Is High-Dose Cyclophosphamide a Treatment Option for Multiple Sclerosis?
Abstract & Commentary
By Susan A. Gauthier, DO, MPH, Assistant Professor of Neurology, Weill Medical College of Cornell University. Dr. Gauthier reports no financial relationships relevant to this field of study.
Synopsis: Clinical stabilization was achieved after the treatment with high-dose cyclophosphamide (Cy) therapy in a small cohort of active relapsing-remitting multiple sclerosis (MS) patients.
Source: Krishnan C, et al. Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis. Arch Neurol 2008 Jun 9 (Epub ahead of print).
The rationale for treating MS with immunosuppressant therapy rests on the hypothesis that MS is an inflammatory, cell mediated, autoimmune disease that affects the central nervous system.1 In general, therapies considered to be immunosuppressant have directed intracellular mechanisms, which involve DNA synthesis and/or immune cell activation, primarily targeting within the bone marrow and other lymphoid organs. Both cyclophosphamide (Cy) and mitoxantrone have a variety of toxicities; therefore, their use has been limited to patients with active disease while on standard injectable therapy.
Krishnan et al treated nine patients who were considered to have aggressive MS with a high-dose regimen of Cy and reported stabilization by clinical and MRI measures. The patients had sustained disability progression or a recent clinical exacerbation within the past year and the majority had failed multiple standard therapeutic regimens. Inflammatory activity was required on MRI as demonstrated by at least two or more gadolinium-enhancing lesions (GELs) on two pre-treatment MRI's. Importantly, patients having had a relapse within three months of enrollment were excluded to ensure disease stabilization was not related to pretreatment relapse recovery. Patients were treated with 50 mg/kg/d of Cy intravenously for four consecutive days, followed by granulocyte colony-stimulating factor on day six.
The disease duration for the cohort ranged widely (1.5-15 years); however, the majority of the patients had significant disability (mean Expanded Disability Status Score [EDSS] = 5.0) and high inflammatory activity on MRI (mean GELs = 6.5). The cohort disability score improved to 3.06 and the GELs decreased to 1.2 after a mean time of 23 months of follow-up. Two patients had clinical exacerbations after treatment with Cy and required additional immunosuppressive therapy and five patients had continued or recurrent MRI activity. There was a significant decrease in brain parenchyma fraction (BPF) between baseline and month three that appeared to stabilize; this finding was consistent with pseudoatrophy and was less likely a toxic effect of Cy. The treatment was well tolerated without serious adverse events and only three self-limited infections were reported.
Commentary
Over the past 30 years, Cy has been used for the treatment of selected MS patients, as well as other nonmalignant immune-mediated inflammatory processes including immune mediated neuropathies and lupus nephritis. There have been more than 40 published reports on the clinical and immunologic effects of Cy in MS, many of which have found conflicting results regarding efficacy.2 The results of these studies initially led to conflicting opinions regarding the use of Cy in MS. However, with improved knowledge of the inflammatory and degenerative processes ongoing in MS, as well as with the advent of MRI, there is a better understanding of how to use Cy in a method that is efficacious.
As compared to previous Cy studies, the dose in the current study was significantly higher and is known to be ablative to mature lymphocytes but to spare hematopoetic stem cells. The first study utilizing this protocol was recently reported and found clinical stabilization in 12 patients who were refractory to standard immunomodulatory therapy.3 In both studies, patients with a higher disability score at enrollment were less likely to have improvement; this finding is consistent with previous studies of Cy. In general, patients earlier within their disease course, in which the inflammatory activity appears to be more prominent, tend to be more responsive. Interestingly, as demonstrated in the present study, clinical relapses as well as MRI activity can still occur at ablative doses of Cy and indicate the persistence of an inflammatory process. This finding questions the benefit of this particular protocol given the potential risk.
In general, given our understanding of the pathological processes involved in MS, the beneficial effect of immunosuppressive therapy is assumed to be in the earlier stages of the illness as compared to the later stages or in patients with primary progressive disease. Nonetheless, cyclophosphamide is limited, by its toxicity, for widespread use in the early stages of MS, and timing of treatment as well as the appropriate protocol requires further study.
References
1. Hafler D, Weiner H. Immunologic mechanisms and therapy in multiple sclerosis. Immunol Rev 1995;144:75-107.
2. Gauthier SA, et al. Immunosuppressive therapy for multiple sclerosis. Neurol Clin 2005;23:247-272.
3. Gladstone DE, et al. High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Arch Neurol 2006;63:1388-1393.
Clinical stabilization was achieved after the treatment with high-dose cyclophosphamide (Cy) therapy in a small cohort of active relapsing-remitting multiple sclerosis (MS) patients.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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