After a wash-out period of 2 months, fingolimod was started on the 18th of March 2015. Previous brain MRI (February 2015) did not show any signs of PML.
Three weeks later (10th April 2015), routine brain MRI at 1.5 T revealed PML-suspicious bifrontal confluent lesions with (sub)cortical involvement. Moreover, multiple milky- way-like Gadolinium enhancing and T2 weighted (T2w) hyperintense punctate lesions were detected by MRI in these areas (Figure 1). In addition, perilesional contrast enhance- ment around confluent PML-suspicious lesions suggestive of IRIS was detectable (Figure 2). Diffusion weighted MRI did not show intralesional hyperdiffusivity nor signs of restricted diffusion at the edge of the lesions (Figure 3); both of which are considered to be typical of PML .
Natalizumab is a disease-modifying therapy (DMT) used in relapsing-remitting multiplesclerosis (RRMS), licenced for use in patients with highly-active disease. It is an α4-integrin receptor antagonist that decreases activated T cell migration across the blood-brain barrier. 1 Natalizumab carries a risk of progressivemultifocalleukoencephalopathy (PML) - a risk that increases with duration of treatment; John Cunningham Virus (JCV) seropositivity and higher index values; and prior use of immunosuppression. 1 Patients may choose to withdraw fromnatalizumab to mitigate PML risk, or less commonly when natalizumab fails to control disease activity, or is poorly tolerated. Fingolimod has been commonly used as an option in those making the switch fromnatalizumab, but is associated with high rates of breakthrough clinical and/or radiological disease activity, although the risks may be lower with shorter washout periods. 2 Rituximab has been suggested as an alternative to fingolimod in patients discontinuing natalizumab due to high PML risk, however, rituximab is not licenced for the treatment of RRMS and is not available in some countries for this indication. 3
Multiplesclerosis (MS) patients treated with natalizumab often face the uncommon but severe complication of developing progressivemultifocalleukoencephalopathy (PML). PML may be further complicated by immune reconstitution inflammatory syndrome (IRIS) after the removal of the drug. Since both PML and IRIS are associated with high morbidity and mortality rates, early clinical and radiological diagnosis of these complications is of paramount importance. Here, we report a case of an adult male patient who was diagnosed with PML after receiving natalizumab therapy for 6 years for the treatment of MS. Upon cessation of natalizumab, he presented with a paradoxical worsening of clinical and radiological findings consistent with an inflammatory brain injury due to IRIS. He was treated with high dose corticosteroid therapy followed by a gradual improvement in clinical and imaging findings. This article illustrates the magnetic resonance imaging (MRI) features of natalizumab‑associated PML‑IRIS, along with a brief overview of its clinical features, complications and management strategies.
Recent onset of highly active MS, escalation of therapy to natalizumab or alemtuzumab following failure of oral medications 7 or switch fromnatalizumab to alemtuzumab or fingolimod due to a high risk of progressivemultifocalleukoencephalopathy 8,9 are common scenarios in which alemtuzumab is used in clinical practice. However, there is presently no information about the effectiveness of alemtuzumab in comparison to the more potent disease modifying therapies. Mixed-treatment analyses of alemtuzumab versus other licensed agents were performed during submissions to reimbursement agencies (e.g. the National Institute for Health and Care Excellence, UK) but public versions of these documents are heavily redacted. This much needed evidence is unlikely to emerge from randomised trials as the cost of such long-term multi-arm trials is prohibitive.
