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Mitoxantrone - factsheet

Date of issue: December 2007

This factsheet is aimed at anyone affected by MS who needs basic information about this drug. It is not intended as a full guide, and should be used only to support discussion with a neurologist or MS nurse.

What is mitoxantrone?

Mitoxantrone is a form of cancer chemotherapy that is occasionally used to treat some forms of MS. It is normally used in relapsing/remitting or secondary progressive MS where relapses are still a significant feature.

Mitoxantrone might be used for someone who experiences very frequent and severe relapses that leave residual disability. Often, it is used for people who have not responded to either beta interferon or glatiramer acetate. It might also be used to stabilise someone with severe, frequent relapses, so that they can subsequently start on beta interferon or glatiramer acetate.

How mitoxantrone works

The way mitoxantrone is thought to work is based on the theory that MS is an autoimmune disease.

MRI scans of people with MS who experience relapses show inflamed myelin in the brain or spinal column. Myelin is the layer of fatty tissue that surrounds nerves in the brain and spinal column, and its presence helps to ensure that electrical messages are sent correctly from the brain to other parts of the body. Once inflamed, myelin can start to be destroyed. This disrupts the messages sent from the brain and so interferes with how the body normally works. It is thought that myelin becomes inflamed as a result of the immune system malfunctioning, so that, instead of protecting the body against viruses and infections, it overreacts to an unknown stimulus and attacks the brain and spinal column.

Mitoxantrone appears to work in MS and in cancer by suppressing the body's immune system for the period of treatment. This gives the body a chance to sort out what has gone wrong with its immune system – a chance to 'restart'.

How mitoxantrone is prescribed

In the UK, mitoxantrone is not licensed for use in MS, so there are no hard-and-fast prescribing guidelines, and use of the drug is wholly at the neurologist's discretion. Mitoxantrone is normally prescribed in specialist centres. In the USA, it has recently been licensed for use in relapsing/remitting and secondary progressive MS, though not in primary progressive MS.

There has been one major clinical trial of mitoxantrone, which found that mitoxantrone had a significantly beneficial effect on the number of relapses. It also seemed to slow the rate of long-term accumulation of disability when compared with people who received no treatment.[1] However, criticisms have been levelled at this trial. Some neurologists argue that the trial involved a relatively small number of patients, that the potential clinical benefits of mitoxantrone are small, and that the long-term side effects are sufficiently serious to warrant more research before this treatment is widely recommended.

More recently, a number of clinical reports of long-term results from observational studies using mitoxantrone have been published. Comparison between the reports is difficult since treatment length and strength of dosage varies, and length of follow-up also varies. Best results were reported by a French study of aggressive relapsing-remitting MS where people experienced several relapses a year. This observational study of 100 people looked at mitoxantrone for six months, followed in 73 cases by some form of maintenance therapy such as beta interferon. One year after treatment, 78 people were relapse-free and over five years, the average time to the first relapse was 2.8 years, and disability remained stable up to five years following treatment. Some significant side-effects were seen, including one case of leukaemia which was in remission five years after treatment.[2]

All the recent studies suggest that the people with MS who respond best to mitoxantrone are those with lower EDSS (disability rating scale) scores.

Mitoxantrone plus glatiramer acetate

Some other studies have suggested that mitoxantrone is most beneficial if followed by some type of maintenance therapy, such as glatiramer acetate (Copaxone) or beta interferon, but this is not conclusive.

In England, promising results have been reported from a small observational study of mitoxantrone followed by glatiramer acetate (Copaxone) as a treatment for people with active, aggressive, relapsing/remitting MS (two or more relapses a year). Individuals received mitoxantrone for six months followed by glatiramer acetate. The combination therapy reduced relapse rates by 90% and disease was stable or improved between one and three years following treatment. One person on the trial developed leukaemia nine months after mitoxantrone treatment.[3]

A larger research trial to investigate this combination further, and compare it with a high dose of beta interferon, has started recruiting at centres around the UK. For more information, see the study website.

How is mitoxantrone given?

Mitoxantrone is given by intravenous infusion, that is, through an intravenous drip. There are varying dosages, depending on the patient's weight. Treatment programmes vary: mitoxantrone may be given every three months, or it may be given monthly for the first three months, and then once every three months. Each treatment must be given in hospital, often as a day-patient.

As mitoxantrone suppresses the immune system, the white blood cell count of people receiving it is likely to fall. Therefore, regular blood tests are carried out for the duration of treatment.

Mitoxantrone is rapidly distributed throughout the body, and then passes out of the body through bile and urine.

Side effects and contraindications

a) temporary side effects

Many people experience some or all of these common side effects:

  • changes in menstruation pattern and/or temporary cessation of periods; in some women this can be permanent (see below)
  • nausea
  • temporary hair thinning (in common with other anti-cancer drugs)
  • blue-green urine for 24 hours after infusion

There is a range of other temporary side effects, so if anything unusual is experienced this should be reported to the neurologist as soon as possible.

b) long-term side effects and contraindications

  • cardiotoxicity – mitoxantrone may damage the heart, and can cause congestive heart disease if taken over a long period of time. To reduce this risk, the total amount any one person may take in their lifetime is limited to 140mg/m2, roughly 8-12 doses taken over two to three years. This dose should not be exceeded because of the risk of developing lifelong, and life threatening, heart damage. Regular echocardiograms (an ultrasound scan of the heart) are required to monitor for this.
  • mitoxantrone related leukaemia – in rare cases, treatment with mitoxantrone can cause some people to develop leukaemia. The risk is low, and is currently estimated at around 1 in 300 people, or 0.3% Research in this area is continuing, and concerns about this risk should be discussed with the neurologist.
  • liver damage – mitoxantrone can cause changes to liver enzyme levels and harm the way the liver works. This normally only lasts for the duration of treatment and is monitored through blood tests
  • cessation of periods – in around 1 in 10 women, mainly those over 35 years old, mitoxantrone can make periods stop permanently, causing infertility. Concerns about this risk should be discussed with the neurologist.
  • pregnancy – mitoxantrone may cause birth defects if either the potential father or mother is receiving it when a baby is conceived. The manufacturers suggest effective contraception should be used whilst on treatment and for up to six months after treatment stops. You may be asked to provide a urine sample for a pregnancy test prior to each infusion of mitoxantrone.
  • breastfeeding – mitoxantrone may be passed on through breast milk so should not be taken whilst a woman is breastfeeding
  • interactions with other medicines – mitoxantrone can interact with a range of medicines so it is important that the neurologist is aware of the full range of medications being taken, including any herbal or complementary medicines

References

  1. Millefiorini E, Gasperini C, Pozzilli C, et al.
    Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome.
    Journal of Neurology 1997;244(3):153-159
    abstract
  2. Le Page E, Leray E, Taurin G, et al.
    Mitoxantrone as induction therapy in aggressive relapsing remitting multiple sclerosis: a descriptive analysis of 100 consecutive patients. [Article in French]
    Revue neurologique 2006;162(2):185-194.
    abstract
  3. Ramtahal J, Jacob A, Das K, Boggild M.
    Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis.
    Journal of Neurology 2006;253(9):1160-1164.
    abstract

Acknowledgements

We are grateful to Dr Mike Boggild, Consultant Neurologist, Fiona Lynch and Kerry Mutch, MS Specialist Nurses, from the Walton Centre for Neurology and Neurosurgery, Liverpool, for their help in compiling this factsheet.