Mitoxantrone
This drug is a potent agent related to those used in chemotherapy. It is similar to drugs used for acute leukaemias and lymphomas. Mitoxantrone has been used principally for acute leukaemia, but because it powerfully suppresses the immune system, it has also been tried in MS. The biggest of the RCTs to date studying this drug in relapsing-remitting MS was from Italy.1 In this study, 51 patients were randomly allocated to receive mitoxantrone once a month IV or inactive placebo. There was a very major reduction (66 per cent) in the number of relapses in the treated group after two years, and a significant reduction in the proportion of patients with confirmed disease progression at two years. The number of new MRI lesions was also lower, but the p value was not significant. As in the interferon trials, there is the paradox of lack of correlation between number of new MRI lesions and disease progression.
Another study compared the results of patients treated with mitoxantrone plus steroids with a control group of patients treated with just steroids. 2 Forty-two patients with clinically very active, progressive disease were randomly allocated to the two groups. After 6 months, there were very large differences between the groups. 90 per cent of the mitoxantrone plus steroid group had no new MRI lesions versus only 31 per cent of the steroid only group. The p value was <0.001.There were also significant improvements in the disability score for patients in the mitoxantrone group at months 2-6, with a final mean improvement of more than one point (p<0.001). Additionally, there were significantly fewer relapses (7 compared to 31; p <0.01), and more patients had not relapsed (14 versus 7; p<0.05) in the mitoxantrone group. Five patients in the steroid only group dropped out of the trial because they were deteriorating so badly.
In 2002, the Lancet reported a large study of mitoxantrone in patients with secondary progressive MS.3 This form of MS has been very difficult to treat to date. The study randomly allocated 194 people with secondary progressive MS to treatment with mitoxantrone or to placebo. The drug was given IV every three months for two years. People in the mitoxantrone group had very significant reductions in disease progression, with about one quarter the worsening of the EDSS measure of disability, about a third less relapses, and about a quarter of the worsening of their neurological status. Importantly, there were no serious side effects or cardiac problems, which have been a concern with this drug. These studies together are significant. Together they show that even advanced MS can be brought under control with the use of this powerful immunosuppressant drug.
Unfortunately, side-effects can be a major problem. People taking this drug can get some of the effects seen with chemotherapy like hair falling out, nausea, vomiting and loss of appetite. Bone marrow suppression is common, meaning that people are more susceptible to infections. Indeed, the chemotherapy may itself precipitate cancer and, in the long term, the incidence of cancers in people treated with this drug is likely to be higher than in the general population. Research published in 2009 suggests this may be as high as 2% of people developing leukaemia within 3-4 years of taking mitoxantrone.4 This is a serious concern as adult leukaemia is often fatal. Heart muscle toxicity has not yet been seen, although it is often seen in related drugs.
An influential Cochrane Database Systematic Review in 2005 concluded that mitoxantrone is moderately effective in reducing relapse rate and disease progression in relapsing-remitting, primary progressive and secondary progressive MS in the short terms studied to date (two years), although longer trials are needed.5 No major side effects related to cancer or cardiotoxicity were reported from the trials studied.
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In 2002, the Lancet reported a large study of mitoxantrone in patients with secondary progressive MS.3 This form of MS has been very difficult to treat to date. The study randomly allocated 194 people with secondary progressive MS to treatment with mitoxantrone or to placebo. The drug was given IV every three months for two years. People in the mitoxantrone group had very significant reductions in disease progression, with about one quarter the worsening of the EDSS measure of disability, about a third less relapses, and about a quarter of the worsening of their neurological status. Importantly, there were no serious side effects or cardiac problems, which have been a concern with this drug. These studies together are significant. Together they show that even advanced MS can be brought under control with the use of this powerful immunosuppressant drug.
Unfortunately, side-effects can be a major problem. People taking this drug can get some of the effects seen with chemotherapy like hair falling out, nausea, vomiting and loss of appetite. Bone marrow suppression is common, meaning that people are more susceptible to infections. Indeed, the chemotherapy may itself precipitate cancer and, in the long term, the incidence of cancers in people treated with this drug is likely to be higher than in the general population. Research published in 2009 suggests this may be as high as 2% of people developing leukaemia within 3-4 years of taking mitoxantrone.4 This is a serious concern as adult leukaemia is often fatal. Heart muscle toxicity has not yet been seen, although it is often seen in related drugs.
