Summary
Mitoxantrone is licensed to treat MS in a few countries (though not in the UK). It is typically used to treat active secondary progressive, progressive relapsing, or worsening relapsing ̶ remitting MS. It is a repurposed chemotherapy agent and is given as an intravenous infusion. It is either given as a monthly infusion for 6 months, or every 3 months for up to 2 years or as a combination of these two protocols. Mitoxantrone is associated with quite severe toxicity (infections, cardiotoxicity, premature ovarian failure and secondary leukaemia) which is why it is not used often now. In some countries it is used as a true induction therapy and is followed by a maintenance DMT, typically interferon-beta or glatiramer acetate. Because mitoxantrone is toxic to the heart there is a limited cumulative dose that can be given safely over a lifetime. I have kept mitoxantrone on the list of essential DMTs because it is generic and hence is available for treating MS in resource-poor settings.
Trade names
Novantrone.
Mode of action
Mitoxantrone is an immune constitution therapy. It works by inhibiting the enzyme topoisomerase II which unwinds DNA. As a result of its actions on this enzyme it disrupts DNA synthesis and DNA repair in cells and causes them to die. White blood cells are particularly sensitive to its actions. Mitoxantrone is derived from a group of chemicals called anthracenediones that are toxic to the heart in high doses.
Efficacy
High to very high.
Class
Non-selective immune reconstitution therapy (IRT), short-term immunosuppression.
Immunosuppression
Yes.
Infusion protocols
- Edan protocol: Mitoxantrone 20 mg intravenous infusion (ivi) monthly in combination with 1 g methylprednisolone x 6 months (6 doses).
- Hartung protocol: Mitoxantrone 12 mg/m2 ivi 3-monthly x 2 years (8 doses).
- Gonsette protocol: Mitoxantrone 12 mg/m2 ivi monthly x 3 months followed by mitoxantrone 12 mg/m2 ivi 3- monthly up to 2 years (10 doses). Please note the Gonsette protocol includes an algorithm to adjust the next dose depending on the recovery of the peripheral blood cell counts.
Additional courses of mitoxantrone can be given beyond what is stated in these protocols provided the total lifetime dose of mitoxantrone does not exceed 140 mg/m² and that cardiac monitoring (echocardiogram [ECG] and ejection fraction) does not show signs of a cardiomyopathy.
Adverse events and events of special interest
Infection
Mitoxantrone causes a low white cell count that may result in an increased susceptibility to infection. Therefore, it is important that all infections are identified early and treated. The presence of an active infection may delay the next infusion. Chest infections and urinary tract infections are common after mitoxantrone. Maintenance of skin integrity is also important because broken skin or ingrown toenails may become areas harbouring infection. People with MS and their families and/or carers should be educated about how to assess and detect infection so that potential problems are recognised early. Please note that individuals treated with mitoxantrone may develop neutropenia and are hence susceptible to neutropenic sepsis, including infection with Listeria monocytogenes.
Nausea and vomiting
Nausea may occur during treatment and the next day. Antiemetic drugs are usually prescribed to help manage this. The doses of mitoxantrone used to treat MS are much lower than those used in cancer, therefore these side effects are milder than those generally experienced by people with cancer.
Hair loss
Hair may become temporally thinner during mitoxantrone treatment but will return to normal once the treatment is finished. Hair loss is uncommon and happens in fewer than 3% of people with MS who receive mitoxantrone. If it does occur, it usually begins 3 ̶ 4 weeks after the first dose has been administered.
Cardiotoxicity
High doses of mitoxantrone have been associated with cardiotoxicity. So a baseline heart scan must be performed before commencing the first dose of treatment. This scan can either be a MUGA scan or an ECG. These routine tests measure the contractility of the heart. The MUGA scan requires the injection of a very low dose of a radionuclide tracer, which is then detected using a machine similar to an x-ray machine. An ECG is a form of ultrasound done using a probe that is applied to the chest. Neither of these tests is painful. The MUGA scan or ECG should be completed at baseline and then 3-monthly before the administration of the next dose of mitoxantrone. Mitoxantrone treatment may have to be stopped if the tests show a significant decrease in cardiac function, i.e. a decrease in ejection fraction below 50%. These problems generally happen in people who receive a total lifetime dose of more than 140 mg/m².
