People with multiple sclerosis (pwMS) on treatment with natalizumab who are John Cunningham virus (JCV) seropositive are at high risk of developing progressive multifocal leukoencephalopathy (PML) [1,2]. The risk is particularly high in those who have (i) been on the drug for longer than 12 months, (ii) had exposure to immunosuppressive therapies in the past, and/or (iii) a high anti-JCV antibody index [1,2].
With the recent licensing of several other MS disease-modifying therapies it is now possible to lower the risk of PML in pwMS who are JCV-seropositive and on natalizumab by switching them to another disease modifying treatment (DMT). One of the caveats of this strategy is so called ‘carry-over PML’ [3,4] PML that develops a few months after having stopped natalizumab and started on a different DMT. In these cases, PML had probably developed already without causing symptoms whilst the patient was still on natalizumab, or shortly after stopping natalizumab.
Carry-over PML can be explained by the complex pathogenesis of PML, which takes months to years to develop [1]. Firstly, wild-type JCV has to acquire several mutations in its genome that presumably make the virus neurotropic and pathogenic; these mutations typically occur in the viral capsid protein and regulatory region of the JC viral genome [5]. The body compartment where the JCV resides and acquires these pathogenic mutations is not known. However, once the virus becomes pathogenic and migrates to the brain (if it is not already resident in the brain), it infects glial cells, causes lytic infection and spreads locally as well as to other areas of the brain to cause PML. As most cases of carry-over PML identified to date have occurred within 6 months of switching treatments [3], with only one reported case presenting at 8 months [3], the at-risk period for carry-over PML is probably less than 12 months after switching from natalizumab to another DMT.
It is very difficult to quantify the risk of carryover PML as the denominator is not known. We are aware of 15 cases of carry-over PML from natalizumab [3], i.e. 15 JCV+ve patients developing PML within 12 months after transitioning over from natalizumab. In addition, there have been five pwMS who have developed PML on fingolimod with no prior natalizumab exposure (Novartis, personal communication). These 20 cases have occurred on a denominator of over 125,000 patients treated with fingolimod worldwide [6]. However, the proportion of those with prior natalizumab exposure is unknown making it difficult to calculate specific risks and to draw any firm conclusions, except to say that carry-over PML post-natalizumab is much more likely to occur on fingolimod than non-carryover, or de novo, PML.
The majority of pwMS treated with natalizumab in the UK have had rapidly evolving severe MS and are at increased risk of rebound MS disease activity typically occurring 3-4 months after stopping natalizumab [7,8]. Rebound activity coincides with the drop in plasma blood levels of natalizumab and the desaturation of the α4β1-integrin antigen, natalizumab’s target, on the surface of lymphocytes [9]. α4β1-integrin binds to vascular cell adhesion molecule-1 (VCAM-1), expressed on the endothelium, and is responsible for assisting in the trafficking of lymphocytes across the blood-brain-barrier.
To prevent rebound disease activity we recommend starting a different DMT as soon as possible after the last infusion of natalizumab, preferably within 4 weeks of the last dose of natalizumab [10]. Natalizumab wash-out periods of longer than 4 weeks have been associated with higher recrudescence of disease activity in the form or relapses and/or Gd-enhancing MRI activity. We tend to use fingolimod as the follow-on agent given the evidence that it is effective in preventing rebound disease activity, provided it is started within 4 weeks of the last natalizumab infusion [11,12]. Published data on the use of pulsed corticosteroids, interferon beta and glatiramer acetate has shown that these agents are not capable of preventing rebound activity [13]. Similarly, real-life data recently presented at meetings indicate that breakthrough disease activity occurs in a proportion of pwMS treated with either dimethyl fumarate [14] or teriflunomide [15].
If a person with MS does develop carry-over PML on fingolimod, a once daily oral DMT, simply stopping this drug allows immune reconstitution and trafficking of cytotoxic T-cells into the central nervous system to counteract and clear JCV [16]. A problem arises, however, if alemtuzumab (an anti-CD52 antibody) or other induction therapies (cladribine, mitoxantrone, haemopoietic stem cell transplant) ar being considered as the next DMT following cessation of natalizumab. These drugs induce long-term immunosuppressive effects (induction) with delayed immune reconstitution. The effects of induction DMTs cannot be reversed quickly. Therefore, if a person with MS at-risk of PML switches from natalizumab to, for example, alemtuzumab and develops carry-over PML they are at very high risk to succumb to PML due to their significantly compromised immune system following induction. . Reconstitution of the T-cell compartment after administration of alemtuzumab takes over 6 months and both CD4+ and CD8+ cell counts rarely return to normal [17]. Therefore, these patients are unable to mount the early cytotoxic CD8+ T-cell response required to clear the JCV infection. Survival from PML is strongly linked to the cytotoxic CD8+ T-cell response against JCV [18].
Genzyme, the company that markets alemtuzumab, has reported one fatal case of carry-over PML, in a patient who switched from natalizumab to alemtuzumab (personal communication; Professor Giovannoni). Should such circumstance arise in the future, which is likely, an immune stimulant such as IL-2 and/or G-CSF, or peripheral-blood progenitor cell transplantation from an HLA-identical JCV-seropositive donor might be tried. The aim is to stimulate the proliferation of autologous, or provide allogeneic, anti-JCV CD8+ cytotoxic cells that would then need to traffic to the brain to clear the JCV infection. Should carry-over PML develop within 3 months of the last natalizumab infusion we would also recommend plasma exchange to lower residual circulating levels of natalizumab below 1ng/ml thereby avoiding the block due to remnant natalizumab of trafficking donor (and self) T-cells into the CNS [9].
