Chemotherapy for Relapsing-Remitting MS?

F. Perry Wilson, MD, MSCE


January 16, 2019

Welcome to Impact Factor, your weekly dose of commentary on a breaking medical study. I'm Perry Wilson.

This week, I want to talk about a really remarkable piece of work. But it's not remarkable in the way that a lot of the reporting is saying. The trial appears in the Journal of the American Medical Association.

Source: Burt RK, et al.[1]

Before we get started, let's parse the title a bit. This is a randomized trial comparing nonmyeloablative hematopoietic stem cell transplantation versus disease-modifying therapy for relapsing-remitting MS.

That's a mouthful, but it's where a lot of people get this study wrong.

When you hear "stem cell therapy," you tend to think about miracle cures for a variety of crazy diseases, using your own cells to regrow damaged tissue. This is definitively not what this study was about. I asked lead author Dr Richard Burt to dispel the hype:

Richard K. Burt, MD. Courtesy of Cura Conference.

"The therapy—Cytoxan and ATG given over 5 days—is designed to knock your immune system down."

That's right: This study used chemotherapy—cyclophosphamide—to nearly wipe out an individual's bone marrow. The stem cell transplant was just there to help reboot the immune system afterwards. Dr Burt told me the therapy would probably work without the stem cell infusion, but it would just be riskier.

So this is actually a study of an old therapy, cyclophosphamide, applied in a new way—not a new therapy.

Dr Burt and his team randomized 110 individuals with relapsing-remitting MS, the most common form of the disease, to this chemotherapy protocol or conventional disease-modifying therapy, which could range from various interferons to more novel biologics.

After about 2.5 years, three of the 55 individuals in the cyclophosphamide group had progression of disease, compared with 34 out of 55 patients in the standard-therapy group.

Source: JAMA. 2019 Jan 15.[1]

You don't see Kaplan-Meier curves that look this good all that often, folks.

And that's not all. Take a look at the quality-of-life numbers:


Dramatically better in the cyclophosphamide group. That's not too surprising, actually. One of the major advantages of the cyclophosphamide protocol is that it's one and done—no need for further therapy. Here's Dr Burt again:


"So, one thing we're very careful [about] in this paper [is] we don't talk at all about cure, and I don't want to imply that; but you know, very few by 5 years relapsed or progressed in the vast majority with no evidence of disease activity."

Functional status decreased in the usual-therapy group, as expected, but it actually improved in the cyclophosphamide group. And if you're the type of person who wants more objective data, T2-weighted lesion volume on MRI decreased by 30% in the cyclophosphamide group compared with an increase of 34% in the usual-care group.


Why does this work? We're not totally sure. Dr Burt believes that the chemotherapy essentially resets the immune system, allowing tolerance to develop. In other words, fixing the immune system in patients with MS might work like how you fix your Internet router: Turn it off and on again.

Alright, I'll give you some caveats here. First, we aren't sure what the appropriate timing of this therapy is. Patients in this study had to have two flares in the past year and a moderate baseline disability score. This probably shouldn't be the go-to therapy for very early or mild disease. Similarly, there is no evidence that this protocol will help in progressive MS.

The other major issue is that this study has been running for a long time, about a decade. In that time, a couple of novel therapies, including ocrelizumab, have entered the scene. Patients on ocrelizumab were excluded from this study. Dr David Hafler, chief of neurology here at Yale, was quite impressed with the results in this study but suspects that you may see similar effects with ocrelizumab.

Indeed, a large randomized trial of ocrelizumab, appearing in the New England Journal of Medicine, seems to have similar rates of progression, as we see in the cyclophosphamide group here.

Source: Hauser SL, et al.[2]

With ocrelizumab costing $65,000 per year and Dr Burt's chemotherapy protocol running at a one-time cost of $125,000, the jury is still out regarding where the most bang for the buck is. But the real winners here are patients with MS, who now have more options than ever before to hit the reset button on a devastating disease.


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