An influential Cochrane Database Systematic Review in 2005 concluded that mitoxantrone is moderately effective in reducing relapse rate and disease progression in relapsing-remitting, primary progressive and secondary progressive MS in the short terms studied to date (two years), although longer trials are needed.5 No major side effects related to cancer or cardiotoxicity were reported from the trials studied.
Overview
Mitoxantrone therapy opens up an extremely promising avenue for treatment of patients with aggressive forms of MS and secondary progressive MS who would otherwise rapidly deteriorate or have few treatment options. There are obviously concerns about its safety, especially with long-term use. A 2006 review concluded that the benefits of mitoxantrone therapy outweighed the risks, especially for people not responding to the usual disease-modifying therapies.6 Indeed a South American study showed that for patients deteriorating despite treatment with interferon beta, mitoxantrone safely stabilized their condition.7 A 2007 study in 45 people with early but very active MS showed that mitoxantrone effectively stabilized their condition.8 One of the patients however developed leukaemia shortly after treatment. Further trials are needed, but at this stage it is certainly not a drug that should be considered for the average person with MS. If the disease becomes very active and progressive, at least there is something that can be done, albeit at some cost.
Many neurologists however will be concerned about the potential for cardiotoxicity when deciding whether to prescribe this drug. Researchers are currently working on analogues of mitoxantrone which do not possess similar cardiotoxicity. One such drug is pixantrone, which in animal studies appears very promising, and may soon be trialed in humans.9,10
Many neurologists however will be concerned about the potential for cardiotoxicity when deciding whether to prescribe this drug. Researchers are currently working on analogues of mitoxantrone which do not possess similar cardiotoxicity. One such drug is pixantrone, which in animal studies appears very promising, and may soon be trialed in humans.9,10
- 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. J Neurol 1997; 244:153-159.
- Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry 1997; 62:112-118.
- Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360:2018-2025.
- Pascual AM, Tellez N, Bosca I, et al. Revision of the risk of secondary leukemia after mitoxantrone in multiple sclerosis populations is required. Mult Scler 2009
- Martinelli BF, Rovaris M, Capra R, et al. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev 2005:CD002127
- Murray TJ. The cardiac effects of mitoxantrone: do the benefits in multiple sclerosis outweigh the risks? Expert Opin Drug Saf 2006; 5:265-274
- Correale J, Rush C, Amengual A, et al. Mitoxantrone as rescue therapy in worsening relapsing-remitting MS patients receiving IFN-beta. J Neuroimmunol 2005; 162:173-183
- Cocco E, Marchi P, Sardu C, et al. Mitoxantrone treatment in patients with early relapsing-remitting multiple sclerosis. Mult Scler 2007
- Gonsette RE. New immunosuppressants with potential implication in multiple sclerosis. J Neurol Sci 2004; 223:87-93
- Gonsette RE. Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity. J Neurol Sci 2004; 223:81-86
- 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. J Neurol 1997; 244:153-159.
- Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry 1997; 62:112-118.
- Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360:2018-2025.
- Pascual AM, Tellez N, Bosca I, et al. Revision of the risk of secondary leukemia after mitoxantrone in multiple sclerosis populations is required. Mult Scler 2009
- Martinelli BF, Rovaris M, Capra R, et al. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev 2005:CD002127
- Murray TJ. The cardiac effects of mitoxantrone: do the benefits in multiple sclerosis outweigh the risks? Expert Opin Drug Saf 2006; 5:265-274
- Correale J, Rush C, Amengual A, et al. Mitoxantrone as rescue therapy in worsening relapsing-remitting MS patients receiving IFN-beta. J Neuroimmunol 2005; 162:173-183
- Cocco E, Marchi P, Sardu C, et al. Mitoxantrone treatment in patients with early relapsing-remitting multiple sclerosis. Mult Scler 2007
- Gonsette RE. New immunosuppressants with potential implication in multiple sclerosis. J Neurol Sci 2004; 223:87-93
- Gonsette RE. Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity. J Neurol Sci 2004; 223:81-86