Expert Perspectives on the Clinical Use of Immune Reconstitution …€¦ · Inc.; Genzyme...

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Expert Perspectives on the Clinical Use of Immune Reconstitution vs Escalation Therapy for MS CME

https://www.medscape.org/viewarticle/902396


Supported by an independent educational grant from EMD Serono


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Target AudienceThis activity is intended for neurologists, primary care physicians, and obstetricians and gynecologists.

GoalThe goal of this activity is to define immune reconstitution and escalation therapies and discuss these approaches to the treatment of multiple sclerosis (MS).

Learning ObjectivesUpon completion of this activity, participants will:

Have increased knowledge regarding the• Technical differentiation between immune reconstitution and maintenance therapy in MS• Factors involved in the identification of patients with MS who may benefit from therapies that induce

immune reconstitutionHave greater competence related to

• Development of an individualized therapeutic strategy that optimizes treatment outcomes in MS

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Disclosures

Moderator

Thomas Leist, MD, PhDProfessor of NeurologyThomas Jefferson UniversityPhiladelphia, Pennsylvania, United States

Disclosure: Thomas Leist, MD, PhD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Actelion Pharmaceuticals, Ltd; Biogen; Genentech, Inc.; Novartis Pharmaceuticals CorporationServed as a speaker or a member of a speakers bureau for: Biogen; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USAReceived grants for clinical research from: Actelion Pharmaceuticals, Ltd; Alkermes, Inc.; Biogen; Novartis Pharmaceuticals CorporationDr Leist does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.Dr Leist does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Panelists

Augusto Miravalle, MDAssociate Professor of NeurologyChiefMultiple Sclerosis DivisionUniversity of FloridaGainesville, Florida, United States

Disclosure: Augusto Miravalle, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Celgene Corporation; Genzyme Corporation; MallinckrodtReceived grants for clinical research from: Novartis Pharmaceuticals CorporationDr Miravalle does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.Dr Miravalle does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

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Mark Freedman, MDProfessor of Medicine and NeurologyUniversity of OttawaSenior Neuroscience ScientistOttawa Hospital Research InstituteOttawa, Ontario, Canada

Disclosure: Mark Freedman, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Bayer HealthCare Pharmaceuticals; Biogen; Chugai Pharma USA, LLC; EMD Serono, Inc.; Genzyme Corporation; Merck Serono; Pendopharm; Novartis Pharmaceuticals Corporation; Sanofi; Teva Pharmaceuticals USAServed as a speaker or a member of a speakers bureau for: Genzyme CorporationReceived grants for clinical research from: Genzyme CorporationDr Freedman does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.Dr Freedman does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Steering Committee

CHAIR

Stephen Krieger, MDProfessor of NeurologyDirectorNeurology Residency ProgramIcahn School of Medicine at Mount SinaiNew York, New York, United States

Disclosure: Stephen Krieger, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Acorda Therapeutics; Bayer HealthCare; Biogen; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Mallinckrodt Pharmaceuticals; MedDay Pharmaceuticals; Novartis Pharmaceuticals Corporation; Teva Pharmaceuticals USA; TG Therapeutics Served as a speaker or a member of a speakers bureau for: Biogen; Genentech, Inc.

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Members

Patricia K. Coyle, MDProfessor and Vice Chair (Clinical Affairs) of NeurologyDirectorMS Comprehensive Care CenterStony Brook University Medical CenterStony Brook, New York, United States

Disclosure: Patricia K. Coyle, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Accordant Health Services, LLC; Acorda Therapeutics; Bayer HealthCare; Bioge; Celgene Corporation; Genentech, Inc.; Roche Holding AG; Genzyme Corporation; Sanofi; Novartis Pharmaceuticals Corporation; EMD Serono, Inc.; Teva Pharmaceuticals USAReceived grants for clinical research from: Actelion Pharmaceuticals, Ltd; Alkermes, Inc.; Genentech, Inc.; Roche Holding AG; MedDay; Novartis Pharmaceuticals Corporation

Anne H. Cross, MDProfessor of NeurologyWashington University School of MedicineSt. Louis, Missouri, United States

Disclosure: Anne H. Cross, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Biogen; EMD Serono, Inc.; Novartis Pharmaceuticals Corporation; Genentech, Inc.; Genzyme Corporation; SanofiReceived grants for clinical research from: Genentech, Inc.

