Transcript of Audio-visual
lecture to be found at
Pathophysiology and Diagnostic Issues in SPMS
PATRICIA K. COYLE, MD
We’re doing this in the context of very timely news. Just yesterday, mitoxantrone was approved by the FDA; so this becomes a very important issue.
Let’s start with pathophysiology and diagnostic issues in secondary progressive MS. Basically, what I want to do is paint a picture of secondary progressive MS, talk a little bit about some of the diagnostic issues, with regard to secondary progressive MS in particular; speculate a little bit on the pathophysiology. This is a cutting edge topic that’s being debated a lot at the current time: are we gleaning a better understanding of secondary progressive MS and exactly what does that mean?
We know that MS is a variable and heterogeneous disorder. We know that MS can be so mild as to be silent from pathologic autopsy data. We know that by expert consensus in 1996 a group of experts came up with a clinical subtyping of MS and we clearly recognized that most MS begins with relapsing disease and there is a benign subset—no clear-cut definition of benign MS—basically a retrospective diagnosis. In my opinion, probably no more than 10% of symptomatic MS, although that might be open for dispute.
We have the 3 progressive forms of MS. First, primary progressive—a very interesting entity: slow worsening from onset, and never has acute relapses; and a lot of data saying it may be biologically different from the rest of MS. It’s the subtype that shows the equal sex ratio; it’s the subtype that shows the somewhat atypical older age onset; and it’s the subtype that seems to have the disease process targeting, in particular, the spinal cord without the same degree of brain and inflammatory involvement.
We have a new progressive subtype that was defined in 1996—progressive relapsing. Also slow worsening from onset, but then going on to superimposed clinical disease attacks in an unusual form; and the major progressive form of MS—secondary progressive. Every patient with secondary progressive MS we know starts out with relapsing disease, but there comes a time in the course of relapsing untreated MS where most individuals will transition to a slow worsening phase. And once that’s really been declared, we change their subtyping from relapsing to secondary progressive MS.
So, relapsing patients who then go on to slow worsening are our secondary progressive population. They may continue to have clinical disease attacks, so it may be secondary progressive with relapses, or they may simply cease having clinical relapses, and we’re just seeing a progressive phase of the disease—secondary progressive without relapsing. We’ll come back to that, because it’s important.
This from the New York State MS Consortium has been published in the journal MS, based on a little over 3000 patients who looked at the whole universe of MS. Not surprisingly, relapsing MS accounts for most patients—55% secondary progressive is your next major subtype of MS, 30% of the whole universe of MS patients.
This diagram points out a couple of features:
In other words, if an MS patient begins with slow worsening that persists for a year or more before there are any relapses, then maybe they should be considered together. Maybe progressive relapsing, and this is not a given, this is what’s being discussed currently, should be collapsed into progressive from the onset and thought of as primary progressive.
There’s also a discussion, fueled particularly by the recent therapeutic trials that we’ll hear about later, that maybe secondary progressive MS should actually be divided. Maybe we should be thinking about secondary progressive MS with relapses and secondary progressive MS patients without relapses. There’s also some discussion, although perhaps more tentative, about the relapsing patient who’s now making incomplete recovery, and with continuing relapses is getting worse and worse. Maybe we should be thinking about that later-stage, more severe relapsing patient as almost akin to the secondary progressive with relapses.
Finally, you look at the rate of deterioration; it seems that once you enter a progressive stage of MS, everybody’s deteriorating in a somewhat similar pattern, at least there are several trials that suggest this. So, some people are speculating, maybe progressive MS is progressive, period—it’s the same thing. And maybe once a relapsing patient has become progressive, secondary progressive, there’s really no difference from primary progressive.
Diagnosis of MS in general is not something we take lightly, because now we have treatments for this disease, and the sooner we diagnose and the sooner we treat, in most patients, the better. So, we no longer can be casual about the diagnosis of MS. We know the data that say, even in relatively expert hands, there’s a built-in misdiagnosis rate; 5% to 10% of the time, we’re going to be wrong. Probably, in my opinion, this justifies never making a diagnosis of MS without doing some laboratory investigation, and there have been statements from experts saying, “Every MS patient now, who’s been diagnosed, should have at least a brain MRI scan.”
How do you diagnose that somebody is truly in a progressive stage? That may not be so easy. There’s a broad differential diagnosis of MS, although most times, we’re talking about a patient presenting with relapsing disease early on. There are entities in these other conditions (non-MS conditions) that may present with an initial relapsing course, followed by a progressive course. So there is at least precedent for seeing another disease process cause relapsing disease followed by progressive disease.
How do we determine progression? Progression, as we’re defining it to help us diagnose a secondary progressive patient, must be independent of relapses. The worsening cannot be in the setting of an acute attack with incomplete recovery; that will not count toward making a determination of secondary progressive disease. We have to be a little careful that we are not seeing deterioration based on simple aging changes in our population—that’s not going to count for worsening of a secondary progressive. We want to make sure we’re not seeing worsening due to another condition; that’s not going to help us make a determination of secondary progressive MS.
We all know that this disease can fluctuate. We all know that the examination we get at one point in time in a patient with MS may be a little bit different if it’s a bad day or if it’s later in the day and the patient is really tired vs examining them first thing in the morning. Some thought needs to be given to that if we’re going to try to determine whether somebody is truly in a secondary progressive phase of the disease. Progression worsening (slow worsening) has to be documented over a finite period of time; a minimum of 6 months by definition. Some people have said, “Gosh, to be certain about that, you probably have to follow a patient a year or more.” Even 6 months is a bare minimum to determine that a relapsing patient has truly gone into a progressive stage.
What are some problems in determining that a relapsing patient has become secondary progressive? How are we going to determine the worsening? Is it going to be by examination? In that case time of day or whether it’s a good day–bad day phenomenon is going to be important. Are we going to use formal EDSS criteria? Helpful, but it better be the same person doing the EDSS, and we better make sure they really were tested in the 500-m walk; and we better begin to use EDSS more rigidly than those of us who use it on occasion, outside of clinical trials, typically do.
Are we going to use self report of the patient? Are we going to ask the patient, “Are you gradually getting worse?” If you have a very astute patient, they can be more sensitive than the examination, at least early on, and that might be helpful. But, suppose that patient is depressed or suppose that patient’s impression is that they’re getting worse. Are we going to rely on self report to make such an important determination? So, there are problems there. We clearly need to separate relapse from slow worsening; we do know that patients with secondary progressive MS can stabilize for significant periods of time. So, all of these are problems in judging progression.
We know that the natural history of untreated MS is for patients to start out with relapsing disease and transition to secondary progressive disease. The Natural History Studies have said that followed twenty-five years or more, 90% of relapsing patients will ultimately become secondary progressive. That is a disabling subtype: progressive MS is bad news; it’s going to limit their mobility, it’s going to limit their ability to work.
At least some studies, not all, have suggested that there may be an element of being time locked, that in earlier onset relapsing MS, the transition to secondary progressive disease may come later than when there is a later onset relapsing MS. This is a helpful feature—in a relapsing patient, if you do have an EDSS on them, it’s unusual to see them in this middle range EDSS. Don Budkin followed patients and found that progressive patients may stabilize for up to several years at a time. So again, it is not a concept that there must be obvious clinical deterioration going on; progressive patients may remain relatively stable for periods of time.
If you look at the EDSS, the Kurtzke Expanded Disability Status scale, 0 to 10 (0 being perfect, 10 you’re dead), the current gold standard for the neurological evaluation of MS, if you look at this scale, patients with MS are at the low and the high end, and you don’t see very many in this middle range of 3 to 5. That may be, in large part, an artifact; nevertheless, it’s a helpful point. Most relapsing patients are at the low EDSS and most progressive patients are at the high EDSS.
