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The observed incidence of CHF in patients with MS who received a mean cumulative dose of 60.5 mg/m(2) MITO was <0.20%. Continued monitoring of patients with MS who are receiving MITO is needed to determine whether the incidence of CHF increases with higher cumulative MITO doses and prolonged follow-up.

To evaluate the incidence of therapy-related acute leukaemia (t-AL) after single-agent mitoxantrone (MITO) treatment, we reviewed medical records of patients in three studies of single-agent MITO therapy for multiple sclerosis (MS) and existing literature on MITO therapy in MS, leukaemia, and solid tumors. Of 1378 MITO recipients in the three MS studies (mean cumulative dose of 60 mg/m2 and mean follow-up of 36 months), one patient had t-AL, an observed incidence proportion of 0.07% [95% confidence interval (CI) = 0.00-0.40%]. There were no cases of t-AL in published reports of nine additional studies of single-agent MITO therapy for MS. There was one published case report of acute promyelocytic leukoemia detected five years after initiating MITO therapy for MS. The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS. Although these observations provide preliminary reassurance, extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk of t-AL after MITO therapy for MS.

There is increasing evidence that multiple sclerosis (MS) is not only characterized by immune mediated inflammatory reactions but also by neurodegenerative processes. In neurodegenerative diseases, neuronal and axonal loss is mediated by oxidative stress and excitotoxicity which constitute a final common toxic pathway. Importantly, peroxynitrite is the key mediator of those two intertwined pathomechanisms. In MS, peroxynitrite is consistently associated with active lesions and produces highly toxic nitrating and oxidizing radical species that alter lipid, protein, DNA and mitochondrial structures and functions. During the remitting phase, peroxynitrite participates to neuron and oligodendrocyte damage in association with inflammatory processes. During the chronic phase, peroxynitrite contributes to self-perpetuating mechanisms responsible for disease progression. Neutralization of oxidative stress and excitotoxicity, and in particular of peroxynitrite derived free radicals, might represent a therapeutic approach to provide neuroprotection in MS.