Gavin Giovannoni, MBBCh, PhDProfessor and Chair of NeurologyBarts and The London School of Medicine and DentistryLondon, United Kingdom

Disclosure: Gavin Giovannoni, MBBCh, PhD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AbbVie Inc.; Bayer HealthCare; Biogen; Canbex Therapeutics Ltd.; Eisai Inc.; Elan; Five Prime Therapeutics; Genzyme Corporation; Genentech, Inc.; GlaxoSmithKline; GW Pharma; Ironwood Pharmaceuticals, Inc.; Merck & Co., Inc.; Merck Serono; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Roche Holding AG; Sanofi-Aventis; Synthon; Teva Pharmaceuticals USA; Vertex Pharmaceuticals Incorporated

Thomas Leist, MD, PhDProfessor of NeurologyThomas Jefferson UniversityPhiladelphia, Pennsylvania, United States

Disclosure: Gavin Giovannoni, MBBCh, PhD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AbbVie Inc.; Bayer HealthCare; Biogen; Canbex Therapeutics Ltd.; Eisai Inc.; Elan; Five Prime Therapeutics; Genzyme Corporation; Genentech, Inc.; GlaxoSmithKline; GW Pharma; Ironwood Pharmaceuticals, Inc.; Merck & Co., Inc.; Merck Serono; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Roche Holding AG; Sanofi-Aventis; Synthon; Teva Pharmaceuticals USA; Vertex Pharmaceuticals Incorporated

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Claire Riley, MDAssistant Professor of NeurologyMedical DirectorColumbia MS CenterColumbia University Irving Medical CenterNew York, New York, United States

Disclosure: Claire Riley, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Celgene Corporation; Teva Pharmaceuticals USA

Editors

Catherine Friederich MurrayScientific Director, Medscape, LLCDisclosure: Catherine Friederich Murray has disclosed no relevant financial relationships.

CME Reviewer / Nurse Planner

Amy Bernard, MS, BSN, RN-BC, CHCPLead Nurse Planner, Medscape, LLCDisclosure: Amy Bernard, MS, BSN, RN-BC, CHCP, has disclosed no relevant financial relationships.

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Expert Perspectives on the Clinical Use of Immune Reconstitution vs Escalation Therapies for MS

Faculty

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Disclosure

Disease-Modifying Treatment for MS

Thomas Leist, MD, PhD: We have a number of treatments for (MS). This group of medications has greatly increased over the last 2 decades. Generally, we have a way in the field of classifying these medications. We consider some as first-line treatments and some as second-line or later treatments. As a field, we also have an evolving approach to the treatment of MS. In decades past, there was often a wait-and-see approach. This has given way more and more over the recent years to an approach where we treat early and towards the patient characteristics that individuals express either at the initial or at the subsequent presentations when they are under our care.

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Evolving Therapeutic Landscape in MS[1-16]

Dr Leist: The field of therapies in MS has greatly expanded from the initial injectable therapies to the oral therapies. Most of our treatments that we currently have are regularly administered, for they are so-called maintenance therapies. But with introduction of monoclonal antibodies and with the expected potential introduction of an oral agent, we are now going into the direction of interrupted intermittent therapies, where patients are only getting very few treatment cycles. The topic today is looking at maintenance therapies vs immune-reconstitution therapy (IRT) and how they present themselves in the field and where treatment decisions are surrounding these drugs.

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Maintenance/Escalation Therapy vs IRT[1-15]

Dr Leist: Maintenance and escalation therapies are, as previously stated, given continuously at a regular schedule. This schedule can be twice daily or, at the other extreme, can be every 6 months if we look at the anti-CD20 therapies. The goal out of this is to suppress recurrent inflammatory activity and modulate the disease process and prevent accumulation of disability in individuals. As previously stated, we have now a group of medications that are pulsed: they are given at regular or at preplanned short courses and are then followed by long-term dose interruptions where no course of medication is given.

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Predictors of Disability: Disease Factors[17-19]

Dr Leist: Dr Miravalle, can you guide us a little bit in a discussion through how you look at patients and what factors would indicate for you that the patient is a higher or perhaps more average risk patient?