These are data from the New York State MS Consortium; there are over 4000 patients. Relapsing MS is plotted in blue; all three subtypes of progressive patients, and their EDSS, are plotted in green. You can see the 2 curves: relapsing patients are all on the lower end of the scale, progressive patients are all on the higher end of the scale. There aren’t many patients in the middle zone. That’s actually an important clinical observation if you have EDSS data. If you have a relapsing patient in here, they’re not going to stay there very long; they are going to move up and it’s probably going to be in the form of progressive disease.
This is that same New York State database of average EDSS, either mean or median (it doesn’t matter), for relapsing and the 3 progressive subtypes, and you see all of the progressive subtypes are more impaired and disabled on their neurologic exam, with a more severe form of MS.
Here’s the annual attack rate (relapse rate) for relapsing secondary progressive and progressive relapsing, the 3 of the 4 subtypes that have clinical attacks; and you see that the secondary progressive subtype has the lowest relapse rate.
If you look over all the prognostic indicators, and there are clinical and laboratory prognostic indicators, what really stand out as probably the critical ones are the early attack rate, the interval between attacks, the time to disability early on, and a progressive course. Progressive MS is bad news; basically, that’s the bottom line.
If we look at what might be clinical clues that a relapsing patient may be getting ready to transition into secondary progressive disease, number one is a high EDSS. A relapsing patient with a high EDSS is somebody that I would be concerned about. The natural history of clinical relapse rate is to fall over time in MS. If you are seeing a relapsing patient in whom the clinical attack rate is increasing, that is another warning sign that this patient is not going to do well. Disease duration: a male with relapsing is at higher risk to transition to secondary progressive disease than a woman with relapsing disease.
In patients who have had MS for several years, the last attack has prognostic significance if it involves multiple neurologic systems and if there is incomplete recovery—that puts that patient in a worse prognosis group; and the likely worse prognosis is going to come in the form of transition to progressive MS. A loss of response to therapies, either symptomatic therapies, steroids, or disease-modifying therapies in a relapsing patient, in addition, is clinically a bad prognostic sign.
No one would argue that an MRI scan can distinguish between a relapsing patient and a secondary progressive patient. Nevertheless, there is accumulating data which show that there are differences between groups of relapsing patients and groups of secondary progressive patients. And this is something that is being explored at the current time. If you look at secondary progressive patients vs relapsing patients, the increasing brain burden of disease becomes relatively independent of contrast lesion activity, in stark contrast to relapsing MS.
In other words, the brain lesion burden is going up, yet you’re not seeing it so tied to gadolinium-enhancing lesion activity. Why? We don’t know why. One hypothesis might be that there has been a previous injury to the axons, for example. It’s a sublethal injury that results in irreversible loss, but months to several years down the pike. The person has been set on an inevitable pathway and cutting down on gadolinium enhancement, for example, doesn’t impact on that.
Or, could there be some change in the damaging mechanism? Could there be a switch? Something that occurs as one is moving from relapsing to secondary progressive, where there can be damage, relatively independent of gadolinium enhancement—which is really an inflammation marker. These are hypotheses. Clearly, secondary progressive has more axon involvement than relapsing MS, based on MR spectroscopy. Atrophy measured with N-acetylaspartate or NAA (an axon-neuron marker) is more marked in general, in secondary progressive patients than in relapsing patients.
You can look at a number of neuroimaging factors and features that would make you worried about a relapsing patient, worried that they may be moving into secondary progressive disease.
Secondary progressive patients are more likely to have periventricular posterior fossa and spinal cord and confluent lesions than relapsing patients, less gadolinium-enhancing activity, and increasing burden of disease.
They have more axon damage and atrophy, an increase in T1 (black holes), ventricular enlargement, atrophy of the spinal cord compared to relapsing patients. There can be disruption of CNS tissue independent of blood-brain barrier damage, as measured by gadolinium enhancement, and there may be impaired lesion recoveries. One does not seem to see the lesion recovery that one may see in relapsing MS and secondary progressive, or suggestions that there may be these neuroimaging correlates that might ultimately help us dissect secondary progressive from relapsing.
There is also very intriguing data that there may be immunologic differences. Again, this is not accepted; these are preliminary studies, but they’re very tantalizing studies. You can, if you select, secondary progressive patients vs relapsing patients, show immunologic differences. As a matter of fact, there are a number of groups right now that are trying to determine whether there are significant immune differences between secondary progressive vs relapsing MS.
Getting back to the concept of, “Is there a switch?” Does something happen immunologically that accounts for movement of relapsing disease into secondary progressive? So that, if you look at auto-reactive T-cells—T-cells attacking brain in the test tube—you can shut them off if you collect them from relapsing patients; you can’t if you’ve collected them from secondary progressive patients.
If you measure markers that would look at up-regulation of immune responses, so called costimulatory molecules, they’re much more expressed on the cells of secondary progressive patients than relapsing patients. You can show that the immune cells of secondary progressive patients are pumping out much more in the way of inflammatory cytokines, as if they’ve been turned on, compared to cells from relapsing patients.
The hope of some groups that are studying this is that we will be able to find an immunologic profile that tells us a relapsing patient is moving on to secondary progressive disease: Is it loss of inhibition of auto-reactive T-cells? Increased poststimulatory molecule expression? Decreased suppressor functional activity? Imagine if we could do a test tube test that would tell us this relapsing patient is getting ready to move on to secondary progressive disease? Ultimately, it might affect our approach to treating that patient before we could even clinically detect that they were going on to progressive disease.
This is very recent data from SPECTRIMS of an MRI technique called magnetization transfer imaging or MTI. Any good MR scan is capable of doing this. It looks at the data from two different molecules—a fixed molecule and a soluble molecule—within the brain tissue. You can get a mag transfer ratio, that’s MTR. This was studied in secondary progressive vs relapsing. Secondary progressive patients had a lower mag transfer ratio in their whole brain, compared to the whole brain of relapsing patients.
In normal-appearing brain tissue of secondary progressive patients, there was much more in the way of mag transfer ratio abnormalities’ decreases compared to relapsing MS. This is a sensitive research MR technique that’s saying, “Yes, we can detect widespread differences between a secondary progressive patient and a relapsing patient by this technique.”
Some very interesting immunologic studies are further suggesting differences between secondary progressive and relapsing. In chemokine-receptor expression (remember, chemokines are cytokines that call cells into a tissue) are of increasing interest in MS. They appear to play a very important role. Matrix metalloproteinases (MMPs) are very important. These are enzymes that allow blood immune cells to enter the CNS in an MS patient. There are strategies looking at blocking matrix metalloproteinase as treatment of MS. There were matrix metalloproteinase differences described between secondary progressive and relapsing MS. The secondary progressive patients had more in the way of antiaxonal antibodies than relapsing MS.
All I’m making of this is the fact that, as it’s being studied, you’re getting more and more data that there may be a different immune and a different MR imaging profile between secondary progressive MS and relapsing MS. Of course, it’s the chicken or the egg, but still, it’s interesting.
We could begin to speculate on what might be the immunopathology of secondary progressive MS; but we’re now beginning to ask the question more cleverly, “Is there a difference between relapsing and secondary progressive or not?” That’s probably important to answer. Is there a fundamental difference between relapsing and secondary progressive or not? We see that with increasing duration of secondary progressive disease, there is less and less inflammation (blood immune cells).
Although inflammation is generally bad in MS, some inflammation is good; not all inflammation is bad. As a matter of fact, inflammatory cells can produce trophic factors that might actually be beneficial. Could it be that you lose inflammation as secondary progressive disease goes on, including perhaps, some positive benefits (growth factor benefits) of inflammation? Do you begin to see a neurodegenerative process take over? Similar to Alzheimer’s, Parkinson’s, ALS. Glutamate-mediated? Calcium influx?
There are some preliminary data suggesting a relapsing vs a secondary progressive patient. As you move from relapsing to secondary progressive disease, there may be a switch moving from a predominantly T-cell process to a B-cell antibody process and a macrophage process (the macrophage is a very important antigen presenting cell). There are at least some preliminary data that there may be an immunologic switch from relapsing to secondary progressive disease.
