December 12, 2003
Amit Bar-Or, M.D.
There are currently four immune modulating therapies approved in the US for the treatment of relapsing remitting MS (RRMS), namely Avonex, Betaseron, Copaxone and Rebif. However, these treatments have not been shown to be of significant benefit for patients with secondary progressive MS (SPMS). Since many patients with RRMS eventually experience chronic progression with associated increase in disability, there has been an ongoing need to identify safe and effective interventions for SPMS.
Recently, Mitoxantrone (Novantrone) became available in the US as the first FDA approved treatment for use in SPMS, as well as for patients with aggressive RRMS. This Viewpoint summarizes a special report in last month’s issue of the journal Neurology in which the American Academy of Neurology’s Therapeutics and Technology Assessment Subcommittee assessed both the evidence leading to the recent FDA approval, as well as the appropriate clinical role of Mitoxantrone, in the treatment of patients with MS.
Mitoxantrone hydrochloride (Novantrone) is a member of a family of agents called anthracenediones that have been used as immune suppressing treatments for different types of Cancer. Its approval by the FDA for treatment of MS was based on one phase III clinical trial (2), and one earlier phase II study (3) in patients with MS, both in Europe. Use of mitoxantrone, however, must be balanced with its potential toxic side effects. Treated patients are at increased risk for injuring their heart muscle in a way that could lead to heart failure. The risk of cardiac toxicity is directly related to the total (cumulative) dose that a patient receives, and can be kept at a reasonable level by limiting the total lifetime dose. This means, however, that a safe regimen at an effective dose can only be given for 2 to 3 years, after which this drug and others in its class should be avoided. Other potential side effects include loss of menstruation (amenorrhea), which was seen to occur in about 40% of the women in the phase III trial. This was usually not permanent. There is also a risk (<1%) of developing cancer due to the immune suppression.
The Committee’s conclusions were that Mitoxantrone appears to reduce the clinical attack rate, and to favorably impact MRI changes related to attacks, in patients with relapsing MS. Mitoxantrone probably offers some benefit on disease progression in patients with SPMS whose are actively worsening. However, because of the potential for serious toxicities, careful consideration should be given before instituting this therapy in individual patients. The potential clinical benefits on disease progression appear to be modest, and the Committee suggested that a second and larger phase III trial should be carried out, prior to extending the use of this agent to a broader population of patients with MS. Among their clinical recommendations, the Committee suggested that: (i) Mitoxantrone use currently be reserved for patients with rapidly advancing disease who have failed other therapies, (ii) The potential toxicity of mitoxantrone considerably limits its use in patients with typical relapsing forms of MS and (iii) mitoxantrone should be provided under physician’s supervision, preferably one who is experienced in the use of chemotherapy agents. Furthermore, treated patients should be monitored routinely for heart, liver and kidney function.
The Committee also made several recommendations for future research, including suggestions that:
(i) Another large multicenter clinical research trial of mitoxantrone would be important to confirm the apparent benefit in patients with SPMS;
(ii) Mitoxantrone should be shown to have clinical benefit on long-term outcomes such as limiting the progression of disability in a longer (2 to 3) year trial, in order to justify its potential risk of side effects;
(iii) Because of the heart toxicity risk of mitoxantrone, a comparison should be carried out of its effectiveness in MS relative to other immune suppressive agents such as pulse-cyclophosphamide, which can be given for more extended periods of time without the risk of heart injury;
(iv) A study should be performed to assess the role of a short course of mitoxantrone in patients with an acute deterioration, to see whether a relatively brief exposure to the drug could halt the activity, so that standard immune modulating therapies may then be instituted. This approach might enable mitoxantrone to be used several times in the future, without exceeding the cumulative dose that poses unacceptable risk of heart injury; and
(v) Attempts should be made to combine mitoxantrone with agents that protect the heart to see whether more prolonged courses (higher cumulative doses) of mitoxantrone can be administered safely.
It is hoped that this special report will help clinicians and MS patients to balance the considerations of potential benefits and risks of mitoxantrone, and to reach the most informed decisions regarding treatment choices. More details of the FDA process and considerations for approval of Mitoxantrone in MS can be found on the FDA web site (4). Future studies will be aimed at confirming the potential of mitoxantrone and evaluating its role in combination trials or in different regimens.
1. D.S. Goodin, MD, B.G. Arnason, MD, P.K. Coyle, MD, FAAN, E.M. Frohman, MD and D.W. Paty, MD, FAAN. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003:61:1332-1338
2. Hartung HP, Gonsette R, König N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002; 360: 2018–2025.
3. 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. Journal of Neurology and Neurosurgical Psychiatry. 1997; 62: 112–118.
4. Immunex Corp. Briefing document on mitoxantrone (Novantrone) for
treatment of multiple sclerosis: on file with the FDA. Available at: http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3582b1k.pdf
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