Mitoxantrone

Summary: Mitoxantrone (Novantrone) is licensed to treat MS in several countries. 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 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 that often anymore. 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 it 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 mitoxantrone is generic and hence is available for treating MS in resource poor settings.

Trade Names: Novantrone, Mitozantrone, Onkotrone

Mode of action: Mitoxantrone is an immune constitution therapy. It works by 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 the anthracenediones that are toxic to the heart in high doses.

Efficacy: High to very high

Class: Non-selective IRT, short-term immunosuppression

Immunosuppression: Yes

Infusion protocols:

• Edan Protocol: Mitoxantrone 20mg ivi monthly in combination with 1g methylprednisolone x 6 months (6 doses)
• Hartung Protocol: Mitoxantrone 12mg/m2 ivi 3 monthly x 2 years (8 doses)
• Gonsette Protocol: Mitoxantrone 12mg/m2 ivi monthly x 3 months followed by Mitoxantrone 12mg/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 course 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 (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 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 as broken skin or ingrown toenails may become areas harbouring infection. MSers 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 MSers treated with mitoxantrone may become neutropenic 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. As the doses of mitoxantrone used to treat MS are much lower than those used in cancer patients these side effects are are milder.
• 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 less than 3% of MSers who receive mitoxantrone. If it does occur it usually begins 3-4 weeks after the first dose has been administered.
• Cardiotoxicity: As high doses of mitoxantrone have been associated with cardiotoxicity it is necessary to have a baseline heart scan before commencing the first dose of treatment. This scan can either be a MUGA scan or an echocardiogram. These are routine tests that 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 echocardiogram is a form of ultrasound and is done using a probe that is applied to the chest. Neither of these tests is painful. The MUGA scan or echocardiogram 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 get a total lifetime dose of more than 140 mg/m².
• Extravasation: Mitoxantrone is an irritant, which 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. In order 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 leukemia (AML) has been reported in MSers and cancer patients treated with mitoxantrone. Typically therapy related leukaemia, with topoisomerease II inhibitors such as mitoxantrone develops within 2-4 years after chemotherapy has been started. Based on the current data the risk of leukaemia in subjects with MS treated with mitoxantrone is ~1 in 200-400.
• Infertility: Amenorrhea (lack of periods) may occur during treatment and should be investigated as 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 woman older than 35 years (14%) and lower in women less than 35 years of age (6.5%). If indicated woman should either be offered GnRH agonists as ovarian protection during the course of therapy or the possible option of egg harvesting and storage.

Pharmacovigilance monitoring requirements and derisking strategies

• Baseline: FBC, U&E, LFTs, TFTs, serum protein electrophoresis, serum immunoglobulin levels, serology (VZV, HIV-1&2, hepatitis B&C, syphilis), TB elispot, uptodate cervical smear and/or HPV 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 MSers' with persistent amenorrhea
• Infection prophylaxis:
  • 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.
  • If you have a history of recurrent urinary tract infections you should be taught to self-monitor for urinary tract infections using home dipstix monitoring of your urine, provided with urine specimen bottles for laboratory testing and possibly an unfilled prescription for a standard first-line antibiotic. The plan being that if you do develop a UTI and self-diagnose it you can collect and drop of your urine for microscopy, culture and antibiotic sensitivity testing (MCS) at your GP or the laboratory and you can then collect your prescription and start your antibiotics. Once the culture and antibiotic sensitivities come back this may prompt your doctor to change the antibiotics. Please note not all GPs support self-monitoring and self-management of your MS.
  • As you are at risk of developing Listeriosis after mitoxantrone you should be give advice about starting a Listeriosis diet and how to institute a behavioural programme to make sure you reduce your chances of getting exposed to Listeriosis. You may also be offered antibiotic prophylaxis to reduce your chances of developing Listeriosis. The following is the ABN guideline and link to a short online web application on this topic (Alemtuzumab Safety Advice).