Augusto Miravalle, MD: Perhaps that is a very important consideration to have nowadays where we have so many available therapies, which is understanding what are the clinical phenotypes and also paraclinical phenotypes that a patient has, that might educate us in terms of long-term prognosis and disease course? I think we are all familiar with MS being a very heterogeneous, in a sense, unpredictable disease.

There are certain factors, both clinically and on MRI and in laboratory studies that we can anticipate as being markers for future disease process and prognosis. Among the clinical factors, I usually pay attention to age at presentation. We do know that the younger a patient is, the more likely that the patient will have a very aggressive inflammatory response, and we do see that with higher rates of relapse, with larger accumulation of number of lesions over time.

Conversely, what we are learning from the pediatric population is that also recovery and remyelination might be more active also early on. That is a topic that we need to continue to learn about. We look into the rate of relapses and the frequency of relapses early on. I pay attention to the degree of recovery after the initial relapse, and we do know that patients who have a fairly poor recovery after the first relapse most likely will continue to experience accumulation of disability and subsequent relapses. That should be a marker that should be paid attention to closely early on, as a potential red flag for potential disability in the future.

In terms of localization and semiology, patients who have multisymptomatic presentation, meaning presenting with multiple symptoms simultaneously in the initial relapses, perhaps they are telling us that the disease is more a multifocal at onset presentation, and that should be another sign of concern early on. Examples being on the 1 hand of the spectrum, you have atypical presentation with a single event with optic neuritis, vs a patient presenting with brain stem disease, spinal cord disease, and cortical lesions. That second patient is telling us that the disease process may be more aggressive than the first one. Those are a few things that I pay attention to early on from a clinical standpoint.

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Predictors of Disability: Patient Factors[17,20,21]

Dr Leist: One point that you have not mentioned is a patient’s family history of autoimmune disease or MS. A second point that you have not mentioned was patient ethnicity. Can you perhaps comment on these 2 points also?

Dr Miravalle: Absolutely. We do know that certain patients with MS have first-degree relatives or family history of MS. It is thought to be 10 to 15% of all MS patients, and there are certain trends that tell us that perhaps first-degree relatives or family history of MS may tell us more about a more aggressive course of the disease over time. As you mentioned before, certain demographics and ethnicities may tell a different story in MS. Perhaps one that is well studied is the African American population in terms of not only disease course but also response to certain therapies. There are some suggestions that perhaps African American individuals with MS may have a varied, if not suboptimal, response to medications like interferons (IFNs) for example, in addition to worse clinical outcomes.

There is also a relationship between gender and outcomes, and perhaps that is reflected based on a higher incidence of spinal cord disease and lower brain stem disease in males. It is not clearly understood whether that is directly related to the gender or whether it is related to where the lesions are. In terms of Hispanic populations, there is an interesting relationship between a higher optical spinal pattern of disease in south American Hispanics with MS, again suggesting that perhaps those individuals, due to the presence of spinal cord lesions, may have worse clinical outcomes.

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Predictors of Disability: Imaging[22]

Dr Leist: Dr Freedman, can you comment on paraclinical tests, including magnetic resonance imaging (MRI), that would indicate different risk patterns of patients?

Mark Freedman, MD: Thank you, Thomas. In the initial profiling of the patients, you want to get all the information you can from all the different sources. I think if you are seeing patients as a second or third opinion, that can sometimes be daunting because you really want to hear about their first attack, you want to hear about the first MRI. You want to know how the disease presented itself. You have nicely reviewed the clinical types of things that we would look at to help prognosticate an individual.

What are the other kinds of things that we can look at? Certain magnetic resonance (MR) and MR at the beginning of the disease is the most predictive. Later on, it loses its correlation. I think that in the very first MRI, the distribution of lesions, the sense of burden, how much white matter disease is present, if the eye can detect atrophy very early on, inappropriate for the age, that is usually a very bad sign and tends to correlate a little bit more with something that perhaps you wanted to mention in time, is how the patients are cognitively.

We have seen this even in children with MS, leading up to their expression of their disease, if you followed their grades for a couple of years, they have already started to decline. There is already evidence of damaging MS, and that might lead us to consider a different type of therapeutic approach. The routine things that we can get on MRI are just the picture; is it really atrophic for age? Is there a large burden? There are much more sophisticated MR measures that are coming out in the clinical trials but are not really in the hands of our clinicians to date.

