Management of worsening multiple sclerosis with mitoxantrone: a review.
BACKGROUND
Mitoxantrone, an intravenously administered immunosuppressant that inhibits T-cell, B-cell, and macrophage proliferation, is indicated for reducing neurologic disability and relapse frequency in patients with secondary progressive multiple sclerosis (SPMS), progressive relapsing MS, or worsening relapsing-remitting MS (RRMS).


OBJECTIVE
This article reviews the pathogenesis and natural history of MS and examines the available treatment options for patients with RRMS, worsening RRMS, or SPMS, with a focus on mitoxantrone.


METHODS
MEDLINE (1966-present) and the Cochrane Central Register of Controlled Trials (1994-present) were searched for relevant randomized, blinded, controlled clinical trials using the terms mitoxantrone, Novantrone, and multiple sclerosis.


RESULTS
Five randomized, blinded, controlled trials and an ongoing open-label Phase IV safety study were identified and included in this review. In one randomized, double-blind trial (N=25), patients with RRMS who received mitoxantrone 8 mg/m2 monthly had significantly reduced relapse rates at 1 year compared with those who received placebo (P=0.014). In a 2-year, randomized, partially blinded trial (N=51), patients with active RRMS who received mitoxantrone 8 mg/m2 monthly had significantly fewer relapses compared with those who received placebo (P<0.001), and significantly fewer patients had confirmed progression of disability (1-point increase in Expanded Disability Status Scale [EDSS] score) (P=0.02). In a randomized, double-blind trial (N=49), patients with relapsing SPMS who received mitoxantrone 12 mg/m2 monthly for 3 months followed by 12 mg/m2 g3mo for up to 32 months had significant improvements in EDSS scores compared with those who received methylprednisolone 1 g IV monthly for 3 months followed by 1 g IV g3mo (P=0.002 at 1 year, P=0.045 at 2 years) and significant reductions in the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) (P=0.002 at 1 and 2 years, P=0.03 at 3 years). In a randomized, partially blinded Phase II trial in 42 patients with active RRMS or SPMS, patients who received mitoxantrone 20 mg IV monthly and methylprednisolone 1 g IV monthly had significantly fewer new gadolinium-enhancing lesions on MRI (P<0.001) and significantly fewer relapses (P<0.01) at 6 months compared with those who received methylprednisolone alone. In a pivotal Phase III trial (N=194), patients with worsening RRMS or SPMS who received mitoxantrone 12 mg/m2 g3mo for 2 years had significantly fewer relapses (P<0.001) and significantly less deterioration in disability, as measured by change in EDSS score (P=0.019), compared with those who received placebo. In a nonrandomized subgroup of patients from this study (n=110), those who received mitoxantrone 12 mg/m2 g3mo had a significant reduction in the number of T2-weighted MRI lesions at 24 months (P=0.027). The most common adverse events in these studies included nausea and/or vomiting (18%-85%), alopecia (33%-61%), amenorrhea (8%-53%), urinary tract infections (6%-32%), and upper respiratory tract infections (4%-53%). Leukopenia was reported in 10% to 19% of patients. Use of mitoxantrone can lead to serious adverse effects, particularly cardiotoxicity, myelosuppression, and, rarely, leukemia. Long-term use of mitoxantrone may compromise left ventricular function. Limited cardiotoxicity was reported in the clinical studies; in the pivotal clinical trial, 2 patients who received mitoxantrone 12 mg/m2 had decreases in left ventricular ejection fraction to <50% of baseline.


CONCLUSIONS
In the available clinical trials, mitoxantrone provided effective treatment for worsening RRMS or SPMS. When mitoxantrone is used as recommended, the risks of substantial myelosuppressive and cardiotoxic effects can be reduced by careful patient selection, drug administration, and monitoring. The lifetime cumulative dose should be strictly limited to 140 mg/m2, or 2 to 3 years of therapy.
Fox
Edward J
EJ
Multiple Sclerosis Clinic of Central Texas, Round Rock 78681, USA. efox@utmb.edu
D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D018450:Disease Progression; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008775:Methylprednisolone / Q000627:therapeutic use; D008942:Mitoxantrone / Q000494:pharmacology / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000473:pathology; D018579:Patient Selection; D016032:Randomized Controlled Trials as Topic
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D008942:Mitoxantrone; D008775:Methylprednisolone