A safer option with regard to carry-over PML risk would be to washout natalizumab for 6 months, thereby allowing immune reconstitution of the central nervous system to occur. Doing this would rely on the immune system to detect subclinical PML, which could then trigger an immune reconstitution inflammatory syndrome (IRIS) [16]. An obvious downside of this strategy is that it will also allow MS disease activity to return, and possibly rebound above levels of activity seen before starting natalizumab treatment [7].
Our preferred option is therefore to bridge patients with a maintenance therapy for a period of time to lower the risk of carry-over PML. We are currently using fingolimod as the bridging DMT based on its proven efficacy after natalizumab. Prior to starting fingolimod we perform (i) a brain MRI scan and (ii) a CSF analysis to rule out the presence of JCV DNA and thereby exclude asymptomatic PML. As a note of caution when interpreting the results there is a significant number of false negative JCV DNA results [19–21]. The latter depends on the sensitivity of the diagnostic assay used. We then start fingolimod usually 2-4 weeks after the last natalizumab infusion. At present we propose a bridging period of 6-12 months; the longer the bridge the lower the risk of carry-over PML.
One could argue that as it is likely the person concerned is being treated with natalizumab because they had rapidly evolving severe, or aggressive, MS, switching them to a lower efficacy drug such as fingolimod for 6-12 months would be delaying them access to the potential benefits of a potentially more effective induction therapy. We don’t think this is a major issue as several studies have now shown that fingolimod prevents rebound in the majority of patients switching from natalizumab to fingolimod, provided the fingolimod is started within 4 weeks after the last dose of natalizumab [11,12]. Our practice and advice is meant to pragmatic and will need to be personalised based on the circumstances of the individual with MS. As a centre we have no problem with a well-informed patient not wanting to bridge with fingolimod, choosing and consenting to be treated with an induction therapy without a natalizumab washout. The shared decision is all about risks and benefits; if induction therapies had a reversible mode of action this discussion would be superfluous. However, as it is very difficult to quantify the precise risk of carry-over PML the decision is likely to be based on perceived risk and the consequences of carryover PML in a person who has been treated with an irreversible induction therapy.
It is important to be aware that the risk of PML after cessation of natalizumab is unlikely to disappear completely, despite a bridge. As mentioned above the pathogenesis of PML is complex, and if JCV has started to acquire pathogenic mutations these are unlikely to be reversed by simply stopping natalizumab. Therefore, we counsel pwMS who are JCV seropositive and have been on natalizumab before switching to another agent that their risk of getting PML in the future may be higher than in someone who has not been exposed to natalizumab.
In addition to testing for JCV DNA in the CSF, a test to detect the level of L-selectin (CD62L) expressing CD4+ T has been proposed for pwMS who are on treatment with natalizumab to predict their future risk of PML. CD62L is involved with α4β1-integrin in the rolling and transmigration of lymphocytes across the blood brain barrier and has been noted to fall below a threshold level in asymptomatic PML cases [22,23]. Levels of L-selectin below a certain threshold have been shown to increase the risk of PML almost 55-fold [23]. The protocol to detect L-Selectin is rather complex, and its role in the risk management of PwMS has yet to be determined. In addition, others have not been able to confirm the utility of L-selectin as a reliable biomarker for predicting PML risk in natalizumab-treated patients [24].
There are a few caveats to take into consideration when switching from fingolimod to alemtuzumab after the bridging period. Firstly, fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator that traps lymphocytes in lymph nodes; it works by internalising the S1P receptor and preventing it from being recycled to the lymphocyte membrane. Without the surface expression of S1P receptors lymphocytes are unable to egress from lymph nodes [25]. Data from animal studies suggest intravenous alemtuzumab targets circulating lymphocytes and is less effective at depleting lymphocytes in lymph nodes [26]. Therefore, we recommend stopping fingolimod, waiting 4 weeks, checking peripheral lymphocyte counts to make sure they are returning towards normal before giving the first course of alemtuzumab. We do not recommend a prolonged wash-out after fingolimod as rebound MS activity has been reported after stopping fingolimod [27][28]. Another reason for doing a short fingolimod washout is to exclude the remote possibility of persistent post-fingolimod lymphopenia. A few cases of persistent lymphopenia have been reported in pwMS treated with fingolimod for many years [29]. Whether persistent lymphopenia can occur after as little as 12 months of fingolimod exposure is unknown. However, the lymphocyte count should recover towards the normal range after fingolimod cessation and before administering alemtuzumab. We suggest a total lymphocyte count of at least 0.8 x 109/L (WHO grade 2 lymphopenia cut-off).
In conclusion, as the complexity of MS disease-modifying therapy increases, the decision-making around sequencing and switching of therapies becomes more difficult. In an ideal world decision making around treatments should be evidence-based. However, as long as the evidence is not available a pragmatic approach is needed. We are sharing our pragmatic approach to help other clinicians make decisions when limited evidence is available. Our motivation is to reduce the risk of using the highly effective drug natalizumab in pwMS who are JCV seropositive; we would like to prevent unnecessary morbidity and mortality as a result of PML.