Cyclophosphamide May Delay Disability in Secondary Progressive MS, but Tolerability Is an Issue, Study Shows

Cyclophosphamide (CPM) may delay the progression of disability in the first years of secondary progressive multiple sclerosis (SPMS), but patients must take it for two years — and many are unlikely to tolerate it for that long.

The study, “Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis,” was published in the journal PLOS One.

Although many treatments for relapsing-remitting MS (RRMS) are available these days, few treatments are available for progressive MS. And only a handful have been tested in randomized controlled trials.

Recent studies suggest that inflammation of the meninges — three layers of tissue covering the brain and spinal cord — may play a key role in the development of SPMS disability.

The inflammation prevents many blood-derived immune cells from crossing the blood-brain barrier, a membrane that separates blood from the brain extracellular fluid in the central nervous system. Most treatments for SPMS fail because they can’t cross through the blood-brain barrier to the central nervous system.

CPM can cross the barrier, but several randomized controlled trials administrating CMP intravenously (IV) in progressive MS patients have yielded conflicting results. Researchers believe the fact that the trials were performed without a maintenance therapy may explain why some treatment efforts failed.

Previous open-label studies suggested that monthly CPM use with induction therapy could delay the progression of the disease. Induction therapy consists of the early use of immunosuppressant drugs followed by long-term maintenance, generally with immunomodulatory agents.

No randomized trial had been performed to test the notion that a combination of CPM and induction would help patients, however.

Now researchers have performed what is known as the PROMESS trial (NCT00241254) to determine whether CPM can delay the progression of disability in SPMS patients. The trial also looked at the safety of IV pulses of CPM administered over two years, when compared with IV pulses of methylprednisolone (MP), a common therapy for relapses of MS.

Researchers recruited SPMS patients who had an Expanded Disability Status Scale (EDSS) score of 4·0 to 6·5. They were treated either with CPM or MP.

The study, which was terminated early due to recruitment problems, included 138 patients. Seventy-two received CPM and 66 MP.

Patients received either IV CPM (750 mg /m² of body surface area) or IV MP (1 g) every four weeks in the first year and every eight weeks in the second year.

The team observed no statistically significant difference between CPM and MP in preventing EDSS progression in the 138 patients.

Patients in the CPM group were 2.2 times more likely to stop treatment because they couldn’t tolerate it than those in the MP group, however. But those who continued CPM treatment were 2.7 times less likely to experience disability progression.

The results suggest that while CPM may decrease the risk of SPMS progression, some patients’ inability to tolerate it may limit its impact.