Abstract: In the context of an increasing repertoire of multiplesclerosis (MS) therapeutics, choosing the appropriate treatment for an individual patient is becoming increasingly challenging. Natalizumab, a humanized monoclonal antibody directed against alpha4beta1 integrin, has proven short-term and long-term efficacies in terms of relapse rate reduction, prevention of dis- ability progression, and reduction of magnetic resonance imaging-detectable activity. It is well tolerated and has further been shown to improve patients’ quality of life. Its use is limited by the risk of progressivemultifocalleukoencephalopathy (PML), which occurs at an overall incidence of 3.78 cases per 1,000 patients. Three major risk factors for the occurrence of natalizumab- associated PML have been identified: John Cunningham virus (JCV) seropositivity, prior use of immunosuppressants, and treatment duration $2 years. Therefore, in patients considered for natalizumab therapy, as well as in patients receiving natalizumab, effective control of MS activity has to be balanced against the risk of an opportunistic central nervous system infection associated with a high risk of significant morbidity or death. Discontinuation of natalizumab is an issue in daily clinical practice, since it is an option to reduce the PML risk. However, after cessation of natalizumab therapy, currently, there is no approved strategy for avoiding postnatalizumab disease reactivation available. In this paper, short-term and long-term safety and efficacy data are reviewed. Issues in daily clinical practice, such as selection of patients, monitoring of patients, and natalizumab discontinuation, are discussed.
Abstract: Natalizumab is a monoclonal antibody, representing a new class of medication for treating relapsing multiplesclerosis (MS). Conventional treatments include interferons, glatiramer acetate and chemotherapies such as mitoxantrone and cyclophosphamide. These therapies offer only modest clinical benefits and are commonly not tolerated due to side effects. Natalizumab has been proven in large-scale, blinded, randomized, controlled trials to have an exceptional effect on preventing relapses, decreasing the risk of sustained progression of disability, and increasing the rate of disease-free patients over a 24-month period compared to placebo. These trials led to the speedy approval of natalizumab for treating relapsing MS, but its use was halted a few months after its induction after several cases of progressivemultifocalleukoencephalopathy (PML), a fatal demyelinating disease affecting the central nervous system. After a long deliberation by an FDA advisory panel and strong support from the MS community, natalizumab was reapproved with stringent restrictions including patient, provider and site registration. Natalizumab is now considered second-line therapy for patients who have failed first-line agents such as interferon or glatiramer acetate. As little is known about additional risk factors for PML and other potential infections, patients and providers must work together to carefully decide if potential benefits outweigh these rare but potentially devastating complications.
Progressivemultifocalleukoencephalopathy (PML) is an opportunistic viral infec- tion of the central nervous system (CNS) ﬁ rst described in 1958 by Åström and colleagues. 1 PML, named after its pathological features, is a progressive multi- focal disease of white matter, which can now be thought of as the classical form of PML. The disease is caused by the JC polyomavirus (JCPyV). The prerequisite for PML is profound suppression of cell-mediated immunity, whether associated with diseases, such as HIV or lymphoproliferative malignancies, or treatment with immunosuppressive or immunomodulatory therapies (multiplesclerosis or rheu- matoid arthritis) or both (systemic lupus erythematosus). Epidemiological data for different PML subgroups is scarce and partly con ﬂ icting because there are no systematic national or international records of PML diagnoses and only a few population-based studies of PML incidence. During the 1980 ’ s and 1990 ’ s with the emergence of HIV in humans, PML was the most important opportunistic infection of the CNS in these patients and most PML cases occurred in this group. In recent times, PML has been increasingly diagnosed in patients treated with biological therapies such as mAbs which deplete lymphocytes or impede leuko- cytes traf ﬁ cking into the CNS. Interest in PML increased in 2005 when its association with the multiplesclerosis (MS) drug natalizumab (NTZ) was discovered 2 and MS patients have become an important population at possible