Extravasation
Mitoxantrone is an irritant that can produce pain and inflammation along the path of a vein through which it is administered. Extravasation occurs when the drug accidentally infiltrates the tissue outside the vein. To avoid extravasation, the cannula must be sited in the non-dominant arm and away from areas of joint flexion. The site should not be obscured and should be checked at regular intervals. An extravasation kit should be available at the bedside in case of emergency.
Therapy-related leukaemia
Secondary acute myelogenous leukaemia (or acute myeloid leukaemia, AML) has been reported in people with MS or with cancer treated with mitoxantrone. Therapy-related leukaemia associated with topoisomerease II inhibitors such as mitoxantrone typically develops within 2 ̶ 4 years after chemotherapy has started. Based on the current data, the risk of leukaemia in subjects with MS treated with mitoxantrone is ~1 in 200–400 subjects.
Infertility
Amenorrhea (lack of periods) may occur during treatment and should be investigated because it may respond to treatment with hormonal replacement therapy. A less common complication is the induction of menopause, which should be fully investigated should it occur. Transient amenorrhea occurs in ~12% of patients and persistent amenorrhea, or premature menopause, in ~10% of patients. The risk of persistent amenorrhoea is higher in women older than 35 years (14%) and lower in women less than 35 years of age (6.5%). If indicated, women should either be offered GnRH agonists as ovarian protection throughout therapy or the option of egg harvesting and storage.
Pharmacovigilance monitoring requirements and de-risking strategies
Baseline
Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum protein electrophoresis, serum immunoglobulin levels, serology (varicella zoster virus, human immunodeficiency virus 1 and 2, hepatitis B and C, syphilis), tuberculosis enzyme-linked immune absorbent spot (TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing, pregnancy test, ECG and cardiac ejection fraction (echocardiography or MUGA scan).
Follow-up
- 1- to 3-monthly (predosing): FBC, U&E and LFTs and in women a pregnancy test
- 3-monthly: ECG and cardiac ejection fraction (echocardiography or MUGA scan)
- 12-monthly: TFTs
- Endocrine work-up for women with MS with persistent amenorrhea.
Infection prophylaxis
- Varicella zoster virus (VZV): if found to be VZV seronegative you will need to receive the VZV vaccine at least 6 weeks before being treated with mitoxantrone to allow sufficient time to develop immunity and protective antibodies against the virus.
- Urinary tract infections (UTIs): if you have a history of recurrent UTIs you should be taught to self-monitor your urine using home dipstix, given a supply of urine specimen bottles for laboratory testing and possibly an unfilled prescription for a standard first-line antibiotic. Then, if you do develop a UTI and self-diagnose it, you can take your urine specimen for microscopy, culture and antibiotic sensitivity testing (MCS) at your GP surgery or the laboratory and then collect your prescription and start your antibiotics. Once the culture and antibiotic sensitivities come back from the laboratory this may prompt your doctor to change the antibiotics. Please note, however, that not all GPs and family practitioners support self-monitoring and self-management of your MS.
- Listeriosis: you are at risk of developing listeriosis after mitoxantrone. To decrease this risk, you should receive advice about starting a listeriosis diet and a behavioural programme to reduce your likelihood of exposure to the infection. You may also be offered antibiotic prophylaxis. For example, the Association of British Neurologists gives the following summary advice for people with MS receiving alemtuzumab (also a risk for listeriosis): ‘We recommend several preventative measures, of which the most straightforward is co-trimoxazole 960 mng three times a week for one month after each cycle of alemtuzumab’. Here too is a link to a short online web application on this topic (Alemtuzumab safety advice).
Rebaselining
A rebaseline MRI needs to be done after completing the course of mitoxantrone. Depending on which protocol you have been treated with, this could be performed at 6 or 24 months.
Pregnancy
Pregnancy is contraindicated when using mitoxantrone as it may harm the developing foetus. While taking mitoxantrone, women who might become pregnant should use effective birth control and should be sure, before each dose, that they are not pregnant. If unsure, a pregnancy test should be performed.
Breastfeeding
Mitoxantrone is excreted in human milk, and significant concentrations (18 ng/ml) have been reported for up to 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 treatment.
