Effect of open label pulse cyclophosphamide therapy on MRI measures of disease activity in five patients with refractory relapsing–remitting multiple sclerosis

doi:10.1016/S0165-5728(99)00039-9

Journal of Neuroimmunology

Volume 99, Issue 1, 1 September 1999, Pages 142-149

https://doi.org/10.1016/S0165-5728(99)00039-9 Get rights and content

Abstract

Objective. To evaluate the response to cyclophosphamide (CTX) of five patients who failed an average three treatments with multiple other therapeutic agents, using serial monthly MRI measures. Methods. Five patients with relapsing–remitting multiple sclerosis (MS) and documented MRI disease activity were started on monthly pulse intravenous CTX at a dose of 1 g/m². CTX was administered without an induction phase according to the protocol similar to the treatment of lupus nephritis. The five patients were followed with monthly MRI and clinical evaluation for a mean of 28 months. Results. All the patients showed a rapid reduction in the contrast-enhancing lesion frequency and in three patients there was a decrease in the T2 lesion load within the first 5 months after starting CTX treatment. The administration of CTX during overnight hospitalization was safe and well tolerated. Conclusions. These findings suggest that aggressive immunosuppressive therapy may be useful in some rapidly deteriorating refractory patients and further controlled study should be considered in order to full evaluate this type of treatment as a potential therapy in MS.

Introduction

While the etiology of multiple sclerosis (MS) is still unknown, the pathogenesis is thought to be most likely autoimmune and T-cell mediated (Hafler and Weiner, 1995). Thus, immunomodulating agents have been used as experimental therapies to modify the course of disease.

Recently, a potential beneficial effect of two immunosuppressive therapies, cladribine and mitoxantrone has been reported (Sipe et al., 1994; Edan et al., 1997).

Cyclophosphamide (CTX), an alkylating antineoplastic agent, has antimitotic and immunosuppressive effects. It is used in the treatment of malignant disease such as lymphoma and a variety of solid tumors (Martindale, 1996) and also in non-malignant conditions including vasculitis, systemic lupus erythematosus, glomerular kidney disease (Merkel et al., 1998). The most common adverse effects of CTX are nausea and vomiting, alopecia, hemorragic cystitis, teratogenic effects, sterility (Martindale, 1996). The rationale for the use of CTX in MS comes from studies in experimental allergic encephalomyelitis in Lewis rats which demonstrated that CTX could reverse the course of the disease even when administered after the symptoms appeared (Paterson and Drobish, 1969).

Several non-blinded, non-randomized trials have shown a potential beneficial effect of CTX in MS (Millac and Miller, 1969; Drachman et al., 1977; Goodkin et al., 1987; Killian et al., 1988; Millefiorini et al., 1990; D'Andrea et al., 1990). A randomized trial in 58 patients with a chronic progressive MS comparing CTX plus ACTH, ACTH alone, plasma-exchange plus corticotropin plus low dose oral CTX treatment groups was reported by Hauser et al. (1983). The patients treated with CTX plus ACTH showed neurological improvement or were stable compared with patients in the other two groups. Other randomized, single-blinded, placebo-controlled studies in chronic progressive MS patients (Canadian Cooperative Multiple Sclerosis Study Group, 1991; Likosky et al., 1991) did not show a statistically significant difference between the placebo and CTX-treated groups. Positive effects of every 2-month pulse CTX in progressive MS were reported in a randomized, single blind study (Weiner et al., 1993). In all previous trials, the primary outcome measure was clinical, based on Expanded Disability Status Scale (EDSS).

The purpose of this study is to evaluate the response to pulse monthly CTX treatment in five patients previously unresponsive to other therapeutic interventions. Because of the value of MRI (McFarland et al., 1992; The IFNB Multiple Sclerosis Study Group, 1993) in assessing the effects of some previously studied therapies including general immunosuppression, MRI was used as primary outcome measure assessed in this study.

Section snippets

Patients

Five patients experiencing a rapid clinical deterioration despite multiple therapeutic interventions were treated with monthly pulse CTX therapy and followed for a mean of 28 months with monthly MRI and neurological evaluation. The patients were hospitalized overnight for the administration of CTX. Below is a summery of each patient's history and clinical findings.

SM, a 38-year-old white female diagnosed in August 1990 with relapsing–remitting MS. Between 1990 and 1992 she had several relapses

Results and discussion

A cohort of five patients with relapsing–remitting or secondary progressive MS was evaluated with MRI and neurological examination to determine the response to monthly pulse CTX treatment given in an open label fashion. All had a history of rapid clinical deterioration, active disease on MRI and failed previous therapies.

About 1–5 months after starting CTX treatment, all the patients showed a reduction in gadolinium-enhancing lesion occurrence compared with their pretreatment lesion frequency.

Acknowledgements

The authors would like to thank Dr. Howard Weiner for his helpful comments and discussion. This work was performed in part in the In Vivo NMR Research Center at the National Institutes of Health.

