Changing Therapy After Breakthrough MS Improves Relapse Rate

Switching to a more aggressive immunotherapy was beneficial for patients who had breakthrough MS symptoms, according to a new study.

SEATTLE-Patients who experience breakthrough symptoms of multiple sclerosis (MS) on first-line disease modifying therapy improve after they switch to natalizumab or other immunosuppressives like cyclophosphamide or mitoxantrone, according to an analysis of data from a retrospective study presented here at the AAN annual meeting.

In this study of patients with breakthrough MS on first-line agents, non-switchers had more than twice the risk of relapse compared with those who switched to natalizumab. In contrast, although the sample size was quite small, switching to other immunosuppressive agents was substantially better than switching to natalizumab, said Tamara Castillo-Trivino, MD, a clinical research fellow at the University of California-San Francisco (UCSF), who led the study under senior author Emmanuelle Waubant, MD, assistant professor of neurology at the UCSF.

Most of the patients taking immunosuppressants (63.6 percent) were receiving very strong immunosuppressants such as cyclophosphamide or mitoxantrone, Dr. Castillo-Trivino said. This could explain the higher benefit when compared with natalizumab, she said.

The risk-benefit ratio of natalizumab versus immunosuppressants is not yet known, she said, because natalizumab is a relatively new drug. [According to another report described here at the AAN annual meeting, natalizumab is associated with a one in 10,000 risk of progressive multifocal leukoencephalopathy (PML). See New Safety Data on Natalizumab for MS and PML Risk, on page XYZ).] Immunosuppressants are associated with increased risk of infections and secondary cancers. Mitoxantrone can induce cardiomyopathy and leukemia, and cyclophosphamide is known to decrease fertility in patients of child-bearing age.

These complications [of immunosuppressants] appear to be dependent on the cumulative dose received, limiting overall patient exposure to these drugs over two to three years, typically, Dr. Castillo-Trivino said.

Figure. DR. TAMARA CASTILLO-TRIVINO: In this study of patients with breakthrough MS on first-line agents, non-switchers had more than twice the risk of relapse compared with those who switched to natalizumab.

Investigators reviewed the medical records of 773 patients who had been seen at least four times at the UCSF MS Center. The patients were identified with breakthrough MS on first-line therapy with either beta-interferon or glatiramer acetate who switched or were offered to switch to second-line agents. Fifty-two patients switched to natalizumab, 12 were offered natalizumab but opted to remain on first-line therapy, and 22 switched to other immunosuppressants (before natalizumab was available), including seven taking cyclophosphamide; seven, mitoxantrone; five, mycophenolate mofetil; and three on other agents.

The UCSF MS Center neurologists defined breakthrough disease based on persistent clinical or radiological activity. All patients were required to have been treated with first-line disease-modifying agents for at least six months (beta interferons or glatiramer acetate).

At baseline, age, gender, race, and disease characteristics were similar among the three groups. Patients who switched to other immunosuppressants had a slightly longer follow-up period after the switch, while those who switched to natalizumab had been on first-line therapy longer than those who switched to other immunosuppressants or remained on first-line therapies.

After a mean follow-up of approximately one year for the natalizumab and non-switcher groups and 3.5 years for the immunosuppressant group, relapse rates were reduced in all three groups. The group that did not switch therapy had an 18 percent reduced annual relapse rate (ARR), but this was not statistically or clinically significant, Dr. Castillo-Trivino said. Those who switched to natalizumab had a 63 percent reduction in ARR, and those who switched to other immunosuppressants had an 88 reduction in ARR compared with when they were on first-line therapies. These analyses were adjusted for age, gender, race, baseline disability, time on first-line disease-modifying therapies, and number of disease-modifying therapies. Follow-up time was included in the model.

We don't have a very long time of follow-up for the patients on natalizumab or the non-switchers, so long-term benefit cannot be assessed, Dr. Castillo-Trivino explained.

The study had several limitations, including its small sample size and the fact that it was not randomized trial. Patients were using immosuppressive agents several years before natalizumab became available. It is unclear whether this had an impact on patient selection, Dr. Castillo-Trivino noted.

Although the study has several limitations, it suggests that real-world therapeutic failures with relapsing MS - according to anyone's definition - benefit from use of more aggressive immunotherapy, said John Corboy, MD, professor of neurology at the University of Colorado-Denver, and co-director of the Rocky Mountain MS Center at the Anschutz medical campus.

The study limitations he cited were its retrospective nature, lack of blinding, lack of a definition of inadequate response, no MRI data, and very small sample sizes. This is basically a good collection of organized anecdotal experience, Dr. Corboy commented.

The greater magnitude of benefit seen with other immunosuppressives compared with natalizumab in this study of breakthrough MS may not be a real finding, Dr. Corboy continued. The numbers of patients are too small in each group to draw that conclusion, he said. Although a large prospective study comparing natalizumab to mitoxantrone or other immunosuppressives would be worthwhile, it will probably not be done, he noted.

There are two obvious first-line choices for breakthrough MS - natalizumab and mitoxantrone, both of which are FDA-approved, he said. Both drugs have serious side effects - acute promyelocytic leukemia and heart failure for mitoxantrone and PML and other infections as well as severe hypersensitivity reactions for natalizumab - but these occur in less than 1 percent of patients. If you asked a panel of MS experts which drug is safer, I would guess that most people would choose natalizumab, Dr. Corboy said.

Dr. Corboy said that given the risks and benefits of both agents, he usually opts for natalizumab for breakthrough MS. The stakes are higher for these vulnerable, sicker patients. I feel our obligation is to recognize that they have more serious disease, which is not responding adequately to initial therapy and to treat accordingly. The cases of PML and other serious adverse events remind us that drugs that help patients may also hurt them, but these patients do better with more aggressive immunotherapy.