OffLabel: cyclophosphamide

Cyclophosphamide is my fifth off label DMT for treating MS in resource poor environments. #MSBlog #MSResearch #OffLabel

"This post is the fifth in a series of posts to try and help neurologists who treat MS in healthcare environments where they cannot access high-cost innovator DMTs. If you want to know the history of this post please read my post on my visit to South Africa. The other four off-label DMTs that I have covered to date are methotrexate, azathioprinemitoxantrone and cladribine."

"I wasn't going to include cyclophosphamide in this list as I personally haven't personally used it to treat MS for close to 20 years. However, I discovered at a recent meeting that quite a number of colleagues are still using the drug in tumefactive and Marburg-variant MS as an induction therapy and they also use it in some patients with highly-active/rapidly-evolving MS in whom they can't use mitoxantrone."

"Tumefactive MS is uncommon and presents with a space-occupying lesion in the brain that looks like a tumour on MRI or CT scan. When these tumour-like lesions are biopsied they turn out be MS. I have several patients that I follow in clinic who presented with tumefactive MS and have now gone onto have a typical relapsing-remitting course. In addition, we occasionally see patients with typical MS who then present with a tumefactive lesion. We usually biopsy these lesions in established MS as MSers are a likely as the general population to develop brain tumours. Interestingly, I have had one tumefactive presentation as part of natalizumab-rebound. In the latter case we did not biopsy the lesion and it slowly regressed. Marburg's MS variant, or acute fulminant MS, is considered to a be MS variant by many, but some feel it is a different diseases. Marburg patients have a fulminant or malignant course typically over a period of weeks to months."

"What about using cyclophosphamide to treat progressive MS? The trial data is not convincing and the observations with the drug are not too dissimilar to what happens with mitoxantrone and other powerful anti-inflammatory drugs; you switch off relapses and MRI activity, but patients tend to continue to progress. It appears as if the progression post cyclophosphamide may be slower that before cyclophosphamide, similar to what occurs with mitoxantrone. The risk:benefit ratio of cyclophosphamide and mitoxantrone in progressive MS is not good, particularly if patients have bladder dysfunction and need an indwelling catheter. The latter not only puts them at risk of getting infections, but the bacteria in the bladder interact with the breakdown products of cyclophosphamide to cause bladder cancer. This is such a problem that the need to catheterise yourself is a relative contra-indication to using cyclophosphamide. We can de-risk this problem slightly by administering mesna a drug that is also excreted in the urine and that protects the bladder from the cyclophosphamide metabolites."

"The above commentary is referring to pulsed intravenous treatment; what about oral cyclophosphamide? The latter can be used for 3-4 months only; the chronic exposure of the bladder to cyclophosphamide metabolites cause a rare, but potentially fatal, complication called haemorrhagic cyctitis. I personally try to avoid using oral cyclophosphamide."

"What dose of cyclophosphamide? There as many regimens of cyclophosphamide out there as there MS patients needing treatment with it. I tend to round the dose depending on body size (~15mg/kg) to either 750mg, 1000mg or 1250mg intravenously 4-weekly, for 4-6, doses in combination with 1g of methylprednisolone. Patients need to be counselled about side effects and the potential impact on fertility. Most MSologists have a lot of experience with using pulsed cyclophosphamide as it is our treatment of choice for CNS vasculitis and CNS SLE; therefore they don't need detailed instructions on how to use it."

"I would like to take this opportunity to thank many of my colleagues who are supporting my OffLabel initiative; knowing that this may be of value to some MSers in the world makes a big difference to me."

La Mantia et al. Cyclophosphamide for multiple sclerosis. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002819.

BACKGROUND: MS is a presumed cell-mediated autoimmune disease of the central nervous system. Cyclophosphamide (CFX) is a cytotoxic and immunosuppressive agent, used in systemic autoimmune diseases. Controversial results have been reported on its efficacy in MS. We conducted a systematic review of all relevant trials, evaluating the efficacy of CFX in patients with progressive MS.

OBJECTIVES: The main objective was to determine whether CFX slows the progression of MS.

SEARCH STRATEGY: We searched the Cochrane MS Group Trials Register (searched June 2006), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3 2006), MEDLINE (January 1966 to June 2006), EMBASE (January 1988 to June 2006) and reference lists of articles. We also contacted researchers in the field.

SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the clinical effect of CFX treatment in patients affected by clinically definite progressive MS. CFX had to be administered alone or in combination with adrenocorticotropic hormone (ACTH) or steroids. The comparison group had to be placebo or no treatment or the same co-intervention (ACTH or steroids)

DATA COLLECTION AND ANALYSIS: Two reviewers independently decided the eligibility of the study, assessed the trial quality and extracted data. We also contacted study authors for original data.

MAIN RESULTS: Of the 461 identified references, we initially selected 70: only four RCTs were included for the final analysis. Intensive immunosuppression with CFX (alone or associated with ACTH or prednisone) in patients with progressive MS compared to placebo or no treatment (152 participants) did not prevent the long-term (12, 18, 24 months) clinical disability progression as defined as evolution to a next step of Expanded Disability Status Scale (EDSS) score. However, the mean change in disability (final disability subtracted from the baseline) significantly favoured the treated group at 12 (effect size - 0.21, 95% confidence interval - 0.25 to -0.17) and 18 months (- 0.19, 95% confidence interval - 0.24 to - 0.14) but favoured the control group at 24 months (0.14, CI 0.07 to 0.21). We were unable to verify the efficacy of other schedules. Five patients died; sepsis and amenorrhea frequently occurred in treated patients (descriptive analysis).

AUTHORS' CONCLUSIONS: We were unable to achieve all of the objectives specified for the review. This review shows that the overall effect of CFX (administered as intensive schedule) in the treatment of progressive MS does not support its use in clinical practice.

Update of Cochrane Database Syst Rev. 2002;(4):CD002819.

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