The combination of cyclophosphamide plus interferon beta as rescue therapy could be used to treat relapsing-remitting multiple sclerosis patients Twenty-four months follow-up
Reggio E, Nicoletti A, Fiorilla T, Politi G, Reggio A and Patti F;
Commented by , 26 Jul 2005
Background
Mitoxantrone is used to treat worsening or progressive multiple sclerosis (MS), that do not respond to standard treatment with interferon beta (IFN beta) or glatiramer acetate. Still, the use of mitoxantrone is limited, primarily due to the cardiotoxic side effect.
Cyclophosphamide (CFX) is a cytotoxic agent used for treatment of malignant neoplasms and immune-mediated inflammatory diseases. A recent study has suggested efficacy of combination therapy with CFX and IFN beta (ref. 1).
Aim
To evaluate the efficacy of CFX and IFN beta, in relapsing remitting (RR) MS patients with treatment failure during IFN beta therapy.
Methods
The authors studied 30 RRMS patients who experienced treatment failure during 12 month of IFN beta therapy (two or more relapses per year or 1,5 EDSS points worsening in one year).
The subjects were treated with monthly i.v. CFX (500 mg/m2 - 1500 mg/m2) as well as the standard IFN beta therapeutic regimen they previously had received. Follow up was 12 and 24 months after entry.
Primary outcome measure was relapse rate, although patients free of relapses and EDSS changes were also evaluated. Brain MRI and clinical assessment was performed before entry (T0) and after 12 (T1) and 24 (T2) months. Safety, tolerability and adverse events were recorded.
Results
Relapse rate was reduced significantly during the study (1.44 at T0; 0.4 at T1 and 0.17 at T2; p<0.001). The percentage of patients free of relapses was 70% at T2 (p<0.0001) and EDSS score changed from 2.6 ± 1.23 at T0 to 2.2 ± 1,5 which was not significant.
There was no significant change in MRI lesion load, but gadolinium-enhancing lesions were reduced from 58 at T0, to 18 at T1 and 3 at T2 (p<0.0001). There were no observed significant adverse events.
Dr Blinkenberg's comments
The study showed a reduction in relapse rate, an increase in relapse free patients and a trend of improvement in EDSS. The study was designed as an open trial, thus providing no evidence of treatment efficacy, or whether the observed effect could be explained by CFX alone. The study and the treatment regimen were considered to be safe.
Treatment of MS with CFX is well described in a Cochrane review and reported to have no significant overall effect (ref. 2). The studies in this review included MS patients with progressive disease and considerable disease burden.
Recently it has been reported, that CFX treatment may be more efficacious in patients with early active RRMS (ref. 3), rather than the progressive stage characterized by more diffuse degenerative processes.
In the current study the authors included patients with a relatively short disease duration and active RRMS. Although the study was open, the results are encouraging and corroborate the notion, that MS patients with active disease should be treated aggressively in the early course, in order to optimize efficacy and gain disease control.
Mitoxantrone is used for induction/rescue therapy in these cases, although alternatives are needed due to the dosage limitations of this drug. CFX and azathioprine may be relevant alternatives, although randomized controlled trials are needed, in order to provide answers in this regard. Natalizumab should also be mentioned in this context, although the future use of this drug is still unknown.
References
1. Patti F, Cataldi ML, Nicoletti F, Reggio E, Nicoletti A, Reggio A. Combination of cyclophosphamide and interferon-beta halts progression in patients with rapidly transitional multiple sclerosis. J Neurol Neurosurg Psychiatry 2001; 71; 404-7 (Note: Free full text article).
2. La Mantia L, Milanese C, Mascoli N, D'Amico R, Weinstock-Guttman B. Cyclophosphamide for multiple sclerosis. Cochrane Database Syst Rev 2005, Issue 2
3. Khan OA, Zvartau-Hind M, Caon C, Din MU, Cochran M, Lisak D, Tselis AC, Kamholz A, Garbern JY, Lisak RP. Effect of monthly intravenous cyclophosphamide in rapidly deteriorating multiple sclerosis patients resistant to conventional therapy. Mult Scler 2001; 7; 185-8