I said earlier that the clinical subtyping had been critiqued—maybe all progressive MS is the same. Once the patient enters secondary progressive disease, they’re exactly the same as primary progressive. Maybe not. If you look at primary progressive compared to secondary progressive or relapsing, they have the least inflammation, with regard to macrophages and T-cells. They have the most oligodendrocyte and axon blocks, although those 2 things are clearly dissociated. They show increased microglial activation (the microglia are the important immune cells of the CNS) but decreased macrophage activation, opposite of secondary progressive MS. In secondary progressive MS, you have increased macrophage activation.
So, here is a fundamental immunologic difference between primary progressive and secondary progressive, suggesting they are not all the same. The primary progressive patient has pathological signs of low grade, ongoing axon injury and loss, as opposed to the secondary progressive patient who shows more in the way of increased and more acute axon damage, pathologic differences suggested in preliminary studies between primary and secondary progressive MS.
Very interesting study from SPECTRIMS of an apoptosis factor and spinal fluid. What’s apoptosis? Program cell death—you put on CSF and it kills cells in a program cell death method. This was present in primary progressive patients, not in relapsing patients. There are some genetic differences, and we’ve got to say these differences are quantitative, not qualitative. No one yet has come up with something only seen in primary progressive and not in the other forms of MS. But there are these tantalizing data suggesting there may be genetic, immune, and neuroimaging differences.
What sort of pathogenesis could we be talking about for progressive and secondary progressive MS? We know MS involves axon loss early on. Gradual axon loss, secondary to inflammation early. Little clinical impact, perhaps due to the fact that the CNS can compensate for that; and reflexes (clinical disease attacks) may reflect completely reversible abnormalities (inflammatory abnormalities) inflammation, edema, demyelinization, or reversible: inflammation goes away, edema goes away. We know that 70% of MS patients will remyelinate.
Ultimately, a threshold is crossed. Ultimately, it can no longer compensate for the ongoing axon loss, and this perhaps is the transition to continued worsening without recovery in secondary progressive disease. Although not proven, it has been postulated by several different groups as a possible scenario.
I want to briefly discuss some of the issues that we need to think about that are aimed more at evaluating treatments for secondary progressive MS. At the current time, we have 5 disease-modifying therapies established by 1 or more phase 3 trials. The cytokine interferon betas, the T-cell strategy, glatiramer acetate (Copaxone®), and our immunosuppressive strategy, mitoxantrone (Novantrone®), which is approved.
We know they have been shown to benefit relapsing MS, with excellent responders, in the whole group response rate.
We have data for the interferon beta disease-modifying therapies in very early, first attack MS; and we have data supporting their use in progressive MS patients as well, although a little bit more controversial with some of the agents.
How do we judge response to a disease-modifying therapy? We all deal with this every day in clinical practice. Clinically, we look at how effectively the therapy decreases attack rate, slows progression, how well the patient tolerates the drug, and MRI parameters. Does it cut down on contrast lesion activity? Does it decrease the increasing burden of disease that we know occurs in untreated MS? Does it reduce atrophy? Does it change the pathology to less damaging lesions? You can get this from a decreased mag transfer ratio which will reflect more damage within the lesion. Can we get a biologic marker? We don’t yet have a biologic marker for a response to treatment. People are looking at blood, people are looking at urine, attempting to define a biologic marker that tells us response to treatment. That’s sort of like a holy grail search in MS.
A number of groups have said, “Gosh, within a year’s time, if you have 3 or more relapses that require treatment, that’s probably a failure.” There have been some consensus groups that have suggested that. Certainly, what you might want to think about in judging a therapeutic failure of a disease- modifying therapy is how bad are the relapses, not just their number. How well does the patient recover from the relapse? And what’s going on with regard to the MR picture associated with that relapse? Is the relapse associated with a lot of MRI disease activity?
With regard to an accentuated disease course, are we seeing an increase in the number of disease attacks pretreatment comparison? Or an increase in the degree of progression pretreatment pattern, associated with the drug exposure? And certainly, MRI activity, which is clinically what many of us use to judge immunotherapy failure. We say, “We’re not sure; let’s do an MRI scan. Has there been an increased burden of disease? They’re not doing well on this drug. Is there a lot of contrast lesion activity? They’re not doing well.” But, there’s no consensus statement on judging immunotherapy failure at the current time.
How might we begin to try to think about developing a way to approach loss of response to treatment? There are probably some MR parameters that would be useful. Is there contrast lesion activity and what’s happened to the burden of disease? And what do you do if you have somebody on a drug and you think they’re failing or not doing well? If they’re on an interferon beta, you can increase it; maybe you can think about using an induction treatment in somebody who is at great risk or really doing badly. Maybe you could talk about adding on a treatment or maybe you could talk about switching classes of treatment. These are all potential options, but again, there’s no consensus expert statement saying how you should approach this.
Therapeutic response: what we’d like to see is a decreased attack rate in a secondary progressive patient, but remember, the natural history of relapses is to fall over time. No treatment, they fall over time. Slowed progression, that can be hard to judge unless somebody’s going downhill quickly.
Laboratory parameters: maybe these are the wave of the future. Maybe, ultimately, measures of atrophy; axon involvement done through NAA; MR spectroscopy measures; maybe MTI; MTR, mag transfer ratio measurements; maybe black holes; maybe total burden of disease; maybe new lesion formation. These are all potential MR parameters that, in combination (optimal combination) might very well at least give us a neuroimaging parameter for response to treatment.
When we look at the secondary progressive population, we realize that they’re starting out more severely harmed by their MS; there’s more permanent damage. There are problems in interpreting response to treatment. It’s not like you are starting out with somebody with minimal, underlying damage. The secondary progressive patient may not have countable, clinical relapses. That’s a nice parameter, typically, to follow—the clinical attack rate. But you may have a secondary progressive patient who doesn’t have clinical attacks. None of the treatments are said to stop (freeze) the disease process. So, if the patient is on a treatment with secondary progressive disease and they’re continuing to worsen, is that a failure? How would they have been worsening if they weren’t on the treatment? That’s a difficult issue.
Side effects are going to be more likely in a secondary progressive patient with significant, underlying prior damage from the disease; with current treatments, it’s not reasonable to ask that any of them would completely stabilize a secondary progressive patient.
Maybe what we need is to begin to talk about supplementing treatment of secondary progressive MS with repair strategies, like cell transplantation, to try to repair some of the fixed damage. Or use of growth factors to cause repair, or immune-modulation gene transfer, or neuroprotective strategies to block glutamate; to block the calcium influx that may be contributing to a neurodegenerative component in the secondary progressive stage of MS.
There are some interesting recent studies that show that if you can increase cyclic AMP levels in neurons, they’ll regenerate and grow; this could be a potential new strategy for treating secondary progressive MS; antiglutamate strategies, antiapoptotic gene expression strategies to block apoptosis, and inhibitors of nitric oxide and its toxin, poroxynitrite. This may be the future with regard to a very important component in the therapeutic approach to a patient with secondary progressive MS who has a lot of fixed damage.
Secondary progressive MS is our major, disabling clinical subtype. It accounts for 30%, a significant chunk of MS. Our current treatment approaches involve early prophylaxis and control of the inflammatory component, and our future may very well involve protective, repair, and replacement strategies.
Review of Recent Clinical Trials in Secondary Progressive Multiple Sclerosis
HILLEL S. PANITCH, MD
I’m going to talk about a few of the clinical trials that have been done recently in secondary progressive MS in an attempt to attack this phase of the disease directly. We kind of have the impression, as was just mentioned, that the earlier we treat the better and that we may very well have an impact on development of secondary progressive disease, delaying it at least for a period of time.