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Neurofilament Levels as Markers of Disease Activity[23-26]

Dr Freedman: I think that as we evolve, we are even looking at serum biomarkers. One that really has a lot of promise is the measurement of serum neurofilaments. We can see age-related changes due to a number of different processes, and they are not specific to MS. I think if we saw a patient very early on in their disease, and we measured their serum neurofilament levels and it was sky-high, that is another indication, like the atrophy we see on MR, that there is damaging disease going on that needs to be checked, and our approach to how we are going to check that therapy is one that we might want to reach for something a bit stronger.

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Benefit of Early Treatment Initiation[27]

Dr Leist: MS is probably not one of the fields where a one-size-fits-all approach is the appropriate approach for individuals, which then also means we have different approaches for individuals, different approaches with respect to treatment. Are there factors that you are taking into account? We will later on have case presentations that will underline this, that will guide you with respect to an approach in an individual patient that varies. For example, is your treatment of a young woman different than your treatment of a 45-year-old male, where perhaps fertility considerations are less significant?

Dr Miravalle: Absolutely. As we learn from our colleagues in stroke, time is brain. Timing is very important in MS and with that, I mean, the earlier we can intervene with the most appropriate therapy, the higher our chances of meaningfully impacting long-term outcomes. When I am facing a patient as you mentioned in the second example, the 45-year-old male, assuming that the patient had MS for a long period of time and that was either not recognized or suboptimally treated, I tend to have a lower threshold of tolerance for accepting any type of disease progression by using suboptimal therapies.

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Monitoring Burden With DMT[1,2,6,9-12,14,15]

Dr Leist: Dr Freedman, is monitoring or levels of adherence something that you take into account when you are approaching the patient from a treatment point of view?

Dr Freedman: Absolutely. In fact, there are many different things that you have to consider on the patient side, on the medication side. If you have a drug that needs to be carefully monitored, and you are dealing with someone who is a travelling salesman and may not be available for these monitorings, the monitoring is for the safety. For example, alemtuzumab needs to be monitored monthly. If a patient finds that onerous and cannot meet the needs of the blood and urine monitoring, that is probably an inappropriate choice for that individual and there are alternatives that would make it easier for that individual to comply. If they can comply, they adhere; if they adhere, they get the benefits.

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Case Study 1

Dr Leist: Maybe it is time to look at individual cases and flesh out what we have discussed from a high-level point of view in more concrete cases. Dr Miravalle, if you could take us through your first case.

Dr Miravalle: Yes, this is a case of a 22-year-old female, she is young, and she is single. When I ask her about pregnancies, she does not have any plans. She is not actively seeking but that is a possibility in the near future. Her MS presented with what I like to call polysymptomatic multifocal disease. With that, I mean she had multiple symptoms simultaneously at the same time. She had sudden-onset dysarthria, binocular diplopia, and loss of balance, and all of those symptoms were confirmed with findings on her physical exam. She had a multifocal presentation with a right internuclear ophthalmoplegia, she was ataxic on the left arm and leg, and also she has mild but clearly obvious bilateral leg weakness. All of those symptoms and signs are localizing to a pathology likely in the brain stem and spinal cord.

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Case Study 1: Workup

The MRI actually confirmed our clinical interpretation of the findings, and she had presented with at least 10 lesions. She had 2 infratentorial lesions and a single spinal cord lesion. Interestingly at presentation, she already had the presence of T1 hypointensities, which I try to pay attention to early on as 1 of the perhaps markers for neurodegeneration or axonal loss early on in her course of the disease. She had a proper confirmatory test on cerebrospinal fluid (CSF).

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Case Study 1: Treatment Considerations

Dr Miravalle: I thought to present this case to you in terms of, what would you do for first-line therapies in a patient that you know is young, perhaps will have pregnancies in the near future, presenting with what we know are potential red flags or clinical and paraclinical markers of a very aggressive disease course?

Dr Freedman: Yes, you mentioned earlier you pay a lot of attention to the first attack and whether there was a recovery. Can you tell me something about that? Did she recover completely? Is her exam back to normal?

Dr Miravalle: No, as a matter of fact, her legs are still weak 6 months after the first event and she complains still of binocular diplopia.

