Mitoxantrone (Novantrone)


Other names: Novantrone (USA)

Mitoxantrone is a chemotherapy drug that is sometimes used in MS as a disease modifying drug (DMD) to reduce the number of relapses a person is experiencing. Although it is not licensed for MS in the UK, it is sometimes used in some specialist centres for people with highly active relapsing MS whose level of disability is developing rapidly. However, in recent years its use has decreased due to the introduction of newer therapies such as natalizumab (Tysabri), fingolimod (Gilenya) and alemtuzumab (Lemtrada). The risk of severe adverse events when using mitoxantrone, especially therapy-related acute leukaemia (TRAL), are also greater than previously thought.

How is mitoxantrone given?

Mitoxantrone is given in hospital by infusion into the vein. The infusion takes 5–15 minutes and may be repeated every one to three months. The actual dose given varies depending on your body surface area which is calculated using your height and weight. As mitoxantrone is not licensed for use in MS in the UK, there are no hard-and-fast prescribing guidelines so use of the drug is entirely at the discretion of the neurologist.

How mitoxantrone works

Mitoxantrone appears to work by suppressing the body's immune system for the period of treatment, depleting the number of cells that are attacking the myelin around nerves. This effectively gives the body a chance to 'restart' and sort out what has gone wrong with the immune system.

As mitoxantrone suppresses the immune system, your white blood cell count is likely to fall, making you more prone to infections. Therefore, regular blood tests are carried out before starting and during treatment. Your doctor will also test your heart function before the start of therapy, prior to each dose and annually for up to five years after completion of therapy.

Side effects and contraindications

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

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

Other common side effects include headaches, constipation, vomiting and diarrhoea.

Serious side effects

Mitoxantrone can also have some long-term, permanent side effects which are more serious:

Cardiotoxicity
Mitoxantrone may damage the heart and can cause congestive heart disease if taken over a long period of time. A study published in 2014 found that the higher the total dose of mitoxantrone given over a period of time, the more chance of cardiac dysfunction. To reduce this risk, the total amount any one person may take in their lifetime is limited to between 8–12 doses taken over two to three years.

Therapy-related acute leukaemia (TRAL)
Treatment with mitoxantrone can cause some people to develop leukaemia and cases are increasingly being reported. The overall risk of developing TRAL is currently estimated at 1 in 137 people, or 0.73%. This compares with a risk of 1 in 33,333, or 0.003%, of developing acute myeloblastic leukaemia in the general population.

Liver damage
Mitoxantrone can cause changes to liver enzyme levels and harm the liver, so blood tests are carried out to monitor liver function during treatment.

Pregnancy and breastfeeding

Mitoxantrone may cause birth defects if either parent is receiving it when a baby is conceived, so effective contraception should be used whilst on treatment and for up to six months after treatment stops. Mitoxantrone may be passed on through breast milk, so should not be taken whilst a woman is breastfeeding.

Mitoxantrone research

A study published in 2016 evaluated the effectiveness and safety of mitoxantrone use in people with primary and secondary progressive MS. The study included 104 participants and concluded that the drug stabilised the disease without causing any significant side effects in most patients. However the study found that greater benefits of using the drug were associated with people with SPMS. The main side effects reported were nausea, increased frequency of infections and hair loss.

A separate study carried out in Germany in 2014 discouraged the use of mitoxantrone in people with PPMS after finding that only a low proportion of participants in their trial (53.7%) responded to the drug.

Another study focused on the German population and looked at incidences of cancer in a group of 676 people with MS who had previously been treated with mitoxantrone. The study found that 37 of these people (5.5%) went on to develop some form of cancer. One of the main points taken from the research was that mitoxantrone increases the risk of developing acute myeloid leukaemia (AML) and colorectal cancer. Despite this, the study concluded that overall incidences of cancer in the group were acceptably low to justify the use of mitoxantrone in severely affected patients with MS if no better alternative is available.

Paediatric MS

Research in the use of mitoxantrone in paediatric MS is limited but some small studies have been carried out. In one particular study, 19 children with aggressive MS underwent mitoxantrone treatment to control either their severe relapses, high EDSS score or new and active brain lesions. Participants saw improvements in each of these areas. The study concluded that mitoxantrone is a good treatment for children with worsening RRMS and SPMS, however more research is required to establish its safety and effectiveness.

There has been one fatal case of mitoxantrone-associated leukaemia in a child with RRMS so the use of mitoxantrone in paediatric MS should be carefully considered.

References
Buttmann M, et al.
Malignancies after mitoxantrone for multiple sclerosis: A retrospective cohort study.
American Academy of Neurology 2016;86(23):2203-2207.
Full article (link is external)
Lasek-Bal A, et al.
Efficacy and safety of mitoxantrone use in primary and secondary progressive multiple sclerosis - study site experience based on the therapy of 104 patients.
International Journal of Neuroscience 2016:1-5.
Summary (link is external)
Ellis R, et al.
Therapy-related acute leukaemia with mitoxantrone: four years on, what is the risk and can it be limited?
Multiple Sclerosis Journal 2015;21(5):642-645.
Full text (PDF, 742KB) (link is external)
Grey Née Cotte S, et al.
Lack of efficacy of mitoxantrone in primary progressive multiple sclerosis irrespective of pharmocogenetic factors: a multi-center, retrospective analysis.
Journal of Neuroimmunology 2015;278:277-279.
Summary (link is external)
Patejdl R, et al.
Fatal acute myeloid leukemia with 11q23 MLL gene rearrangement following mitoxantrone treatment in a case of childhood-onset multiple sclerosis.
Journal of Pediatric Hematology/Oncology 2015;37(5):413-414.
Summary (link is external)
Cocco E, Marrosu MG.
The current role of mitoxantrone in the treatment of multiple sclerosis.
Expert Reviews in Neurotherapeutics 2014;14(6):607-616.
Summary (link is external)
Etemadifar M, et al.
Safety and efficacy of mitoxantrone in pediatric patients with aggressive multiple sclerosis.
European Journal of Paediatric Neurology 2014;18(2):119-125.
Summary (link is external)
Fleischer V, et al.
Cardiotoxicity of mitoxantrone treatment in a German cohort of 639 multiple sclerosis patients.
Journal of Clinical Neurology 2014;10(4):289-295.
Full article (link is external)
Morrissey SP, et al.
Mitoxantrone in the treatment of multiple sclerosis.
The International MS Journal 2005;12:74-87.
Summary (link is external)
Edan G, et al.
Rationale for the use of mitoxantrone in multiple sclerosis.
Journal of the Neurological Sciences 2004;223:35-39.
Summary (link is external)

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