But if we wait for patients to reach the secondary progressive stage, is the horse really out of the barn? Or, do we have the opportunity to have some impact on the severity of their disease, the rate of further progression, and their ultimate clinical outcome?
Let’s start with everything there is to know about multiple sclerosis. The basic event is reflected in a periodic, possibly random, occurrence of inflammatory reactions that we can see best on the gadolinium-enhanced MRI. Gadolinium enhancements show us active inflammation; they build up this lesion burden; they are reflected, to some extent, in the clinical relapses that occur, but there’s a preclinical phase where the disease is certainly present, but has not yet been expressed clinically. The relapsing-remitting phase, which is easiest to identify, where there’s about 1 clinical attack for every 5 to 10 gadolinium enhancements.
And then, the secondary progressive phase which, as you can see, is really very heterogeneous. There are still relapses going on and a fair amount of gadolinium enhancement on MRI. The later secondary progressive phase, where the amount of inflammatory activity gradually diminishes; the clinical relapses diminish, the so-called burden of disease or volume of T2 lesion increases; cerebral atrophy begins to become very prominent. Brain volume begins to diminish very early in the relapsing-remitting phase and becomes more prominent the farther out you go in secondary progressive.
The first study that I want to run through is the European Secondary Progressive Trial of Interferon Beta 1b, which in Europe is called Betaseron®. This was a study carried out in the mid-’90s, a multicenter trial in 718 patients who all had secondary progressive MS, but different kinds of secondary progressive MS. They were randomized to receive either the drug in the standard approved dose of 8 MIU every other day by subcutaneous injection, or a placebo given in the same way. They were treated for up to 3 years. As it turns out, the trial was terminated early by the Safety Committee for overwhelming evidence of efficacy.
The inclusion criteria were very similar to what most of these trials include: age, 18-55, relapsing-remitting MS followed by a progressive course, which is the definition of secondary progressive, for at least 6 months; baseline EDSS Was 3-6.5, including that range where people are making a rapid transition from relapsing-remitting to secondary progressive. These are the most active patients because they stay at this level, at least from the 4-5 or 5.5 range, for a relatively short period of time.
In order to get into the trial, these patients had to have a history of 2 relapses or an increase in 1 point on the EDSS in the previous 2 years. Now, bear in mind, that these were all classified as secondary progressive patients but they didn’t have to progress in the previous 2 years; they could have just had 2 relapses and been otherwise clinically stable.
Primary outcome measure was time to onset of confirmed progression of disability. As measured on the EDSS scale a 1 point increase (1 point of worsening) confirmed 3 months later or a half point if the baseline EDSS was 6 or 6.5 because progression at that stage of EDSS is much more apparent since it depends on need for unilateral or bilateral support for ambulations. There were a number of secondary outcome measures as well, variables related to the relapses and MRI assessments.
A Kaplan-MeIer curve, showing the probability of remaining free of progression for a period of up to 36 months (even though the trial was terminated somewhat early and many of the patients didn’t get to 36 months) shows that the interferon beta curve and the placebo curve diverge relatively early and stay that way during the study. There’s a very highly significant difference in P value of .008, showing that the interferon beta-1b patients reached their primary end point more slowly than the placebo-treated patients.
The study also showed some interesting things in terms of the breakdown of these patients into subgroups. Some of the patients had relapses and some did not. Patients who had relapses during the trial showed the treatment effect, and patients who had no relapses during the trial had about the same level of treatment effect, about a 20% reduction in progression for those 2 groups.
That was also reflected in the relapse rates themselves. In addition to the effect on progression, there was a reduction in relapse rates by about 30%—31.3 %, actually—in the interferon beta-treated group.
There was an effect on MRI activity from baseline and mean T2 lesion volume with a reduction at Year 1 and Year 2 in those patients who were treated with interferon beta. The same kind of thing was also shown for gadolinium-enhancing lesions, which were done in 2 segments—the first 6 months of the trial and the period of time from 18-24 months. During those 2 time periods, there was a dramatic reduction in gadolinium-enhancing lesions.
What this shows is that in addition to its well-known effects on relapse rate and MRI activity, interferon beta-1b also was effective in slowing the development of progressive disease in this cohort of patients.
A group of American investigators decided that it would be useful to confirm this study and the North American Interferon Beta-1b Study was organized; NASP stands for North American Secondary Progressive Study. This was the largest study ever done in MS up to that time, and it involved 939 patients who were recruited over a period of about 2 years and randomized to 3 treatment groups.
These patients received either interferon beta-1b at the conventional dose of 8 MIU every other day, a dose based on body surface area, 5 MIU/m 2 of body surface area, which amounted to a slightly greater total dose than the conventional group, or placebo; and they were equally randomized to these 3 groups. They were evaluated every 3 months for 3 years; all patients had unenhanced MRI scans yearly. A subgroup of 163 patients at several centers had monthly gadolinium-enhanced MRIs throughout the whole study period.
These patients were aged 18-65 (18 to 55 in the European study). They were required to have a diagnosis of clinically definite or laboratory-supported definite MS for 2 years or more, which meant relapsing-remitting MS, followed by a progressive course of 6 months. They must have increased by 1 EDSS point in the previous 2 years.
This turns out possibly to have been a critical difference. That is, all these patients were not only classified as secondary progressive, but they must have shown evidence of progression in the previous 2 years by at least 1 point on the EDSS scale, or a half point if the EDSS was 6.5. They were required to have had 1 documented relapse at any time, not necessarily in the previous 2 years, and an EDSS of 3-6.5.
The primary outcome measure was similar to the European study—time to onset of 1 point increase in the EDSS sustained for at least 6 months. The difference is that, in the European study, it had to be sustained for 3 months, and in the US study, it had to be sustained at 2 consecutive examinations 3 months apart for at least 6 months. The number of secondary outcome measures included mean change in the EDSS, relapse rate, and several MRI measures, as well as some neuropsychological testing.
The demographics of the 3 treatment groups are very similar—age, sex ratio, EDSS scores, change in disability scale over the previous 2 years, and number of relapses in 2 years. All were comparable across the 3 treatment groups.
This was the primary outcome measure. There was no statistically significant difference in any of the 3 treatment groups over the period of 3 years of observation. Distinctly different from the outcome of the European trial and the placebo group, the 2 treatment groups progressed at essentially the same rate throughout the 3 years.
When it comes to secondary outcome measures, the results were much better and confirmed what we know about interferon beta-1b and the treatment of relapsing-remitting MS. For one thing, the annual relapse rate was reduced: first of all, there was somewhere between a 30% and 40% reduction in relapse rate (annualized relapse rate) over that period of time. The annualized relapse rates were in the range of 0.25-0.3, which are extremely low, indicating that these are in fact, secondary progressive patients who are not having many relapses.
Nevertheless, the treatment effect is seen and for the 8 MIU group it looks pretty good: 43% reduction; for the 5 MIU/m 2 group it’s almost 30%, which we have come to expect in interferon trials. As you look at this study, which has not yet been published, you’ll see that for some reason that we don’t really understand, the variable dose group seems not to have done quite as well as the standard dose group in any respect, although the differences between those 2 groups are not statistically significant in most cases.
The effect on MRI was quite pronounced. The percent change in lesion area in the placebo group was an 11% increase from baseline; in the 2 treated groups, there was essentially no change from baseline over the entire term of the study, all very statistically significant.
In terms of enhancing lesions, the same thing was true. There was a subgroup of 163 patients who were imaged monthly and showed a reduction in gadolinium enhancements. This is probably the only place where the variable dose patients showed slightly more of an effect than the standard dose–treated patients. For both of them, the effect was pronounced.
The investigators were disappointed that this study did not confirm the European trial and a number of retrospective analyses and subgroup analyses were done to try to figure out why. For one thing, what would happen when the entire cohort was broken down into the patients who had relapses and those who did not, those who showed evidence of clinical activity vs those who did not?