Dr Freedman I think that in the context of how we have been discussing prognostic factors, she is young, that is a good prognostic factor, but her type of presentation, the multifocality of it, the involvement of brain stem, spinal cord, and more importantly the residual deficits, the young nervous system can compromise very slowly and usually compensation mechanisms are very good. Repair mechanisms are good. It is unusual for someone to present like this. I think we are seeing someone who has either extended beyond her ability to compensate or it is telling us about the disease itself being a much more damaging type of MS than your run-of-the-mill MS. There were times that patients like this would have no other choice but to go on an injectable therapy because it was the only thing we had. Our experience has been very clear and perhaps the 2 of you can disagree, but such a patient treated with say, the injectable therapies is almost surely going to fail and fail soon. Why wait for failure? Consideration should be given to this individual that you might want to risk a riskier type of therapy in an effort to try to quell the disease right from the start. You want to be careful; the first few years dictate how this disease is going to play out. I would opt for something more aggressive as a first-line treatment.

Dr Leist: Obviously, one of the features that you mentioned is the T-1 hypointensity. I see T-1 hypointensities that are not associated with acute lesions or that it is nonpermanent T1 hypointensity. That to me indicates that this disease process has a relatively damaging effect on the central nervous system. The fact that she has also not recovered, you have been in your description not eloquent with respect to her ethnicity, for example, and the point again, that may be something that also comes into play in terms of selecting or not selecting medications. I agree that this will be a patient where what we consider high-efficacy medications will be first-line consideration.

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Pregnancy Considerations With DMT Use[1-3,5,6,8-15]

Dr Leist: The second thing is, you mentioned the point that she is at the time in her life where she has not yet made decisions whether or not she wants to have children and when this will be happening. We all know that she will need to have disease control. I am talking about this in the context of alemtuzumab, cladribine, or potentially an anti-CD20 therapy where the treatment effect may persist beyond the presence of the actual medication. What do you think about that approach?

Dr Miravalle: Yes, it is exactly along the lines of what I was considering. I think the unknown pregnancy category in this patient is making the concept of an induction or immune reconstitution approach more attractive as you mentioned before, because that allows us to discontinue in the future, in case it is needed for pregnancy reasons.

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Reduced Risk of CIS Conversion to CDSM With Cladribine[28]

Dr Leist: We have a number of trials in first-event patients, the clinically isolated, or we call it first treatment trials. All of them have indicated that the medications that are used have a significant effect in this particular population and may actually at times even interrupt McDonald MS development, next lesion. Dr Freedman, how do you look at wait-and-see in a patient such as this one vs early step-in? Is this a patient where you have the red flag up and say we need to go, or is this a patient that if she were to tell you, “I really want to first discuss with my boyfriend, or whoever, what we are going to do and maybe we can reconvene in a year or 2 to maybe decide what to do,” where would you be in that discussion?

Dr Freedman: I think it is important for us to be able to convey our what seem unanimous feelings about this case being one of a high risk for early progression. We need to be able to interpret that in her terms so that she understands why we are anxious about her disease and why we feel it is necessary to act now, and that a wait-and-see is very likely going to lead to further deterioration, and more importantly, the longer we wait to introduce a therapy, the less effective it may be. Really, in the early years, the therapies can be quite effective. In this context, we have 1 of these drugs that we are talking about, IRT, that has been tested in patients exactly like this. In a study called ORACLE, for instance, the cladribine introduction has shown that in such a patient, it has exceeded the outcomes of all the other trials that have been introduced at clinically isolated syndrome (CIS). A more potent therapy can have an even better overall outcome.

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Case Study 2

Dr Leist: Thank you. If I may ask you, Dr Freedman, to go through your case.

Dr Freedman: We have talked about the young girl; now are dealing with a more middle-aged individual. A 42-year-old retired professional hockey player, which, over the years, has taken its toll on his body, with lots of injuries more or less to his spine. He started to have problems with neck and back — typical issues, numbness, tingling, occasional weakness. Did not want to go to surgery. Over the years, every time he had an exacerbation of his neurologic symptoms, he blamed it on his back or his neck, and unfortunately so did his general practitioner (GP). They kept on accumulating these spells, thinking it was due to musculoskeletal problems, but one day it became a little different. His numbness, rather than being in 1 foot or an arm or shoulder or a hip, started to ascend in both legs. He reported now a numbness level around his umbilicus and suspicion became that maybe there is another process.