Male fertility
Although mitoxantrone causes transient oligospermia, male infertility has not been a problem. In contrast to other chemotherapy agents (e.g., alkylating agents such as cyclophosphamide), after cessation of mitoxantrone therapy there is complete recovery of sperm production without morphological changes in vitro or genotoxic effects on germinal cells in vivo. In view of this, it is not necessary to offer male patients the option of routine sperm banking.
Vaccination
Immunisation may be ineffective when given during mitoxantrone therapy. Immunisation with live virus vaccines is generally not recommended until after the immune system has reconstituted.
Summary of Product Characteristics (SmPC)
Switching-2-mitoxantrone
Mitoxantrone repeat course
As mitoxantrone is an Immune Reconstitution Therapy (IRT), breakthrough activity may trigger the need for additional courses to be given, provided the total lifetime dose of mitoxantrone does not exceed 140 mg/m² and that cardiac monitoring (ECG and echo/MUGA) do not show signs of underlying cardiomyopathy.
Other DMTs
Provided the baseline screening tests are acceptable and there are no specific contraindications, it is feasible (from a clinical perspective) to use mitoxantrone after another licensed DMT; please check the licensing regulations in your country.
Interferon-beta and glatiramer acetate
There are no specific cautions.
S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)
The development of mitoxantrone-related cardiomyopathy and/or cardiac arrhythmia is a contraindication for using fingolimod and other S1P modulators (siponimod, ozanimod and ponesimod) after mitoxantrone. It is important to be extra-vigilant when doing the routine baseline cardiac checks post-mitoxantrone. If it has been some time since mitoxantrone’s last dose, I recommend checking a cardiac ejection fraction with echocardiography or a MUGA scan.
Alemtuzumab and HSCT (non-selective cell depleting DMTs)
A persistently low peripheral white cell count post-alemtuzumab, HSCT or other DMT, i.e. a neutrophil count <1000/mm³ or a total lymphocyte count <800/mm³ is a relative contraindication to using mitoxantrone. Another hit on the bone marrow and primary and secondary lymphoid organs may render an individual more immunosuppressed and worsen their leukopaenia. The decision to use mitoxantrone in this situation has to be based on the potential benefits versus the risks of these treatments and the risks of untreated active MS.
Cladribine (selective cell depleting DMT)
A persistently low peripheral lymphocyte cell count post-cladribine, i.e. a total lymphocyte count <800/mm³ is a relative contraindication to using mitoxantrone. The effect of mitoxantrone on primary and secondary lymphoid organs may worsen the lymphopaenia and is a risk factor for developing grade 3 or grade 4 lymphopaenia, i.e. <500/mm³ or <200/mm³, respectively. However, the decision to use mitoxantrone in this situation has to be based on the potential benefits of the treatment versus the risks of lymphopaenia and the risks of untreated active MS.
Anti-CD20 therapies (selective cell depleting DMTs)
Anti-CD20 therapies (ocrelizumab, ofatumumab and others) are selective B-cell depleting agents, so mitoxantrone is theoretically much safer than the other less selective and non-selective agents post-ocrelizumab.
Natalizumab
As mitoxantrone is an IRT that can’t be rapidly reversed, it is critical to ensure that there is no asymptomatic PML. Carry-over PML from natalizumab to mitoxantrone is potentially fatal. Therefore, a baseline MRI scan and possibly a CSF examination is essential to exclude the possibility of PML before starting mitoxantrone.
Dimethyl fumarate
DMF reduces the lymphocyte count by approximately 30% and in some people with MS by more than this. Therefore, individuals with lymphopaenia on DMF may be more susceptible to developing clinically significant prolonged lymphopaenia post-mitoxantrone.
Teriflunomide
Because teriflunomide is an antiproliferative agent, it may delay or prevent the recovery of the peripheral white cell count post-mitoxantrone. One option is to do an accelerated teriflunomide washout to prevent this potential problem. Interestingly, rheumatologists who use leflunomide, a prodrug converted to teriflunomide, don’t use an accelerated washout when using antiproliferative agents post-leflunomide. I, therefore, don’t think an accelerated washout is necessary.
Special circumstances
The presence of other specific comorbidities and adverse events may make it difficult to start mitoxantrone after other DMTs.