If you adjust for relapses in the previous 2 years, prior to beginning experimental therapy, there was no difference between the 2 groups in terms of treatment effect. If you adjust for relapses on the study, there is no difference between the 2 groups in terms of treatment effect. It looks like there might be in the placebo group, placebo-treated patients who had relapses on the study seemed to progress more rapidly than those who did not relapse. But the 2 treatment groups, especially this one, showed that there was really no effect in any of these categories.
The primary outcome was negative. Here are the conclusions. Treatment effect was not detected for sustained progression of disability. We’ve got a little bit of a dichotomy that we need to figure out. Treatment effects were seen with most of the secondary and MRI measures. There was no significant difference between the 2 dosing arms. The treatment effect on progression was not influenced by the dosing regimen or the presence of neutralizing antibodies. Of course, neutralizing antibodies are an important issue when it comes to treatment with interferons. When this was analyzed, it was shown that it was not those patients who developed neutralizing antibody who accounted for the lack of effect on progression. Obviously, there are significant differences compared to the European trials.
There have been a number of reasons suggested why the results of the North American Secondary Progressive Study differ from those of the European study. One reason is that we were dealing with a different population of patients; even though both of them were classified as secondary progressive, they may have been at opposite ends of that spectrum that we saw earlier which was included under the secondary progressive rubric. The age of entry was different—6 years older in the North American trial; the age at onset of MS was different; duration of MS was different. Now, some of these are small differences, but they’re still all statistically significant. Number of relapses in the prior 2 years was very different, twice as many in the European patients as in the North American patients; and the converse, of course, were relapse free. Many more of the North American patients were not having relapses; they were, in fact, at the more progressive end of the secondary progressive spectrum.
Change in EDSS in the prior 2 years didn’t appear to be too much different, but it was statistically significant. Although the baseline EDSS was the same and the difference was brought out very clearly on the frequent scanning substudy, which measured gadolinium enhancements and showed that it was almost twice as frequent in the European trial as in the North American trial. All in all, a much more clinically active and MRI active group of patients made up the European trial.
This might be the reason behind the differences in the 2 studies. We’re looking at this end of the secondary progressive group; in the North American study, we were looking at this end, and there are a number of reasons for that. For example, in the US and Canada, interferon beta-1b was already approved for treatment of relapsing-remitting MS by the time this study got started. It had not been approved in Europe. As we all know, many patients and many neurologists who were in this part of the secondary progressive phase, that is, still having relapses, were treated with interferon beta and were not available for inclusion in this trial.
Also, there were a couple of competing trials in which investigators were trying to enroll the same cohort of patients. The patient population that wound up being enrolled in the North American study was, in fact, somewhat different. There may be other reasons as well, like the way the study was conducted.
Rebif® is an interferon beta-1a, which is essentially identical to Avonex® but is made by a different company. It is given in a different way, subcutaneously, 3 times a week and in a different dose, which is considerably higher than the dose of Avonex that’s used in the US.
A study was done called SPECTRIMS. This was a trial that enrolled 618 patients who were classified as secondary progressive and randomized to 3 treatment groups—a placebo, a low-dose, and a high-dose treatment arm. These patients were followed for 3 years under a protocol very similar to the North American Secondary Progressive Study, and they were a very similar group of patients.
Aged 18-55, a little younger than the North American Secondary Progressive cohort, they had clinically definite secondary progressive MS defined in the usual way and had to have shown progression of disability for 6 months or more, with an increase of at least 1 point during the last 2 years. So, like the North American cohort, they were required to have progressed during the 2 years prior to the study, with or without superimposed exacerbations.
The primary end point was time to onset of confirmed progression of disability, a 1 point increase in EDSS, a half point if the EDSS was 5.5 or more, and a number of secondary outcome measures as well, basically, relapse rate and MRI activity.
The Kaplan-Meier curve showing time to progression in patients without prestudy relapses looks very much like the Kaplan-Meier curve for the study as a whole and shows the group that did not have relapses prestudy. There’s no difference between combined treatment groups and the placebo group.
It turns out that when you broke this group down into the more active and less active components, there was, in fact, a treatment effect that was almost statistically significant, with a P value of .005, and the interferon beta-1a patients did better than those treated with placebo, pretty much throughout the whole course of the trial.
As far as relapses are concerned, again, we have a reduction in relapse rate of some 30% in both groups and a dramatic effect on MRI activity.
This is the change in T2-weighted lesion load from baseline, showing that the placebo group increased over the course of the study and both doses of interferon beta-1a resulted in stabilization of the lesion load. The outcome is very similar to that of the North American trial, different from that of the European trial.
Comparison of the European trial shows there was a significant prolongation—63% delay in the time to progression and a 22% decrease in the percent of the patients who progressed. In the SPECTRIM study, the results were not significant at all; there was no delay in time to progression and no change in the number of patients who progressed.
The conclusion is pretty much the same, in terms of what the reasons behind the difference might be. The population in SPECTRIM was older, it had a longer duration of MS, had higher EDSS value, a higher proportion had EDSS of greater than 5.5, and many fewer were relapsing.
We are left then with a real puzzle, “ Is interferon beta-1b or interferon beta-1a suitable treatment for secondary progressive disease?” We have 1 very well-conducted study in Europe suggesting that it is. We have 2 other studies, 1 done in Europe and in Canada, the other in Canada and the US, suggesting that it’s effective, but it’s only effective on the most active patients, on those having relapses, and is not effective in slowing the rate of progression.
I think the question remains with us, “Why do some patients with secondary progressive MS seem to do well on interferon beta treatment while others do not?” I think that we can use these studies to learn something not only about whether the drugs are useful but to tell us something about the nature of MS as well. They confirm what has been shown by MRI studies and by some of the immunologic studies, that there is a change in the nature of the disease—whether it’s in the underlying pathology or just in the phenotype remains to be shown—but there certainly is a change in the disease and there’s a change to susceptibility to interferon beta treatment.
Where does that leave us? What we need is a really good treatment for secondary progressive MS. I think this is about as close as we’re going to come for a while. I want to spend the rest of the time talking about mitoxantrone in multiple sclerosis.
Mitoxantrone is a drug that you’re going to hear a lot more about. If you have had a chance to look at the news you know that it was approved, after a long period of waiting, by the FDA for treatment of secondary progressive MS and for treatment of worsening relapsing-remitting MS.
Let me just run you through the evidence for the usefulness of mitoxantrone in secondary progressive disease. This comes from the Mitoxantrone in Multiple Sclerosis (MIMS) trial that was done in Europe from 1993 to 1997. It was a phase 3 trial done as a double-blind, placebo-controlled, 2-year study at 17 centers in 4 European countries, with a relatively small number of patients—only 194 patients. The principal investigators were Drs Hartung and Vonsett, and the drug was administered as an intravenous infusion at either of 2 doses: 5 mg/m 2 or 12 mg/m 2 of body surface area, or as placebo, every 3 months for 2 years. This is a drug that’s given in an entirely different way than any of the interferons. Patients don’t have to inject it either subcutaneously or intramuscularly; they come into a clinic and they get it as an IV infusion of a blue-colored liquid. In fact, the placebo patients got methylene blue as the placebo to mask the color of the drug.
The inclusion criteria were age 18-55, clinically definite or laboratory supported definite MS, and here is a striking difference from the other studies that I’ve shown you. These patients carried a diagnosis of either secondary progressive or something called remittent progressive MS. It turns out to be either what we now call progressive relapsing MS or, in most cases, it’s relapsing-remitting MS with a fixed neurologic deficit increasing after each relapse. Remittent, that is, progressive that is getting worse, but relapsing-remitting, as it would be classified in the categories that we currently use.
This is reflected in the labeling of the drug, as it was approved by the FDA. These patients, although some of them were in fact relapsing-remitting, must have progressed by 1 point on the EDSS scale in the preceding 18 months and should have had a baseline EDSS from 3-6.