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Case Study 2: MRI Findings

Dr Freedman: This led to imaging, and the imaging told us not only did he have a spinal cord lesion appropriate to this obvious presentation of a transverse myelitis, but the brain MRI showed multifocal lesions — already perhaps some early atrophic disease that maybe have been a result from his hockey injuries, but also could be due to the underlying process, which very much looks like it is MS. How many years has this been ongoing? You can gather that if he has some atrophy, he has some T1 holes, he has some active lesions and inactive lesions, it could have been going on for as much as decades. The question is, how do we approach this individual who may have presented earlier had he not had this professional career that everyone blames his problems on.

Dr Miravalle: Unfortunately, this is not uncommon. We do see that there are some clinical confounders that may early on explain symptoms and, in a sense, delay the recognition of the disease, whether it is from a diagnostic standpoint or even for the treatment management. I think we all encounter in our clinical patients like that, in terms of the numbness, the paresthesia, the sensory symptoms are through to be secondary to a radiculopathy or in this case a post-traumatic etiology as opposed to MS.

Dr Freedman: They get better.

Dr Miravalle: They get better. Exactly. That, in a sense, delays the treatment.

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Dr Freedman: There are a few red flags in this patient, one being the time factor that we are delaying the onset of highly effective therapies due to these confounders. The age also: even though at 45, he is young, but for MS, we should assume that this patient had MS and recognized or suboptimally treated for a decade or more. The gender, the presence of spinal cord disease, the presence of highly active enhancing lesions — all of those factors should be taken into account. This will be a classic patient that I will have a low threshold for choosing a highly effective therapy early on. I will try to balance the efficacy and safety of course, but if possible I will go first-line to a highly effective therapy.

Dr Leist: We also have to have discussions with the patient, what can be achieved because he has accumulated certain disability. Obviously he has all the disease conditions. We also note that he has cognitive issues or cognitive complaints, which obviously may be due, in part, to his prior professional pursuit, but it may also be a direct reflection of unappreciated disease activity. We really need to intervene with what we consider effective treatment. If he accumulates additional lesions, then this is going to be somebody with a progressive course that probably is very difficult to halt in any meaningful way. We do not have in the case scenario whether there are other things that the patient could potentially modify besides the treatments that we are considering, for example, if this is somebody that, beyond his professional career, has picked up smoking. This would be something that would have to be discussed with the patient. There are other approaches surrounding all of this. Obviously if his disk disease would be of such nature that there is actually a compressive feature in addition to the intraspine lesion, that would be also be something that one would have to have him see a neurosurgeon for and address it or potentially address it. One plus 1 sometimes is not 2; the spinal cord that is injured twice normally reacts in a different way than a spinal cord that has 1 underlying pathology. What is your approach in such a patient, Dr Freedman?

Dr Freedman: I think the most important aspect of this case is that time is against you in MS. The time factor is not clear in this man, but it is clear that he has evolved. If that is the case, we know the older you are and with the accumulative burden that he has that his risk for progression is going to be very high. We probably have 1 shot at him and we want to make it our best shot. I think there is another indication here for a definitive cell-depleting therapy that would be given in an interrupted manner; the so-called pulsed IRT would be appropriate as a first-line therapy, should we be able to get it, of course, the logistical coverage, etc. That would be my recommendation for him.

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Case Study 3

Dr Leist: Thank you. Let us move on to the third case. This is a 32-year-old African American woman that delivered a healthy boy, after, from a pregnancy point of view, an uncomplicated period of time. She did have a relapse during the pregnancy. She was originally diagnosed with MS 7 years ago.

Case Study 3: Workup Postpartum

Dr Leist: In the postpartum period, she had a follow-up MRI, and this indicates that she has 2 new lesions, at least 1 of which is gadolinium enhanced (GdE) and she has also known disease in the spinal cord. She intends to breastfeed for a total of 6 weeks. She has multiple symptoms: fatigue. She has increased weakness in the right leg and has now, following the last attack during pregnancy, difficult with ambulation.

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Dr Leist: She was on glatiramer acetate during the pregnancy and preceding the pregnancy, because at the time, she wanted to become pregnant and they both thought that this would be an approach, even though this is an off-label approach. During the pregnancy, she has clearly stipulated that that would not be a treatment that is going to hold her in place. We have a 32-year-old new mother that has now myelopathic features; what is your approach?