Despite the marked reduction in peripheral lymphocyte count, the incidence of serious infections in patients treated with ﬁngolimod was comparable to patients receiving placebo or IFN β1a in the phase III studies. Lower respiratory tract in- fections were reported slightly more often in ﬁngolimod- treated groups (5.7 –6.8%) than in groups receiving either placebo or IFN β1a (3.5–4.5%). 22 The 0.5-mg dose of ﬁngolimod was not associated with an increased risk for herpes virus infections in the FREEDOMS or TRANSFORMS groups. One case of fatal disseminated varicella in a patient without prior exposure and one case of fatal herpes simplex encephalitis occurred in the 1.25-mg ﬁngolimod group in the TRANS- FORMS study. Opportunistic infections such as cryptococcus, toxoplasmosis, and disseminated histoplasmosis were not seen with ﬁngolimod treatment in clinical trials. A case of progressivemultifocalleukoencephalopathy was recently re- ported in a John Cunningham virus- (JCV-) seropositive patient who switched fromnatalizumab to ﬁngolimod. 31 Due to the limited details available, the contribution from ﬁngolimod is uncertain. The in ﬂuence of prior immunosuppressant use on risk of infection with ﬁngolimod remains unclear. The inci- dence of infections seen in phase III studies did not correlate with the degree of ﬁngolimod-induced lymphopenia. 32
Abstract: Targeting sphingosine-1-phosphate pathway with orally available immune-modulatory fingolimod (Gilenya™) therapy ameliorates relapsing–remitting multiplesclerosis (RRMS) by decreasing relapse rate as shown in FREEDOMS and TRANSFORMS. Fingolimod has also been shown to be superior to interferon-beta therapy as evidenced by TRANSFORMS. Albeit multiple benefits in treatment of multiplesclerosis including high efficacy and ease of admin- istration, potential untoward effects such as cardiotoxicity, risk of infection, and cancer exist, thus mandating careful screening and frequent monitoring of patients undergoing treatment with fingolimod. This review outlines mechanism of action, observations, side effects, and practice guidelines on use of fingolimod in treatment of RRMS.
In addition to the authors, the following investigators participated in the International NatalizumabMultipleSclerosis Trial (principal inves- tigators are in boldface type): Institute of Neurology, London (MRI Analysis Center) — G.J. Barker, D.G. MacManus, C. Webb, C. Middleditch, S. Lewis, T. Pepple, E. Riddle, C. Coombs; University of California at Davis, Sacramento — M. Agius, D. Richman, J. Adams, M. Buonocore; University of Nebraska Medical Center, Omaha — J. Al-Omaishi, K. Markopoulou, K. Healey, P. Sorensen; Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom — D. Bates, J. Forsyth, J. Curlis, P. English; University Hospital Queens Medical Centre, Nottingham, United Kingdom — V. Orpe, T. Jaspen; University of Washington, Seattle — J. Bowen, M. Chang, H. Lew, M. Burke, T. Richards; Mayo Clinic, Scottsdale, Ariz. — J.L. Carter, D. Dodick, J. Takata, M. Malikowski, K. Nelson; Washington University School of Medicine, St. Louis — D.A.H. Cross, J. Trotter, D. Derrington, J. Lauber, C. Mar- tinez, G. Foster, T. Conturo; University of British Columbia, Vancouver, Canada — V. Devonshire, J. Oger, L. Wang, W. Morrison, L. Costley; North Staffordshire Royal Infirmary, Stoke on Trent, United Kingdom — C. Hawkins, C. Mathews, C. Gibson; Hospital for Joint Diseases, New York — J. Hebert, I. Rozentsvit, L. Capolino, J.P. Kelly; Carolinas Medical Center, Charlotte, N.C. — M. Kaufman, S. Putman, A. Diedrich, R. Follmer, S. Dombrow- ski, C. Graves, B. Harwick; Wayne State University, Detroit — A.C. Tselis, M. Din, C. Caon, M. Cochran, Z. Latif, R.P. Lisak, M. Zvartau-Hinds; Foothills Hospital, Calgary, Alta., Canada — L. Metz, J. Scott, D. Patry, M. Yeung, J. Heuser, C. Wallace, S. Curtis; Maimonides Medical Center, Brook- lyn, N.Y. — A. Miller, E. Drexler, M.J. Keilson, K. Bruining, A. Schneider, R. Wolintz, L. Sciarra, H. Oltazewska; Rocky Mountain MultipleSclerosis Center, Englewood, Colo. — R.S. Murray, A. Bowling, R.E. Kramer