The primary outcome measure was all a single measure. This was a multivariate analysis, in which each of these 5 measures were taken in sequence and looked at for statistical significance: the mean change in EDSS, ambulation index, mean change in the standardized neurologic scale (a European scale that we don’t use in the US), the number of treated relapses, and the time to the first treated relapse.
It turned out to be statistically significant and the first of the primary outcome measures, the change in EDSS, was considered to be probably the most clinically meaningful. A number of secondary outcomes were tested as well, including the proportion of patients increasing by 1 point on the EDSS, confirmed 3 and 6 months later; time to wheelchair; proportion of the patients who were relapse free; the overall rating, which was done by the patients and the examining physicians, “are you better, worse or the same,” and some quality-of-life and other measures.
The mean change in the EDSS, which was the index for the primary outcome measure, showed a statistically significant effect in the mitoxantrone; treated group. The 12mg/m 2 group did best. There was a dosing effect, in this group the mean EDSS decreased, whereas it increased in the placebo group. Although this is a relatively small difference, it is statistically significant at a level of .0194.
Another important outcome measure was the percentage of patients without a treated relapse; that is, the Kaplan-Meier curve showing the percent of patients free from a relapse that required treatment. This leaves out some relapses that were not treated, but in effect, “Is the time to the first relapse serious enough to require steroid treatment?” The placebo group and the high-dose mitoxantrone group are shown here, and there is a very significant and widening gap between these 2 curves.
Mitoxantrone not only delayed progression, but it also reduced relapses and the time to the occurrence of that first serious relapse.
This shows the change in progression in terms of proportion of patients progressing in a placebo group. Nineteen percent reached the 1 point criterion and in the mitoxantrone group, 7%. There was a 64% reduction in the proportion of patients progressing as well as in the progression rate.
Was it effective on MRI? It’s a little bit difficult to see. These are the placebo patients who had gadolinium-enhanced MRI scans. At baseline Year 1 and Year 2, there was a slight reduction in the percent of patients with gadolinium-enhancing lesions. In the high-dose mitoxantrone-treated group, there was a marked reduction compared to baseline; 29% of patients had enhancements and at 24 months, only 3% did.
There are adverse events associated with the use of mitoxantrone, as you might expect. Mitoxantrone is a chemotherapeutic agent; it’s a cytotoxic drug classified as an anthracenedione that’s used in cancer chemotherapy. It is already approved in the US for treatment of hormone-refractory prostate cancer and for acute nonlymphocytic leukemia. In Europe, it’s widely used for other kinds of malignancies, particularly solid tumors such as breast cancer.
It is a fairly mild cytotoxic drug, but it does have the side effects that you’d associate with that kind of agent. In this study, these were the effects that were seen: nausea was at the top of the list with about three quarters of the patients complaining of nausea in the mitoxantrone group compared to 20% in the placebo group; hair thinning, but not frank hair loss; and some other adverse events as well. Menstrual disorders were notably prominent in women in the study, and there have been some questions about this. A recent reanalysis suggests that maybe serious menstrual disorders, that is, cessation of menses for prolonged periods of time, occur much less frequently, if you consider that a problem. Amenorrhea, although not lined up here very well, is not as prominent as was originally thought.
Those are some of the more conventional side effects, but the serious side effect that one has to take into account in using this agent, is its cardiotoxicity. It’s related to the anthrocyclines, which are well known to have myocardial toxicity and can result in heart failure in patients, particularly those treated with high doses for malignancies.
In the studies that have been done, there have been no significant cardiovascular side effects, but we really don’t know what the risk is in MS patients treated with mitoxantrone who have received prior treatment with radiation or other chemotherapy. In the randomized phase 2 trials that preceded the pivotal trial that I showed you, there was no evidence of significant cardiac dysfunction. In this European phase 3 trial, there were minor changes in left ventricular ejection fraction, which decreased by 10% in 28 patients treated with mitoxantrone, and 11 patients on placebo.
No one experienced frank heart failure and in the follow-up of these patients, who are now some 4 years or more posttreatment, there has been no occurrence of cardiac failure. Moreover, in other studies conducted in Europe, particularly a large study of over 400 patients in Germany, some of whom were followed for up to 9 or 10 years, there has been no occurrence of significant heart failure, although some patients do in fact have a reduction in their left ventricular ejection fraction.
However, in the product labeling for mitoxantrone, you will see that long-term clinical use is going to require attention to the possibility of cardiotoxicity and the recommendation is that the ordinary cumulative dose should not exceed 140 mg/m 2 of body surface area for the patient’s lifetime.
What does that mean in terms of actual treatment? It means about 3 years of treatment, a little less than 3 years of treatment, in terms of the approved dose of 12 mg/m 2 . That should allow a patient to receive a 140 mg/m 2 for almost 3 years, between 2.5 and 3 years.
Another issue that has come up recently is that in some patients we ought to worry to some extent about the possibility of secondary malignancies, particularly acute myeloid leukemia. This comes from a French study of women with breast cancer. In the study of over 3000 patients with breast cancer, some patients developed secondary malignancies. None of us who are used to using chemotherapeutic drugs for MS will be surprised to learn that agents such as azathioprine, methotrexate, or cyclophosphamide, which are well known to be associated with some risk of secondary malignancy, are used pretty freely in MS and that this does not seem to be a problem. Whether it’s going to be a problem in patients treated with mitoxantrone is not known, but I doubt it.
First of all, most of the patients—all of the patients, in fact, treated with mitoxantrone in the breast cancer study—also received other cytotoxic agents and many of them received radiotherapy as well. It’s unlikely that we’re going to be treating with combinations of cytotoxic drugs; however, in the occasional patient who has been treated with azathioprine or cyclophospharmide you think about treating the patient with mitoxantrone, is that going to be a problem? I don’t know—it potentially could be.
In conclusion, mitoxantrone at this dose significantly reduced progression of disability and relapses; it effected shorter time to relapse and gadolinium-enhancing lesions. However, there’s this caveat of possible long-term toxicity that we’re not surprised about, but have to be aware of.
Treatment Options for Secondary Progressive Multiple Sclerosis
Fred D. Lublin, MD
What I’m going to try to do is tie together what you’ve learned about secondary progressive MS and progressing forms of MS from the prior 2 speakers and see how that relates to current therapies. A little bit of this will be redundant from what you had because we try to keep it data based.
What we could say now, in the United States, which had been the case in Canada and Europe, secondary progressive multiple sclerosis is now a treatable condition. We can add that on to the list of relapsing-remitting or relapsing forms of multiple sclerosis. It actually makes for a continuation of what’s been a very exciting 7 years since 1993 when we first had disease-modifying therapies approved.
In addition to agents that control symptoms—and that’s not limited to any particular kind of multiple sclerosis, we now have the potential to attenuate the rate of progression. Some of the agents used in secondary progressive MS are also used for relapsing-remitting and are under investigation in primary progressive; and you heard about some of the difficulties with assessing therapies for primary progressive disease.
Currently, for relapsing-remitting MS or relapsing forms of MS, there are 4 therapies that have been approved either in the United States; in the United States, Canada and Europe; or IN Canada and Europe.
Off-label use, at least in this country, is IVIG. There have been a couple of studies that aren’t too bad, that have been performed in Europe. None has been perfect and neither has been accepted as therapy for any form of disease here. Although it is used more frequently in Europe, here it’s used more anecdotally. There is—and I’ll come back to this later—a study under way that may change that.
Azathioprine has been around forever. Again, it is used a great deal in Europe. There’s not a lot of good data to recommend it. There is a meta-analysis looking at all the azathioprine studies, which suggest that it’s effective in relapsing-remitting disease. But I always hark back to an article in the New England Journal of Medicine about 3 years ago, on meta-analysis, which kind of concluded that if you need a meta-analysis to show that your agent works, then your agent doesn’t work. That you need to show efficacy in at least one good, well-designed clinical trial.
