OffLabel: mitoxantrone

Mitoxantrone is number 3 on my off-label essential MS DMT list. #MSBlog #MSResearch #OffLabel

"This post is the third in a series of posts to try and help neurologists who treat MS in healthcare environments where they cannot access high-cost innovator DMTs. If you want to know the history of this post please read about my recent visit to South Africa."

"Mitoxantrone is an important drug in MS and despite its safety profile still has a place in the treatment of MS. In the majority of countries in the world mitoxantrone is not licensed to treat MS; however, it is licensed in the USA, France and Germany. It is not licensed elsewhere because the drug is off-patent and their are generic equivalents available. The drug is a chemotherapy agent and used to treat leukemia and breast cancer. It works in MS by depleting your immune system and allowing it to recover. There are two protocols that are commonly used in MS. Firstly, the Edan protocol is pulsed monthly infusions of 20 mg per month for 6 months followed by a maintenance therapy. The Edan protocol is usually used in MSers with highly-active RRMS and you need to get the disease under control as soon as possible."
"The second or Hartung protocol is 3-monthly infusions of mitoxantrone at 12mg/m-squared given for 24 months. I tend to use this protocol on patients with relapsing SPMS who are not eligible for other DMTs. I tend to avoid using mitoxantrone in patients who are permanently catherised, or who have recurrent urinary tract infections, because of the risk of sepsis."

"Please note all mitoxantrone-treated patients need to go onto a maintenance therapy once the 6 or 24 months of treatment are over. MS disease activity typically starts to reoccur 12-18 months after the last infusion. In study 1 below that some of the MSers were continued on methotrexate and azathioprine, two drugs that are on my off-label essential list of DMTs for resource-poor healthcare environments. Therefore there is no reason why MSers should not be actively treated in countries, or environments, that don't have access to high-cost DMTs." 

"Whilst receiving mitoxantrone the chances of you getting an infection are increased. If you begin to have any symptoms of infection, such as fever, chills, sore throat, cough, pain with urinating, or urinating more often, please call your GP or neurology team. MSers who are treated with mitoxantrone are known to be at increased risk of developing a specific type of leukaemia in the future; this an uncommon complication, occurring in approximately 1 in 200-400 subjects with MS who are treated with Mitoxantrone. Clearly female MSers who are pregnant, are trying to become pregnant, or are breastfeeding should not be treated with mitoxantrone because it may harm the baby. You should use birth control while taking mitoxantrone to avoid becoming pregnant. We may have to adjust the dose of mitoxantrone depending on your blood counts. As mitoxantrone is potentially cardiotoxic, or can damage the heart. you will need to have regular testing of your heart and blood to help avoid this serious side effects. We essentially monitor cardiac function with ECG and ny measuring the cardiac ejection fraction using an cardiac echo or a nuclear medicine scan called a MUGA scan every 3 months."

"Mitoxantrone is given intravenously by an infusion the dose you receive will be dependent on which regime your consultant wishes to prescribe for you. The most common is side effect of Mitoxantrone in patient with MS are nausea, hair thinning, loss of menstrual periods, bladder infections and mouth ulcers or sores. The nausea is usually mild and generally lasts less than 24 hours and is easily managed with anti-emetics."

"Mitoxantrone causes your white blood cell count to go down, which increases your chance of getting an infection. This risk is greatest 2-3 weeks after each dose. You need to be vigilant for any symptoms or signs of an infection, i.e. call your neurology team if you begin to have fever, chills, sore throat, cough, pain with urination or you are urinating more often."

"Mitoxantrone can lower the number of platelets in the blood, which can interfere with blood clotting. Most people have only slight hair thinning when treated with mitoxantrone. Some women experience changes in their menstrual periods on mitoxantrone. Amenorrhea (the term used when periods stop) may occur during treatment and should be investigated as it may respond to treatment with hormonal replacement therapy. A more rare complication is the induction of menopause, which should be fully investigated, should it occur; this occurs in approximately 6% of woman under the age of 35 and 15% of woman over the age of 35.  Mitoxantrone is dark blue in colour, so it may turn your urine a blue-green colour for a few days after each dose. The white part of your eyes may also have a slight blue colour during treatment. When I worked as a house officer on haemoncology ward we used to refer to mitoxantrone as the 'blue devil'."

Study 1: Le Page et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry. 2008 Jan;79(1):52-6. 

BACKGROUND: Mitoxantrone was approved by the French health authority (AFSAPPS) in October 2003 to treat patients with aggressive multiple sclerosis (MS).

OBJECTIVE: To report the long term effectiveness and safety of mitoxantrone as induction therapy in patients with aggressive relapsing-remitting MS, and to assess treatment response factors.