The presence of structural and/or functional mi- crovascular changes within lesions of the CNS can be inferred from the identification of angiographic abnormalities (arteriovenous shunting and paren- chymal blush) and abnormal contrast enhancement on CT or MR studies, despite the often unclear pathologic substrate for these alterations. In the past, PML has been described as angiographically occult; however, among a group of six patients with pathologically proved PML, we observed four cases of lesion-related arteriovenous shunting. With one exception these lesions failed to enhance on CT or MR studies. We hoped to gain some insight into the pathophysiological derangements in the ce-
The following people participated in the study (names of principal investigators are in bold): Data and Safety Monitoring Board — C. Pol- man (chair), Vrije Universiteit Medical Center, Amsterdam; J. Camm, St. George’s Hospital Medical School, London; M. Daumer, Sylvia Lawry Centre for MultipleSclerosis Research, Munich; F. Lublin, Corinne Goldsmith Dickinson Center for MultipleSclerosis, New York; Steering Committee — L. Kappos (chair), University Hospital, Basel; J. Antel, Le Centre Universitaire de Santé McGill, Montreal Neuro- logical Institute, McGill University, Montreal; G. Comi, San Raffaele Hospital, Milan; A. Korn, Novartis Pharmaceuticals Corporation, East Hanover, NJ; X. Montalban, Hospital Vall d’Hebron, Barcelona; P. O’Connor, St. Michael’s Hospital, Toronto; E.W. Radue, Uni- versity Hospital, Basel; Study Group — Canada: J. Antel, L. Durcan, A. Baror, Le Centre Universitaire de Santé McGill, Montreal Neuro- logical Institute, McGill University, Montreal; P. Duquette, G. Bernier, Centre Hospitalier Universitaire–Notre-Dame Hospital, Montreal; M. Freedman, H. MacLean, F. Costello, Ottawa Hospital, Ottawa; P. O’Connor, T.A. Gray, M. Hohol, St. Michael’s Hospital, Toronto; J. Oger, S. Hashimoto, V. Devonshire, UBC Hospital, Vancouver; Denmark: P.S.G. Sørensen, P. Datta, J.C. Faber-Rod, Neurocentret, Rigshospitalet, Copenhagen; J. Frederiksen, S. Knudsen, V. Petrenaite, Kobenhavns Amts Sygehus, Glostrup; Finland: M. Färkkila, J. Halavaara, H. Harno, Postitalon Lääkäriasema Oy, Helsinki; I. Elovaara, H. Kuusisto, J. Palmio, Finn-Medi Tutkimus Oy, Tampere; L. Airas, V. Kaasinen, M. Laaksonen, Turku University Hospital, Turku; France: P. Vermersch, Hôpital Roger Salengro, Lille; J. Pelletier, L. Feuillet, L. Suchet, Hôpital de la Timone, Marseille; Germany: E. Mauch, C. Gunser, K. Oberbeck, Akademisches KH der Universität Ulm, Schwendi; P. Rieckmann, M. Buttmann, M. Klein, Julius-Maximilians-Universität, Würzburg; Italy: A. Ghezzi, M. Zaffaroni
Among the current therapy groups, CDMF patients were more likely than CF patients to report abdominal pain, diarrhea, flushing, flu-like symptoms, and nausea as treatment side effects (see Table 4). The reported occur- rence of the remaining side effects was similar between the two groups. Logistic regression model results sum- marizing the treatment effect in predicting the occur- rence of each side effect are presented in Table 5. After adjusting for covariates, CDMF patients had an increased risk of experiencing abdominal pain (odds ratio, i.e. OR 15.79), flushing (OR 12.51), and any of the solicited side effects (OR 7.49). Results from the univariable model and the multivariable model yielded similar results. Other side effects for which a pronounced increase in risk was observed for CDMF patients after adjustment were diar- rhea (OR 2.30) and nausea (OR 3.16).