Dr Miravalle: Unfortunately, here, we have another combination of clinical and paraclinical factors that tells us something about a poor prognosis, anywhere from her ethnicity, African American, to the unusual fact that she had a relapse during the pregnancy while being on glatiramer acetate. That is also telling us that there is a suboptimal response to her current disease-modifying treatment (DMT). Usually, as we all know, during the pregnancy period, patients are, from a relapse standpoint, relatively stable. The fact that the patient had a relapse during the pregnancy period while on DMT should not be ignored. I think this is a difficult conversation we will have to have with a patient like that, in terms of the need to initiate highly effective therapies, perhaps with intravenous (IV) monoclonal antibodies, and how that can potentially impact the breastfeeding period. That will be a patient that I will consider highly effective therapies again for many reasons.

Dr Leist: Dr Freedman, she had the relapse during her pregnancy. Would you consider giving her IV immunoglobulin (IVIG) or steroids preemptively before you move on to an additional therapy?

Dr Freedman: I think to start with, this lady had a plethora of bad red flags, even before we get into the pregnancy: she has had MS for 7 years, she is African American, she had 3 attacks in her last year prior to the pregnancy despite being on glatiramer acetate (GA). She kept the GA through the pregnancy, probably not unexpectedly, it was not controlling her beforehand. She had a high incidence of relapse before that, which usually predicates a high relapse rate following the delivery. GA has, in retrospect, been shown to be safe but has not been shown to be effective.

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Case Study 3: Potential Role for IVIG?[29,30]

Dr Freedman: The only trials that actually have been done as a controlled study was IVIG through the pregnancy and usually postpartum. I would have opted for IVIG but that is behind us now. I would try to convince her to try to stop breastfeeding, because we would not be able to assure her of any kind of safety to the infant with whatever we are going to now introduce because all of these medications will get into breast milk to some degree. We need to try to figure out if she is intent on having another baby soon, but I think the notion of IRT in her might actually be ideal because should she decide to get pregnant, we can always position that pregnancy usually within a time period of 1 of these treatments. We really want to nail down her disease early because she has a bad prognostic. Rather than go with another first-line or whatever, I think she warrants a more aggressive approach.

Conclusions

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Thank You

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Abbreviations

BMT = bone marrow transplantBT = blood testCIS = clinically isolated syndromeCDMS = clinically definite multiple sclerosisCNS = central nervous systemCSF = cerebrospinal fluidCV = cardiovascular monitoringDMT = disease-modifying treatmentEDSS = Expanded Disability Severity ScaleEMA = European Medicines AgencyFDA = US Food and Drug AdministrationGA = glatiramer acetateGd = gadoliniumGdE = gadolinium enhancedGM = gray matterHBVs = hepatitis B virus screeningHCVs = hepatitis C virus screeningHSCT = hematopoietic stem cell transplantationhyperR = hypersensitivity reactionIFN = interferonIM = intramuscularIR = infusion reactionIRT = immune-reconstitution therapyIS = immunosuppressionIVIG = Intravenous immunoglobulinMTI = magnetic transfer imagingMR = magnetic resonanceMRI = magnetic resonance imagingMS = multiple sclerosisNEDA = no evidence of disease activityO = ophthalmologyP-MSSS = Patient-Derived Multiple Sclerosis Severity ScorePPMS = primary progressive multiple sclerosisRIS = radiologically isolated syndromeRMS = relapsed multiple sclerosisRRMS = relapsing-remitting multiple sclerosisR-SPMS = relapsing secondary progressive multiple sclerosisSC = subcutaneousTBs = tuberculosis screeningU = urinalysis

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Related Links

Clinical Advances in Multiple Sclerosis https://www.medscape.org/sites/advances/ms Immune Reconstitution in MS: How Does This Impact Treatment Decisions? https://www.medscape.org/viewarticle/892112 Practical Perspectives on Clinical Controversies in MS: A Case-Based Approach https://www.medscape.org/viewarticle/898012 Expert Perspectives on New Data in MS From the 2018 Annual Neurology Meeting https://www.medscape.org/viewarticle/897713 Best of the Best: Highlights of Recent Data in MS https://www.medscape.org/viewarticle/895623

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