For secondary progressive disease, we’ve got Betaferon, the European name for interferon beta-1b, based on the study that Hill outlined for you. I think it’s important to say that that was a very well-done study. They carried out their assessments and they carried out the trial in excellent fashion; they’re very good data.
We have mitoxantrone (Novantrone), the data that you’ve just heard from Hill Panitch. Again, off-label, azathioprine, same problems. Cladribine is an interesting agent, because cladribine is an example of a modern study that was performed like a 1950 study, in that it was just a terribly designed study that did not show any clinical benefit at all to cladribine. The study was done in patients with chronic MS; it included both primary progressive and secondary progressive; and there’s now pretty good evidence that you probably shouldn’t mix those groups in the same study to try and get an outcome measure; and it failed. The results were all over the place, looking at different dosages.
However, cladribine was extremely effective at decreasing gadolinium-enhancing lesions. One of the issues that we need to talk about and address more is the dichotomy between effects on MRI and effects on our clinical measures. It’s a long discussion and we’ll come into it a bit as we go through some of these other things.
Cyclophosphamide, I’ll show you a little bit about. Glatiramer acetate was studied, again in a chronic progressive group small study. It was kind of interesting because the original glatiramer acetate group that Bornstein did with relapsing disease, was actually, for its time, a brilliantly designed study—probably the first real, modern-design clinical trial; but this one in progressive disease was not as cleverly designed and it produced conflicting results. Interferon beta-1a (Avonex) is being tested right now in a double dose in a clinical trial for secondary progressive disease in what’s called the IMPACT trial; and we should have data on that in about 1 year. That’s an interesting study and it’s especially interesting because there’s some dose information that we can get from that.
Dr Panitch told you about the Rebif secondary progressive trial. There is a study called, I think, the ESSOM study and IVIG in secondary progressive disease going on in Europe. It’s a very well-designed study and if it is successful, I think we will see a lot more IVIG usage in various forms of multiple sclerosis. I think that will be enough to probably make it acceptable therapy.
Primary progressive disease has been extremely difficult to treat, and it’s only recently that people have segregated primary progressive, as opposed to the old term, chronic progressive. Although I do see that the word chronic slips into the labeling information for Novantrone, at least parenthetically just to confuse people. And so, for primary progressive disease, there is no therapy. There’s no agent that’s been shown to be effective at all.
Glatiramer acetate is being tested right now in a well-designed, large phase 3 trial, which will have or may have already 900 patients in it. It will be the first large-scale, well-designed trial for primary progressive disease; we won’t see data on that for at least another 3 years – longer actually.
Interferon beta-1b has not been looked at. Alan Thompson reported a small study of primary progressive disease looking at 3 groups—a placebo group, an interferon beta-1a (Avonex) route of administration, and then a double dose once a week of (Avonex). The primary outcome measure was change in disability; he didn’t meet the primary outcome measure; there was no difference.
There were about 12 other secondary outcome measures, one of which was T2 lesion volume was significantly better in the 30 µg dose—the standard dose of Avonex—as opposed to the 60 or the placebo. No other measures were significant, so it’s a negative study. The most important aspect of that study was that you can, in fact, carry out a well-designed trial in primary progressive disease; and hopefully, we’ll see some more come up later. Mitoxantrone has not been looked at in primary progressive disease.
The first significant report of this was, I believe, either in 1983 or 1985 in the New England Journal of Medicine. It was the same issue that reported a successful trial of cyclophosphamide and a successful trial of hyperbaric oxygen, one after another. It was a landmark day for the New England Journal of Medicine, but a black day for MS neurology—for the most part, because hyperbaric oxygen was fraud. The cyclophosphamide wasn’t, but it wasn’t really a very well-designed study. For the time it was okay, but it doesn’t really meet the standards we have now. It’s an immunosuppressive agent; it’s been used in dozens of different protocols—induction, maintenance, etc, and it has significant side effects associated with it.
The study done out of Boston where there were some good centers also included a lot of northeastern US centers that weren’t very skilled at carrying out clinical trials. It also was complicated by the fact that plasma exchange was involved in it, as were steroids, so it was a little difficult to understand with not terribly impressive data.
It was redone by the Canadians, again with similar design, but slightly similar dosing; and the Canadian study, which I think was a better design, although it didn’t cover every possible cyclophosphamide iteration, showed no effect whatsoever of cyclophosphamide. So, I don’t think there’s much to recommend it, although the MRI people will tell us that any of the agents we can talk about today—any of the cytostatic agents they test in individuals, looking at gadolinium enhancements they will find some people who respond to some of them.
We get back into the issue in progressive disease, whether stopping gadolinium-enhancing events is a significant enough event. One can even take it one step further and say the autoimmune response not always being bad is, in fact, the case. Maybe stopping gadolinium-enhancing lesions in progressive disease may not even be a good idea. There are some interesting changes going on in the way we view the paradigm of the immunopathogenesis and underlying pathology of MS.
The only good data for secondary progressive disease right now are on Rebif, but the Avonex double-dose trial should be available in the next year. Three studies that fail and 1 study succeeds, or give us a 2 to 2 split. Either way, it will be interesting information.
This is a rehash of the Rebif data. The main issue that we’re wrestling with in the field is that the primary outcome measure, which was a change in disability, wasn’t met. But all of the other outcome measures—for whatever value they are: relapse rate, lesion load, gadolinium-enhancing events, and such—were significant. We think that may be telling us something about the underlying pathogenesis, but that’s not entirely clear.
We have the split and Hill Panitch gave you a pretty good idea of what the differences were in the population. The fact is that the Europeans carried out the assessments better than they were done in the United States—at least, Europeans in the Betaferon study. In the Rebif study, it would suggest that they didn’t. So, that’s an issue as well. And again, we have this dichotomous data that we have to try and integrate into our thinking.
The other thing that one has to look at here and think about for the future, and the not-too-distant future, is that these are very partial therapies, and they’re not stopping progression. Even when they succeed, they’re just slowing progression. We need to come up with some strategies to do much better.
Methotrexate was studied by Dr Goodkin using rheumatoid arthritis type dosages. He showed that it was well tolerated in secondary progressive patients. Using a composite outcome measure, showed a significant difference; there also was a difference using MRIs; and there was reduced T2 lesion load.
The problem with this outcome was that it was actually a very modest result, even though robust statistically, and that all the benefit was in measures of upper-extremity function and not in ambulation and lower-extremity tests. It’s not clear how valuable an adjunct this is for progressive disease when, for the most part, in most patients, you’re trying to keep their ambulation from deteriorating, with the hope that the rest of it will follow through.
Similarly, periodic use of steroids (again, this was Dr Goodkin) using bimonthly pulses, 500 mg/d, for 3 days every other month with a brief oral taper. This was actually an important study because there was a lot of anecdotal usage and still is a lot of anecdotal usage at pulse steroids, whether patients are clearly worsening or not worsening, as opposed to just treating acute exacerbations. That’s never been properly tested. Here it was properly tested and it didn’t meet its primary outcome measure, although there certainly was a strong hint that there may be something going on with at least some of the secondary measures. The issue that makes me less excited about this particular therapy was in terms of the effect on gadolinium-enhanced MRIs where you give monthly steroids.
We have mitoxantrone (Novantrone) that just got approved for treatment. It’s worth looking at this dosage because if you talk to your oncologist, they’re not going to be familiar with this dosing because this is MS dosing, not oncologic dosing. You may find other differences when you talk to oncologists because how oncologists view morbidity and mortality in multiple sclerosis, at least, oncologists who do bone marrow transplants—you may find that you’re talking a bit of a different language.
In any event, 12 mg/m 2 IV infusion every 3 months was, in fact, very well tolerated. By oncologic standards, they think this is a great drug; they think it’s extremely well tolerated compared to the other poisons that they’re using. That is of some importance, relative to other oncologic agents. I think for neurologists you’re going to need to get your feet wet with this a little bit and have some back-up when you initially start; and then people get used to using it.
