cumulative lifetime dose of mitoxantrone is to combine treatment with mitoxantrone with a drug that protects the heart from damage. A very small study by Lemez and Maresova (1998) of seven cancer patients who were given a heart protecting drug, dexrazoxane, along with mitoxantrone or a related drug, daunorubicin, found that the dexrazoxane permitted fairly high cumulative doses of mitoxantrone or daunorubicin without heart damage. More study needs to be done to see if such a strategy might be effective in MS.

Secondary Leukemia

A known effect of treatment with chemotherapy drugs is an increased risk of developing a secondary cancer. The most common secondary cancer is a specific type of leukemia. It has been rather difficult to figure out what mitoxantrone’s contribution to this risk is in patients with cancer, because mitoxantrone is usually given in a mixture with other chemotherapy agents. The available data suggest that the risk of developing leukemia from mitoxantrone treatment alone is very low, but previous or concurrent treatment with another chemotherapy agent or
with radiation increases the risk. In one study of patients with MS who were treated with mitoxantrone, only 2 of 802(0.2%) subjects developed leukemia (Brassat et al., 2002), indicating the risk is quite low.

The leukemia caused by mitoxantrone and drugs that are closely related to it, which are called anthracyclines, is different from the leukemia caused by a different group of more classic chemotherapy drugs called “alkylating” drugs(Retain & Rowley, 1992;Pedersen-Bjergaard, & Rowley,1994). The classic kind of secondary leukemia related to alkylating drugs is therapy related acute myeloid leukemia(t-AML). It usually occurs 4to 5 years after the end of chemotherapy, and does not respond well to treatment. This disease is associated with damage to a patient’s chromosomes, and when the chromosomes are examined, it is common to find that parts or all of some chromosomes are missing or that parts of one chromosome are inappropriately stuck onto another chromosome.

The secondary leukemia caused by the family of drugs that includes mitoxantrone is also a form of t-AML, but it has different features. It occurs soon after the end of chemotherapy, that is, in less than 4 years, has varying responses to treatment, and the type of chromosomal damage is different from that of the classic t-AML. In particular, the chromosomes often show a characteristic mutation where a specific part of chromosome 11 is reciprocally switched with part of another chromosome (often chromosome 9 or 4) or in which chromosomes 8 and 21 trade equivalent pieces of genetic material. Researchers are interested in this new form of t-AML because they hope to learn more about the genetics of AML and about how to treat it by studying the chromosomal damage.

Mitoxantrone Study in PPMS

The Kita et al. (2004) study is currently underway to look at how mitoxantrone works inPPMS. If successful, this would be the first therapy to be formally studied and approved for the treatment of PPMS. Sixty-one patients were enrolled in the24-month study scheduled for completion in January 2005.Preliminary results state that 55patients have received at least four doses (12 mg/m2) of mitoxantrone, each given every third month. The primary outcome is the number of patients who continue with the therapy for over 3 months without progressing on the Extended Disability Status Scale(EDSS) or on the 9-Hole Peg Test and the Timed 25-FootWalk. The secondary out come is to look at the change in whole-brain volume over a year’s time. Results will not be available until the study is completed in early 2005. Three patients dropped out of the study due to cardiac toxicity, but the safety profile appears to be similar to previous studies in relapsing and SPMS populations. No cases of secondary leukemia have been seen (Kita et al., 2004).

RENEW Study

Many remaining questions about mitoxantrone’s long-term effectiveness and safety may be answered by the RENEW study. This ongoing, multi-center, open-label, observational study of patients with worsening RRMS, progressive relapsing MS (PRMS), and SPMS is designed to evaluate the long-term safety of mitoxantrone therapy. Clinical relapses during the therapy are also being monitored for efficacy. Over 500 patients, who are, or have been, treated with mitoxantrone, have been enrolled. Blood counts, liver enzymes, and LVEF are being monitored and the resulting information has been collected since April 2001. Thus far, the side-effects are similar to what has been observed in previous studies. There have not been any cases of leukemia or CHF, although there have been 11 cases of decreased LVEF and several infections (Smith, Lopez- Bresnahan, & Beagan, 2004).

Future Studies

The benefits from mitoxantrone treatment are thought to last at least 12 months after the end of treatment.

There are several models of mitoxantrone therapy being3looked at, which might enhance the beneficial effect of this immunomodulatory agent in MS care:

Combination of mitoxantrone with cardio protective drugs to extend the cumulative dosage

Combinations of mitoxantrone with other immunomodulatory agents to enhance efficacy

Utilization of mitoxantrone as an “induction” agent; thereby allowing an early, and potentially more beneficial, effect of immunodulatory control in MS.

The above noted models are similar to the treatments now utilized in cancer care. There is an increasing awareness that the complex nature of MS might respond best to these measures.

Studies in which mitoxantrone is combined with other drugs may help develop treatment regimens in which lower doses of mitoxantrone could be used to arrest the worsening MS, preserving the opportunity to treat patients with mitoxantrone again when disease progression resumes. Similarly, heart-protecting drugs may allow much higher cumulative doses of mitoxantrone to be used safely. It would also be useful to study whether treatment with mitoxantrone would permit drugs like glatiramer acetate or interferon beta to regain their effectiveness in patients who had stopped responding to them before mitoxantrone treatment. This might greatly extend the time which disease progression could be kept stable following mitoxantrone treatment.

Since there is no good treatment for PPMS, further study examining the effectiveness of mitoxantrone treatment in this condition would be worth performing.

Long-term studies, like the RENEW study are needed to learn about the effectiveness and adverse effects of mitoxantrone over time.

Clinical and Practical Considerations

The packet insert included by Serono with Novantrone lists a number of specific guidelines that should be followed by health care providers. Mitoxantrone should be given at a dose of 12 mg/m2 in 5- to 15-minute intravenous infusions every 3 months.

However, there is some recent experimental evidence from the animal model that shows that short infusion times may increase the potential for cardiomyopathy; it is the opinion of the author that it should be infused over no less than 45 to 60 minutes. This has not yet been adapted as common clinical practice.

The cumulative dose of mitoxantrone should not exceed 140 mg/m2, so careful record keeping is essential. LVEF should be tested before treatment with mitoxantrone and before all doses, once a cumulative dose of 100 mg/m2 is reached.

We are currently recommending that mitoxantrone be given for a total of four doses; at which time the clinical situation should be assessed and primary immunomodulatory therapy (e.g., interferon beta or glatiramer acetate) re-initiated if the patient has stabilized neurologically. Limiting the dosing preserves the potential to safely use the drug again in the future if the patient begins to worsen again.

Complete blood counts and liver function tests should be obtained before each dose. Mitoxantrone should not ordinarily be given to people with neutrophil counts that are lower than 1,500 cells/mm3 or when liver function tests show abnormalities. Mitoxantrone should not be given during pregnancy, and women of childbearing age should be given a pregnancy test before each treatment, even if they are using birth control.

Because of the potential complications, only registered nurses who are certified to give chemotherapy should give patients mitoxantrone. It is absolutely important that the IV used to administer mitoxantrone be properly inserted. The only safe delivery route is through a blood vessel. If the IV needle goes through the wall of the blood vessel, delivering the drug to the surrounding tissue, it can result in tissue death leading to an open sore that may require surgery to repair (Berghammer, Pohnl, Baur, & Dittrich, 2001).

Mitoxantrone is an expensive drug, but at least one study suggests that half the cost of the treatment is recovered in savings when compared to other costs of treating MS (Scott & Figgitt, 2004).

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