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In line with our findings, an open-label study of intravenous cyclophosphamide in 14 patients with rapidly deteriorating RRMS (defined as a higher than three-point increase in the EDSS score in the previous 12 months despite disease-modifying therapy and intravenous prednisone) reported improvement and neurological stability within six months which was sustained for at least 18 months after the cyclophosphamide initiation (Khan et al., 2001). Gobbini et al (Gobbini et al., 1999) reported clinical stability in five patients with rapidly deteriorating RRMS who were treated with cyclophosphamide for six months and led to a rapid reduction in gadolinium enhancing brain MRI lesions. Cyclophosphamide has the ability to penetrate the blood-brain barrier and has an excellent bioavailability within the central nervous system (Awad and Stuve, 2009).
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. Retrospective chart review was performed to identify patients with TMS who did not respond to corticosteroid and plasma exchange and were treated with cyclophosphamide. Demographic, clinical, treatment, and outcome parameters were collected.
. We identified 12 patients with TMS who were treated with cyclophosphamide. Median follow-up was 17 (range 1-72) months after cyclophosphamide administration. The tumefactive attack was the first clinical symptom in 5/12 patients. The median age at index attack onset was 36 (range 22-57). The median age at the first demyelinating attack was 29.3 (range 20-55). The most common clinical presentation at the index attack was the visual disturbance, followed by motor symptoms. The index attack was accompanied by headache in 5/12 patients. Median attack related Expanded Disability Status Scale (EDSS) score was 6 (range 3-9.5), which improved to 5.25 (range 1-10) after treatment with cyclophosphamide. All patients were treated with corticosteroids and plasma exchange prior to treatment with cyclophosphamide. EDSS score improved in 8/12 patients and targeted neurological deficits improved to a moderate or marked degree in 9/12 patients after cyclophosphamide administration. The number of gadolinium enhancing lesions decreased in 10/12 and 8/12 patients had lack of disease activity (no new T2 or GAD lesions) in a median (range) time of 11 months (1-16) after the last dose of cyclophosphamide.
. Cyclophosphamide could be an effective option for the treatment of TMS, refractory to corticosteroids and plasmapheresis, and is associated with improvement of clinical and radiological disease activity.
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The course of the disease is largely unpredictable and its clinical presentation is variable, but its predilection for certain parts of the CNS, which includes the optic nerves, the brain stem, cerebellum, and cervical spinal cord, provides a characteristic constellation of signs and symptoms. Several variants of MS have been nowadays defined with variable immunopathogenesis, course and prognosis. Many new treatments targeting the immune system have shown efficacy in preventing the relapses of MS and have been introduced to its management during the last decade.
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Immunosuppressives have been used in multiple sclerosis (MS) since 1966. Today, we have many treatments for the relapsing forms of the disease, including 8 US Food and Drug Administration-approved therapies, with more soon to be introduced. Given the current treatment landscape what place do immunosuppressants have in combating MS? Trial work and our experience suggest that immunosuppressives still have an important role in treating MS. Cyclophosphamide finds use in treating patients with severe, inflammatory relapsing remitting MS or those suffering from a fulminant attack. We tend to employ mycophenolate mofetil as an add-on to injectable therapy for patients experiencing breakthrough activity. Some progressive (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) patients may stabilize after treatment with either cyclophosphamide or mycophenolate. We rarely employ mitoxantrone because of potential cardiac or carcinogenic effects. We prefer to use cyclophosphamide or mycophenolate mofetil in preference to methotrexate because evidence of efficacy is limited for this drug. We have less experience with azathioprine, but it may be an alternative for patients with limited options who are unable to tolerate conventional therapies.
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However despite circumstantial evidence from pathology and the animal model, experimental allergic encephalomyelitis (EAE), the proof has come from the ability to clearly show that immunosuppression modifies disease. Monitoring patients treated with an immunosuppressive drug such as cyclophosphamide (Gobbini et al., 1999) have demonstrated that some patients show a profound decrease in disease activity (Fig. 1). Controlled trials of other immunosuppressive therapies such as cladribine (Giovannoni et al., 2010) or mitoxantrone (Krapf et al., 2005) have yielded a relatively similar results.
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Effect of open label pulse cyclophosphamide therapy on MRI measures of disease activity in five patients with refractory relapsing–remitting multiple sclerosis

Abstract

Introduction

Section snippets

Patients

Results and discussion

Acknowledgements

Semin. Arthritis Rheum.

Lancet

Lancet

Lancet

Risk for sustained amenorrhoea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy

Ann. Int. Med.

The Canadian cooperative trial of cyclophosphamide and plasmaexchange in progressive multiple sclerosis

Lancet

et al. Cyclophosphamide in relapsing remitting multiple sclerosis

Ital. J. Neurol. Sci.

Cyclophosphamide

J. Neurol.

Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria

J. Neurol. Neurosurg. Psychiatry

Cyclophosphamide in chronic progressive multiple sclerosis. Maintenance vs. non-maintenance therapy

Arch. Neurol.

Immunologic mechanism and therapy in multiple sclerosis

Immunol. Rev.

Serial gadolinium-enhanced magnetic resonance imaging scans in patients with early, relapsing–remitting multiple sclerosis: implications for clinical trials and natural history

Ann. Neurol.

Intensive immunosuppression in progressive multiple sclerosis

New Engl. J. Med.

Treatment of Wegener's granulomatosis with intermittent high-dose intravenous cyclophosphamide

Am. J. Med.

Treatment of progressive multiple sclerosis with pulse cyclophosphamide/methylprednisolone: response to therapy is linked to duration of progressive disease

Nurology

Interferon beta-1b is effective in relapsing–remitting multiple sclerosis: I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial

Neurology