There was some nausea; it wasn’t particularly bad. Hair thinning, but not really much alopecia. There’s some gynecologic problems that on reassessment are not particularly onerous. Leukopenia was of almost no concern; it was remarkably well tolerated in that regard. The nadir is somewhere at around 2 weeks and it wasn’t even looked for, at that point, but rather, you take a look at the white count before the next dose, but it hasn’t been a big issue. It does turn urine and sclera a bit blue. When we tested this in white mice, it turned them a little blue also.
You heard about the dose-related cardiotoxicity, and this is something we’re going to have to watch. There’s not a lot of good data yet to tell us 10, 15, 20 years down the road where we stand with this, but we’re going to be the group that gets that experience in MS patients, so we need to keep an eye on it. As best one can tell now, with the short exposure, it doesn’t look to be something that is progressive in the absence of dosing. And dosing will inevitably increase. There was one case reported in Germany by Maw, who has an enormous experience, over 10 years in using this. One patient he had treated up to what he thought was a safe dosage, and it was, who then went elsewhere, and didn’t tell them that they had had the drug and got subsequent courses of the drug, in fact, did develop congestive heart failure. So, it’s something one’s going to have to be careful about, because MS patients do go around to different doctors and get different therapies.
The dose-related cardiotoxicity is up to about 140 mg/m 2 . The incidence in oncologic patients was about 2.6% of anything significant. We’re going to need to pay attention to this, as we figure out how to integrate this particular agent into our long-term treatment armamentarium. We have a pretty good idea of what it’s going to be short term, based over the Q3 months for 2-3 years. But given the robustness of the results, we’re going to have to think about how we can do this more long term. And I just might add that the results on the 1 point change are, far and away, the strongest results of any MS trial, in terms of looking at the 1 point change in disability.
The potential for secondary leukemia has been mentioned; it’s in a black box on the labeling information that you’ll see. This is almost exclusively data from patients who, a, have cancer and, b, have been treated with multiple agents. I’m told that there is one case of a promyelocytic leukemia that occurred about 5 years ago, and after the patient with MS was treated with 5 courses of mitoxantrone. The chromosomal analysis of that patient raised some question as to whether that was a primary or secondary tumor. The end is somewhere between 0 and 1, in terms of patients with MS who have run into any secondary leukemias. None in the pivotal trials that were done in Europe with this agent, and none in the anecdotal usage—well-documented anecdotal usage—out of Germany by Dr Maw.
Studies have, for the most part, been relapsing-remitting, secondary progressive, primary progressive, and they’re done that way, so that we have homogeneous groups of patients. But in this group, they essentially took patients with relapsing disease of any sort—meaning primary, secondary progressive, progressive relapsing, relapsing- remitting, who were doing badly, who were getting worse over time and used that as their assessment.
We used a similar group of patients in the linomide trial, the entrance criteria were actually very similar. That trial had to be stopped for its own toxicities, but it’s a group of relapsing patients, with or without relapses, but it’s a relapsing form of multiple sclerosis.
It had an effect on progressive disability. It also had effects on time to relapse and number of relapse, and it had effects on MRI. To me, the gold standard of assessment in multiple sclerosis trials is if everything goes in the right direction. And, this was, in fact, the case with the original Betaseron trial; it’s what got it approved, because, at the end of the FDA hearings, someone said, “Look, everything that’s significant goes in the right direction.” Everything that was insignificant still trended in the right direction; and here, you have even stronger data, in terms of progression of disability and the others. So, everything trended in the right, and that’s a comforting feeling when choosing an agent. In fact, during the 2- and then, 1-year follow up at 3 years, all the adverse events were manageable.
This 64% really is the most robust reduction of a percentage of one point disability worsening of any of the modern trials.
Gadolinium-enhancing lesions: so, disability, relapse rate, gadolinium enhancing lesions, it all falls into place.
This was a second study that in fact the FDA used in making a decision about this drug, which was Professor Edan’s study from France, in which he took individuals and was looking at gadolinium-enhancing scans. He did a run-in period and then he split them off into a group that just got methoprednisone and another group that got 1 g methoprednisone a month, and a 20 mg intravenous dosage of mitoxantrone monthly; 12 mg/m 2 for me would be about 20 mg. So, it was a fairly standard dosing.
The primary outcome measure was MRI lesions. One of the interesting aspects of this particular trial, and maybe the most ground-breaking aspect, was that the primary outcome measure was an MRI measure and the FDA advisory panel accepted it as an outcome measure for a clinical trial in MS; and that had not been done before.
The results show you that, if you’re getting both drugs, you really get a fairly rapid decrease in gadolinium-enhancing lesions which, in the mitoxantrone–methoprednisone group continues, at least, out through Month 6. The other interesting aspect that relates to pulsed steroids is that the pulsed steroids didn’t have as profound effect on gadolinium-enhancing events over time. Nevertheless, it showed an advantage over the short term.
The other important aspect of this particular design is that it gets us into something that we’re starting to think about now, and that is, using an agent such as mitoxantrone as an induction therapy. As you can see, you can get an effect pretty quickly, and if you look at the additional data, you start to see an effect also on the mean EDSS. Remember, a negative score on EDSS is improvement. So, one of the things that we will be addressing in future months is how to use this agent in combination, certainly as an induction agent, as well.
This was relapse rate from the same study, but it’s only a 6-month study, so there’s not a lot you can say in that period, even though there was a significant reduction in 6 months, which is not bad, for such a short period of time.
We discussed the issue of secondary leukemia. This paper came out in August in the Journal of Clinical Oncology. Patients had received mitoxantrone for treatment of breast cancer along with radiotherapy, cyclophosphamide, and fluorouracil.
It’s a little hard to put this into a quantitative context with other therapies, because the other therapies that were compared in this study were from a decade prior to this. But it’s there and I think you’re probably going to have to mention it when you discuss it with your patients. I know we’re going to watch very carefully to see if this is a real problem or just another black box. We discussed the fact that none of the MS studies that have been formally done have shown anything. I did mention the one case report, which raised the issue of a possible induction.
Questions and challenges: things to think about. How do we define inadequate response to treatment? And why is that an important question here? Once you have someone on ABC drugs who’s failed, there’s not a lot you can do, but maybe move between A and B, or A and C, or B and C. But there’s not a lot to help us with that.
The question is, if someone is breaking through or doing pretty poorly, how do we define that to know who it is we ought to be putting on mitozantrone? The indication’s pretty clear when you read the labeling information, but it may not be so clear in the clinics.
How do we treat patients who experience progression on 1 of the ABC drugs, and that sort of, has become self-evident. At least, anecdotally in the European experience, both Edan and Maw have experienced treating patients with Novantrone after they’ve been treated with interferon beta, and they report, again anecdotally, no particular difficulties with doing that. We’ve discussed a bit the implications of the different results, outcomes of the interferon beta measures in secondary progressive disease.
What are the relative efficacies that are available? Monotherapy as well. There are no good, well-done, head-to-head trials of any of the agents that we have, to try and say that there is an ordered effectiveness of them. What combinations might be most appealing? There’s lots of combinations being tested; and this is an exciting area of MS research right now because these are modest therapies that don’t stop disease, but slow it. One would hope that by combining neoplastics or antivirals or antibiotics or antiepileptics, of improving upon those therapies. It’s not that straightforward though. When you mix immunomodulated agents, it is possible that the immunomodulating effect of one agent might interfere with the immunomodulating effect of another, and you may get untoward effects. One has to look at safety first. What is the potential role of mitoxantrone?
Secondary progressive MS is a treatable disease. We have therapies for it now. We can delay the time of onset to sustained progression. We can reduce relapse rates. We can reduce MRI activity and lesion load. Early intervention still appears to be the most appealing way to go in treating patients with multiple sclerosis and eliminating long-term irreparable damage.