This was an observational, single-arm prospective study and, as such, has recognized limitations. Since the data presented are longitudinal comparisons within the same population, it is uncertain whether the reported improvements in PROs are a direct result of treatment with natalizumab. However, evidence from randomized clinical trials has shown that, in contrast to natalizumab- treated patients, the HRQoL of MS patients receiving placebo worsens over time . Some of the PRO data could also be affected by recall bias, as the patients were asked to consider a period of up to 4 weeks in the past. In addition, results could be affected by selection bias, as the full set of 12-month data was only available for 333 of the 1,275 patients who were enrolled in the study. However, most of the patients were excluded from ana- lysis because they did not meet study eligibility criteria. In addition, a sensitivity analysis comparing the demo- graphics and characteristics of the patients completing the 12-month survey found that they were not signifi- cantly different from those of the patient group complet- ing the baseline survey. Furthermore, a sensitivity analysis that included data for all available time points from all patients who received at least one natalizu- (A)
Currently, a small number of conditioning protocols have been proposed and used in MS: the most protocol used in Europe is BEAM. This regimen includes 300 mg/ m 2 carmustine (1,3-bis[2-chloroethyl]-1-nitrosourea) at day -7,200 mg/m 2 etoposide and 200 mg/m 2 cytarabine (ara- binosylcytosine) from day -6 to day -3, and 140 mg/m 2 melphalan at day -2. BEAM is considered as an inter- mediate-intensity regimen. However, although effective on MRI and clinical grounds it has some drawbacks [6, 7]. In particular, there is a long-term risk of cancer associated with the treatment especially related to drugs such as eto- poside and melphalan . BEAM is a myeloablative reg- imen, inducing a profound decrease of WBC and platelets, which prolongs for 8–14 days. In this period, early toxicity is common, with fever in almost all the cases, sepsis in the majority of patients, frequent Cytomegalovirus reactivation and occurrence of other infections. Moreover, in an auto- immune disorder such as MS, a lymphoablative regimen is probably more appropriate than a deeply myeloablative therapy such as BEAM. Therefore, while at the moment BEAM plus anti-thymocytes globulin (ATG) has to be considered the best treatment schedule in the AHSCT context, the search of other conditioning regimens with a better safety profile, with more lymphoablative than my- eloablative properties and a similar efficacy has to be pursued. Currently in Italy a trial with a new low-intensity conditioning regimen that aims to evaluate the safety profile, the activity on MRI and on clinical progression is ongoing: this new ‘‘Light’’ regimen includes cyclophos- phamide 120 mg/kg followed by ATG at 3.75 mg/kg/day for 2 days .
archetype RR remains confined in the kidneys of most healthy individuals and that rearrangements which confer neurotro- pism need to occur prior to viral migration to the brain to destroy the myelin-producing glial cells. Whether JCV can reach the brain and establish latency in the central nervous systems (CNS) of otherwise-healthy individuals are matters of debate. While some investigators detected JCV DNA in 28 to 68% of frozen (8, 27) and 18 to 71% of formalin-fixed, paraf- fin-embedded (FFPE) (4, 7, 20) brain samples of patients with- out PML, others reported negative results (3, 6, 10, 23). Clearly, characterizing JCV sites of latency is imperative in the prevention of viral reactivation and PML. Recently, a group of PML patients has emerged among those treated with mono- clonal antibodies, including natalizumab (13, 17, 26), efali- zumab (16, 19a), and rituximab (5), for multiplesclerosis, psoriasis, hematological malignancies, and rheumatologic diseases. Mechanisms of JCV reactivation in these patients has yet to be defined. To better understand JCV organ tropism and characterize the types of JCV RRs in different compartments, we used archival pathology samples to detect JCV DNA and proteins and to analyze JCV RRs in various organ systems in HIV-positive individuals with and without PML and in HIV- negative subjects.
