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Treating Active Neuromyelitis Optica with Mitoxantrone
Abstract & Commentary
By Susan Gauthier, DO, MPH, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Gauthier reports no financial relationships relevant to this field of study.
Synopsis: Twenty highly active patients with neuromyelitis optica (NMO) stabilized after treatment with mitoxantrone. All patients tolerated treatment without significant safety concerns. Mitoxantrone may be an option for NMO given its differential inhibitory effect on subsets of B-cells.
Source: Kim S, Woojun K, Park M, et al. Efficacy and safety of mitoxantrone in patients with highly relapsing neuromyelitis optica. Arch Neurol 2010; Dec13 (epub ahead of print).
Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system that is thought to be primarily B cell mediated given the presence of anti-aquaporin 4 autoantibodies in the serum of the majority of patients. The clinical manifestations of NMO are relapsing episodes of optic neuritis and multi-segmented inflammatory lesions within the spinal cord, wherein patients accumulate a significant amount of disability within a short period of time. Patients with NMO traditionally have been treated with a similar approach as patients with relapsing multiple sclerosis (MS); however, NMO patients have a poor response to standard immunomodulatory therapy (interferon beta or glatiramer acetate). Through the recent advancement regarding the pathogenesis of NMO, the treatment strategy has shifted to treating the disease with B cell specific agents. As a result of this paradigm switch, Kim et al reported on 20 highly active NMO patients treated with mitoxantrone and studied the selective B cell inhibitory mechanisms induced by this treatment.
Patients selected for this retrospective study either met the diagnostic criteria for NMO or NMO spectrum disorder and had at least two relapses within the year prior to treatment. The monthly induction protocol varied between 3 to 6 months followed by an every 3-month infusion to a maximum treatment dose of 100-120 mg/m2. Baseline relapse rate and EDSS (disability score) was compared to follow-up post-treatment scores, wherein the mean follow-up was 17 months after the start of treatment. The median annualized relapse rate was reduced from 2.8 to 0.7 (P < 0.001) and mean EDSS improved from 5.6 to 4.4 (P < 0.001). Patients tolerated the treatment without significant infections. One patient had an asymptomatic decrease in ejection fraction (64% to 54%) and there was no therapy-related acute leukemia in a mean safety follow up of 41 months. To study changes within specific leukocyte subsets after six monthly infusions, 10 patients had serum collected for a flow cytometric analysis. CD19+ B cells were selectively decreased after treatment with mitoxantrone as compared to T cell subsets. Among B cells, mitoxantrone preferentially decreased CD27+ memory B cells as compared to CD27– naive B cells.
Mitoxantrone is a known effective antineoplastic agent that blocks DNA synthesis and impairs DNA repair. It is currently the only FDA-approved intravenous immunosuppressant for the treatment of relapsing forms of MS. Although mitoxantrone has a broad immunosuppressive effect, multiple studies throughout the years have demonstrated that it has a profound effect on the humoral immune system, yet how this relates to its beneficial effect in MS is unknown. Unfortunately the use of mitoxantrone in the treatment of MS has been limited by its cardiac toxicity and a more recently reported treatment-associated acute leukemia. Nevertheless, given the limited treatment options for NMO and the aggressive nature of the disease, there is a rationale to consider higher risk therapeutics, such as mitoxantrone, to stabilize actively relapsing NMO patients. The current report was a small retrospective study; therefore we can only conclude that mitoxantrone potentially may stabilize active NMO patients. However, the authors were able to show that mitoxantrone preferentially inhibited memory B cells in this population. Putting this together, it is reasonable to consider mitoxantrone for active NMO patients, although as the authors acknowledge, it remains to be determined if short-term treatment with mitoxantrone will provide long-term stabilization. In addition, considering the risk of this drug, it would be difficult to recommend it as first-line therapy. The authors suggested a potentially safer alternative treatment protocol, which is a 6-month induction of mitoxantrone followed by a less toxic immunosuppressant for maintenance; however, this will need to be evaluated further. More selective B cell agents, such as rituximab, also are being studied in NMO and are considered to be a more tolerable and targeted treatment strategy. Safety issues related to the chronic use of this drug have not been explored.