MATERIAL AND METHODS: 100 consecutive patients with aggressive relapsing-remitting MS received mitoxantrone 20 mg monthly combined with methylprednisolone 1 g for 6 months. Relapses, Expanded Disability Status Scale (EDSS) and drug safety were assessed every 6 months for up to at least 5 years. Within 6 months after induction, 73 patients received maintenance therapy (mitoxantrone every 3 months (n = 21); interferon beta (n = 25); azathioprine (n = 15); methotrexate (n = 7); glatiramer acetate (n = 5)).

RESULTS: During the 12 months following initiation of mitoxantrone, the annual relapse rate (ARR) was reduced by 91%, 78% of patients remained relapse free, MRI activity was reduced by 89%, the mean EDSS decreased by 1.2 points (p<10(-6)) and 64% of patients improved by 1 point or more on the EDSS. In the longer term, the ARR reduction was sustained (0.29-0.42 for up to 5 years), the median time to the first relapse was 2.8 years and disability remained improved after 5 years. Younger age and lower EDSS score at the start of mitoxantrone treatment were predictive of better treatment response. Three patients presented with an asymptomatic decrease in left ventricular ejection fraction to less than 50% (one reversible). One patient was diagnosed with acute myeloid leukaemia (remission 5 years after diagnosis).

CONCLUSION: Mitoxantrone monthly for 6 months as induction therapy followed by maintenance treatment showed sustained clinical benefit for up to 5 years with an acceptable adverse events profile in patients with aggressive relapsing-remitting MS.

Study 2: Edan et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011 Dec;82(12):1344-50.

OBJECTIVES: The long-term impact of interferon-beta-1b (IFN) might be improved by short-term immunosuppression with mitoxantrone(MITOX) in aggressive relapsing-remitting multiple sclerosis (ARMS) patients.

METHODS: In this 3-year clinical and MRI study, 109 ARMS patients (two or more relapses in the previous 12 months and one or more gadolinium (Gd)-enhancing MRI lesion) were randomised into two groups: 54 patients received MITOX monthly (12 mg/m(2); maximum 20 mg) combined with 1 g of methylprednisolone (MP) for 6 months followed by IFN for the last 27 months, and 55 patients received IFN for 3 years combined with 1 g of MP monthly for the first 6 months. The primary endpoint was the time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months.

RESULTS: The time to worsen by at least one Expanded Disability Status Scale point confirmed at 3 months was delayed by 18 months in the MITOX group compared with the IFN group (p<0.012). The 3-year risk of worsening disability was reduced by 65% in the MITOX group relative to the IFN group (11.8% vs 33.6%). MITOX patients had a reduced relapse rate by 61.7%, a reduced number of Gd-enhancing lesions at month 9 and a slower accumulation of new T2 lesions at each time point.

CONCLUSIONS: Although there were limitations in this investigator-academic-driven study, the data do suggest that mitoxantrone induction therapy prior to INF beta-1b may have a role in aggressive disease.

Study 3: Hartung et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002 Dec 21-28;360(9350):2018-25.

BACKGROUND: Treatment options for patients with secondary progressive multiple sclerosis are few. Encouraging results in open-label studies prompted this randomised trial of mitoxantrone in such patients.

METHODS: 194 patients with worsening relapsing-remitting or secondary progressive multiple sclerosis were assigned placebo or mitoxantrone(5 mg/m(2) [exploratory group] or 12 mg/m(2) intravenously) every 3 months for 24 months. Clinical assessments were made every 3 months for 24 months. The primary endpoint was a multivariate analysis of five clinical measures. Analyses of mitoxantrone 12 mg/m(2) versus placebo were based on patients who received at least one dose and returned for at least one assessment of efficacy.

FINDINGS: Of 194 patients enrolled, 188 were able to be assessed at 24 months. There were no drug-related serious adverse events or evidence of clinically significant cardiac dysfunction. At 24 months, the mitoxantrone group experienced benefits compared with the placebo group for the primary outcome (difference 0.30 [95% CI 0.17-0.44]; p<0.0001) and the preplanned univariate analyses of those measures: change in expanded disability status scale (0.24 [0.04-0.44]; p=0.0194), change in ambulation index (0.21 [0.02-0.40]; p=0.0306), adjusted total number of treated relapses (0.38 [0.18-0.59]; p=0.0002), time to first treated relapse (0.44 [0.20-0.69]; p=0.0004), and change in standardised neurological status (0.23 [0.03-0.43]; p=0.0268).

INTERPRETATION: Mitoxantrone 12 mg/m(2) was generally well tolerated and reduced progression of disability and clinical exacerbations. Further studies are needed to identify the patients with these forms of multiple sclerosis who are most likely to respond to therapy, the best treatment protocols, and the frequency of long-term drug-related side-effects.

If you are interested there are a large number of other posts on this blog about mitoxantrone that you may want to read: 

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