were required to have an active course of disease (one or more relapses in the previous year or two or more in the previous 2 years) and IFN β or GA was to be stopped at least 3 months before the trial. Randomization was conducted in a 1:1:1 ratio to the high-dose (fingolimod 1.25 mg) or the low-dose (fingolimod 0.5 mg) treatment group or to placebo, each administered once daily. The primary clinical outcome measure was the ARR, defined as the number of confirmed relapses per year. A confirmed relapse needed to be associ- ated with an increase of at least 0.5 points in the EDSS score, 1 point in each of two EDSS functional system (FS) scores, or 2 points in one EDSS FS score. The key secondary clinical outcome measure was time to confirmed disability progres- sion after 3 months, as measured in an increase of 1 point in the EDSS score (or 0.5 points if the baseline EDSS score was 5.5) confirmed after 3 months. 28 In addition, clinical
The authors’ affiliations are as follows: the Mellen Center, Cleveland Clinic, Cleveland (J.A.C.); Vrije Universiteit Medical Center, Am- sterdam (F.B.); the Neurology Clinic, San Raffaele Hospital, University Vita e Salute, Milan (G.C.), the Regional MultipleSclerosis Center, Presidio Ospedaliero di Montichiari, Montichiari (R.C.), and the MultipleSclerosis Center of the Veneto Region, Department of Neuroscience, University Hospital of Padua, Padua (P.G.) — all in Italy; the Department of Neurology, Heinrich-Heine University, Düs- seldorf (H.-P.H.), and Neurologisches Facharztzentrum Berlin, Klinisches Studienzentrum, Berlin (K.T.-W.) — both in Germany; Re- gional MS Center, Center for Neurological Disorders, Milwaukee (B.O.K.); the Neuroimmunology Unit, Hospital Vall d’Hebron, Barce- lona (X.M.), and the MS Unit, Servicio de Neurologia, Hospital Universitario Virgen Macarena, Sevilla (G.I.) — both in Spain; the De- partments of Neurology and Research (CRMBM), CHU Timone, Marseille, France (J.P.); Novartis Pharma (A.V.) and the Departments of Neurology and Research, University Hospital (L.K.) — both in Basel, Switzerland; and Novartis Pharmaceuticals, East Hanover, NJ (J.J., T.S., S.W., S.A.).
How do these mutations occur in PML and why, despite a very high prevalence of JCV, do only a small proportion of immune deficient patients develop PML? Absence of clustering of the mutations on the viral phylogenetic tree suggests that they arise independently in individual patients rather than persist in the general populations as pathogenic viral variants. It is worth noting that this hypothesis appears to be strongly supported by the original observation of Loeber and Dorries  where the investigators reported the isolation of two viral strains from kidney and brain of the same PML patient. The genome of the virus isolated from the brain was almost identical to that isolated from the kidney with two exceptions; presence of phenylalanine instead of leucine in position 55 and a rearrangement of the regulatory region. Previously no significance could be attached to the L55F mutation and that observation led to the generation of the hypothesis on the sole importance of viral control region rearrangement in ‘‘PML-genic’’ adaptation of the virus. Based on our findings we would like to propose that VP1 mutations play a very significant role in the mechanism of PML emergence. Once a specific mutation affecting sialic acid binding occurs it allows virus to spread to the brain and infect oligodendrocytes. The fact that the mutant virus was not detected in the kidney  may suggest that that particular change in glycan binding does not offer any selective advantage to the mutated virus in kidney. The mutations might have occurred and hence allowed the virus to establish the residence in the brain under the conditions of immune suppression shortly or long before the PML. Since no viral replication was detected in brains of asymptomatic individuals we believe it is unlikely that compartmentalized evolution (i.e. intra CNS) prior to PML development could account for the presence of mutated VP1 in CNS of PML patients. However, the issue of JCV latency in normal brain still remains controversial so it is still formally possible that non-mutated virus had entered the brain and mutations arose in the brain and not periphery, e.g. kidney.