Susan Jeffrey

October 04, 2013

COPENHAGEN, Denmark — A new randomized trial shows that although cyclophosphamide (CPM) was more effective than methylprednisolone at reducing progression in patients with secondary progressive multiple sclerosis (SPMS), a high dropout rate in both groups limited the power of the trial and underlines a lack of tolerability with both agents.

Despite the limitations caused by the high rate of dropouts, "according to the multistate model, CPM is a risk factor for treatment interruption, but is protecting patients who continue the treatment from progression," Bruno Brochet, MD, chief of neurology at CHU de Bordeaux, France, concluded.

In the CPM group, patients were "2.6 times more likely to stop the treatment but 2.4 times less likely to progress" than those receiving methylprednisolone, he added. Safety outcomes were as expected, mainly vomiting.

The results were positive in terms of the efficacy of CPM to limit the progression of disability in SPMS, "but it underlined also the well-known problems of tolerability (rather than safety) of this drug," Dr. Brochet told Medscape Medical News. "However, no severe safety concerns emerged."

He speculated that the tolerability of CPM might be improved by the use of new-generation antiemetic drugs.

The population studied in this trial had recent onset of the secondary progressive phase and rapid accumulation of disability within the year prior to enrollment, Dr. Brochet pointed out. "In this specific population, which is at risk of severe disability, this treatment could be considered as an option."

These results, from the PROMESS trial, were presented here at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Asked for some perspective on these findings, session moderator Vesna Brinar, MD, PhD, professor of neurology at the University of Zagreb School of Medicine, Croatia, said she did not find the results compelling. She was particularly concerned about the high dropout rate and said she would use either of these drugs only in highly selected patients with very active disease.

Strategies Limited

Therapeutic options are very limited in SPMS, Dr. Brochet said. Interferon β is the only licensed drug used in patients with SPMS with additional relapses, he noted. Pathological studies have suggested that inflammation, specifically meningeal inflammation and microglial activation, still play a role in the secondary progressive phase of the disease.

CPM is a nitrogen mustard alkylating agent often used to treat autoimmune diseases and vasculitis that was first used in MS in 1966, he said. The first randomized trial in progressive MS, in 1983, was positive but used a very high dose to reach immunosuppression.

"After that, it was suggested that monthly IV [intravenous] pulses could be helpful, but there were only open studies," Dr. Brochet added. Those studies did suggest encouraging results, however, and an acceptable safety profile of CPM treatment.

"Therefore, we decided to organize this study, which compared monthly injections during the first year, and every 2 months during the second year, of cyclophosphamide or methylprednisolone in 27 centers in France," he said. Treatment was given in a dose of 750 mg/m2 body surface area for CPM and 1 g of methylprednisolone.

The aim was assess the efficacy of CPM vs methylprednisolone in delaying the time to 4-month confirmed disability measured using the Expanded Disability Status Scale (EDSS) in patients with SPMS. Patients were eligible if they were aged 18 to 65 years and were in a phase of gradual progression of disability for at least 6 months but less than 4 years. They also had to have a documented reduction in walking distance in the last 12 months. The EDSS score range was 4.0 to 6.5 in these patients.

In all, 178 patients were randomly assigned: 72 to CPM and 66 to methylprednisolone. The rate of dropout was high in both groups but higher with CPM: 45% vs 36% in the methylprednisolone group. In the CPM group, most patients ended treatment because of adverse events, he noted. Baseline characteristics were well balanced, with an average EDSS score of 5 in both groups.

Because of the high number of dropouts, the investigators used a multistate model analysis. This analysis showed that patients treated with CPM had a reduced risk for EDSS progression (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.19 - 0.92) relative to those receiving methylprednisolone. However, they were also more likely to stop treatment over the course of the trial than those in the methylprednisolone group (HR, 2.56; 95% CI, 1.13 - 5.79).

Secondary endpoints showed no difference between groups on the cumulative probability of 4-month confirmed EDSS progression with CPM vs methylprednisolone, or the percentage of patients with confirmed EDSS deterioration (18.1% vs 31.8%; P = .06). "It doesn't reach statistical significance," Dr. Brochet said of this difference, "but there was a trend consistent with the multistate analysis."

The groups did not differ for the timed walking distance or the Multiple Sclerosis Functional Score or any of its components. The percentage of patients who were relapse free trended higher with CPM but also did not reach statistical significance (73.6% vs 56.1%; P = .07).

Quality of life was measured using the SEP-59, the French version of the MS-QOL 54 tool; of 15 different measures, only 1, physical functioning, was significantly higher with CPM treatment than with methylprednisolone (P = .0454).

Safety and Tolerability

The mean number of adverse events per patient was 8.6 with CPM vs 6.2 with methylprednisolone, Dr. Brochet reported. The most frequent adverse events were "as expected," he said. Gastrointestinal events occurred frequently with CPM, mainly vomiting (31 vs 3) and nausea (48 vs 19).

Infections were well balanced between groups (129 vs 109), as were nervous system events, mainly MS exacerbations in both groups (68 vs 78).

There were 29 serious adverse events: 16 in the CPM group and 13 with methylprednisolone. Events with CPM included sudden cardiovascular death (n = 1), ovarian cancer (n = 1), breast cancer (n = 1), pericarditis (n = 1), psychosis (n = 1), rash (n = 1), surgery (n = 2), thrombophlebitis (n = 1), osteonecrosis (n = 1), infections (n = 2), fractures (n = 3), and hyperglycemia (n = 1).

Among patients receiving methylprednisolone, serious adverse events included myocardial infarction (n = 1), pulmonary embolism (n = 1), pneumonia (n = 1), seizure (n = 1), pancreatitis (n = 1), fever (n = 1), suicide attempt (n = 1), fractures (n = 2), wound (n = 1), surgery (n = 1), and miscellaneous (n = 2).

"These results have already been confirmed by sensitivity analyses, but other analyses are planned," Dr. Brochet concluded.

The study was funded by the Ministry of Health, France. Dr. Brochet or his institution has received honoraria for speaking at scientific meetings and serving as a member of scientific advisory boards for Bayer Pharma, Biogen-Idec, Merck Serono, Genzyme, Novartis, and Teva, and his institution has received research grants from Bayer Pharma, Teva, Merck Serono, Novartis, Biogen-Idec, Sanofi-Aventis and Roche. Disclosures for coauthors appear in the abstract.

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Abstract #169. Presented October 4, 2013.

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