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.

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.

Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial.

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.

The influence of polysomnography on the Multiple Sleep Latency Test and other measures of daytime sleepiness.

INTRODUCTION: According to its guidelines, the Multiple Sleep Latency Test (MSLT) should be performed following an all-night polysomnography (PSG). However, the sleep quality and consequently the MSLT results may be affected by PSG and by the fact that a subject sleeps under unfamiliar conditions. The aim of this study was to examine whether PSG performed in a sleep laboratory has any influence on the MSLT and other measures of daytime sleepiness. METHODS: Twenty healthy subjects with a mean age of 35.9+/-10.1 years underwent two MSLT examinations, and the 2 examination days were at least 4 weeks apart. In addition, on each occasion a monotonous vigilance task (VT) was performed and the subjects were asked to fill out the Epworth Sleepiness (ESS) and Visual Analogue Scales (VAS). In a cross-over design, a group of 10 subjects underwent a MSLT (MSLT-P) following a PSG and, on a second occasion, a MSLT (MSLT-N) was performed without a prior PSG. Vice versa, a second group of 10 subjects underwent first MSLT-N and then MSLT-P. RESULTS: None of the MSLT parameters differed significantly between MSLT-P and MSLT-N. The other measures of daytime sleepiness (VT, ESS, VAS) also showed no evidence of significant differences between days with and without a prior PSG. CONCLUSIONS: The results of MSLT and other measures of daytime sleepiness in healthy subjects are not influenced by the fact whether or not the subjects had a PSG the night prior to MSLT.