Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria.
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.
                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.
                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).
                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. We designed a randomized, placebo-controlled, multicentre trial involving 51 relapsing-remitting multiple sclerosis patients to determine the clinical efficacy of mitoxantrone treatment over 2 years. Patients were allocated either to the mitoxantrone group (27 patients receiving I.V. infusion of mitoxantrone every month for 1 year at the dosage of 8 mg/m2) or to the placebo group (24 patients, receiving I.V. infusion of saline every month for 1 year) using a centralized randomization system. Disability at entry and at 12-24 months was evaluated by four blinded neurologists trained in the application of the Kurtzke Expanded Disability Scale (EDSS). In addition, the number and clinical characteristics of the exacerbations over the 24 months were recorded by the local investigators. MRI, at 0, 12 and 24 months, was performed with a 0.2 T permanent unit. MRI data were analysed by two blinded neuroradiologists. All patients underwent a clinical evaluation. A statistically significant difference in the mean number of exacerbations was observed between the mitoxantrone group and placebo group both during the 1st and the 2nd year. Although there was no statistically significant benefit in terms of mean EDSS progression over 2 years, the proportion of patients with confirmed progression of the disease, as measured by a one point increase on the EDSS scale, was significantly reduced at the 2nd year evaluation in the mitoxantrone group. Forty-two (23 mitoxantrone, 19 placebo) patients underwent all MRI examinations during the 24-month period. We observed a trend towards a reduction in the number of new lesions on T2-weighted images in the mitoxantrone group. Our study suggests that mitoxantrone might be effective in reducing disease activity, both by decreasing the mean number of exacerbations and by slowing the clinical progression sustained by most patients after 1 year from the end of treatment. To evaluate the efficiency of mitoxantrone in multiple sclerosis.
                Forty two patients with confirmed multiple sclerosis, selected as having a very active disease on clinical and MRI criteria were randomised to receive either mitoxantrone (20 mg intravenously (IV) monthly) and methylprednisolone (1 g iv monthly) or methylprednisolone alone over six months. In the steroid alone group five patients dropped out due to severe exacerbation.
                Blinded analysis of MRI data showed significantly more patients with no new enhancing lesions in the mitoxantrone group compared with the steroid alone group, (90% v 31%, P < 0.001). In the mitoxantrone group there was a month by month decrease almost to zero in the number of new enhancing lesions, and in the total number of enhancing lesions, whereas both remained high in the steroid alone group. The differences were significant for both indices at all months from 1-6. Unblinded clinical assessments showed a significant improvement in change in EDSS at months 2-6 in the mitoxantrone group, with a final mean improvement of more than one point (-1.1 v + 0.3; P < 0.001). There was a significant reduction in the number of relapses (7 v 31; P < 0.01), and an increase in the number of patients free of exacerbation (14 v 7; P < 0.05).
                In this selected group of patients with multiple sclerosis with very active disease, mitoxantrone combined with methylprednisolone was effective in improving both clinical and MRI indices of disease activity over a period of six months whereas methylprednisolone alone was not. Further double blinded long term studies are needed to properly evaluate the effect of mitoxantrone on progression in disability.
MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (~12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature.
MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients’ risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.