Treatment of RRMS with high dose cyclophosphamide induction
CyclophosphamideBackground: Previous studies have described stabilization of aggressive multiple sclerosis (MS) with one-time induction therapy with high-dose cyclophosphamide (HiCy). The long-term benefit of this stabilization followed by conventional therapy has not been explored.
Objective: The objective of this study was to evaluate the safety and clinical outcomes following treatment of relapsing-remitting MS with HiCy induction therapy followed by glatiramer acetate maintenance.
Methods: A retrospective review of a closely followed population of thirty two MS patients treated with HiCy (200mg/kg intravenous infusion over 4 days) followed by maintenance with glatiramer acetate was performed.
Results: Annualized relapse rate was reduced from 1.37 in the 2 years prior to treatment to 0.27 over a mean post-treatment follow-up period of 14 months (range 0.5-33.8). The projected probability of relapse-free survival at 2 years was 0.64 (95% CI 0.37-0.82). The projected probability of Expanded Disability Status Scale (EDSS) progression-free survival at 2 years was 0.77 (95% CI 0.43-0.92). The mean number of gadolinium-enhanced lesions was reduced from 0.86 (SD 1.6) at baseline to 0 at 12 months and 0.08 (SD 0.28) at 15-24 months. A total of 55% of patients had no evidence of disease activity in follow-up. Infectious complications occurred in 47% with no long-term morbidity and no deaths.
Conclusions: Induction therapy with HiCy followed by long-term maintenance with glatiramer acetate is well tolerated in patients with MS, and appears to be efficacious in reducing the risk of relapse, disability progression, and new MRI lesions.
Summary: Recent developments, including the development and licencing of Nataluzimab and Fingolimod have increased the therapeutic avenues available for patients with relapsing remitting multiple sclerosis who continue to get severe relapses despite treatment with the first line disease modifying drugs of interferon beta or glatiramer acetate. However, both Nataluzimab and Fingolimod have side effects which require discontinuation, including infusion reactions, liver function abnormalities and thyroid abnormalities for Nataluzimab, and symptomatic bradycardia, severe headaches and flu like symptoms for Fingolimod, and for these reasons a proportion of patients will not be able to have either treatment. For these patients it is important to have alternative treatments to attempt to prevent relapse associated disability.
In this study the authors performed a retrospective analysis of 40 patients treated with high dose cyclophosphamide for relapsing remitting multiple sclerosis at John Hopkins. These patients were treated according to a standardised protocol and had detailed and standardised radiological and clinical follow up with MRI, assessment of relapse number and EDSS assessment every 3 months for 2 years.
This is the largest and most detailed retrospective review to date of the use of cyclophosphamide in patients with relapsing remitting MS. All but one patient had been prescribed disease modifying drugs prior to cyclophosphamide without good clinical effect, and the patients had a median of 2 relapses in the prior 2 years. Cyclophosphamide treatment followed by glatiramer acetate lead to a reduction in annualised relapse rate, and significant reduction in number of gadolinium enhancing lesions at 3 and 12 months. Side effects were however common with 84% of patient experiencing nausea and vomiting and 47% experiencing infections. Whilst an important addition to the therapeutic literature this was not a clinical trial as there was no comparator arm.
Authors: Harrison DM, Gladstone DE, Hammond E, Cheng J, Jones RJ, Brodsky RA, Kerr D, McArthur JC, Kaplin A.
Source: Multiple Sclerosis 2011, August 24 & Pubmed PMID: 21865410 (01/09/11)
Treatment: CCSVI both IJV ballooned 09/2010, No DMDs, Tysabri on hold after 24 Infusions, after LDN, ABX Wheldon Regime for 1 year.