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Classifying PML risk with disease modifying therapies

Multiple Sclerosis and Related Disorders, Volume 12, February 2017, Pages 59–63

Abstract

Objective

To catalogue the risk of PML with the currently available disease modifying therapies (DMTs) for multiple sclerosis (MS).

Background

All DMTs perturb the immune system in some fashion. Natalizumab, a highly effective DMT, has been associated with a significant risk of PML. Fingolimod and dimethyl fumarate have also been unquestionably associated with a risk of PML in the MS population. Concerns about PML risk with other DMTs have arisen due to their mechanism of action and pharmacological parallel to other agents with known PML risk. A method of contextualizing PML risk for DMTs is warranted.

Methods

Classification of PML risk was predicated on three criteria:: 1) whether the underlying condition being treated predisposes to PML in the absence of the drug; 2) the latency from initiation of the drug to the development of PML; and 3) the frequency with which PML is observed.

Results

Among the DMTs, natalizumab occupies a place of its own with respect to PML risk. Significantly lesser degrees of risk exist for fingolimod and dimethyl fumarate. Whether PML will be observed with other DMTs in use for MS, such as, rituximab, teriflunomide, and alemtuzumab, remains uncertain.

Discussion

A logical classification for stratifying DMT PML risk is important for both the physician and patient in contextualizing risk/benefit ratios. As additional experience accumulates regarding PML and the DMTs, this early effort will undoubtedly require revisiting.

Highlights

  • To date, several disease modifying therapies (DMTs) have been associated with progressive multifocal leukoencephalopathy (PML).
  • Both physicians and patients frequently conflate the risk of PML observed with the various DMTs despite very different incidence rates.
  • DMTs can be classified in three separate risk categories based on three factors: 1) whether PML is observed in the context of treating multiple sclerosis with that DMT or only when it is employed in the treatment of other conditions; 2) the latency from the time of drug initiation to the development of PML; and 3) the incidence rate of PML with the agent.
  • A risk stratification table assists physicians in putting the risk of PML with DMTs into a readily understood framework.

Keywords: Disease modifying therapy, Multiple sclerosis, Progressive multifocal leukoencephalopathy, Natalizumab, Fingolimod, Dimethyl fumarate, Rituximab.

1. Introduction/background

With rare exception, progressive multifocal leukoencephalopathy (PML) evolves in the context of an underlying immunological abnormality, almost always, an impairment in cell-mediated immunity. In a survey of 230 published and unpublished cases from 1958 through 1984, more than 60% occurred in association with hematological malignancies (Brooks and Walker, 1984), most frequently Hodgkin's disease and chronic lymphocytic leukemia, the same underlying predisposing disorders in the seminal publication initially describing PML (Astrom, Mancall et al., 1958). In that survey, other predisposing disorders observed in descending order included immune deficiency disorders, granulomatous and inflammatory disorders, myeloproliferative disease, carcinoma, and undetermined causes (Brooks and Walker, 1984). Within the first decade of the AIDS pandemic, HIV/AIDS was recognized as a major predisposing disorder for PML ultimately occurring in about 5% of all AIDS patients (Berger et al., 1987) and responsible for more than 56% of all PML between 1979 and 1987 (Holman et al., 1991). Surprisingly, despite the large number of individuals with multiple sclerosis (MS) treated with a wide variety of broadly immunosuppressive regimens, including high dose corticosteroids, azathioprine, and cyclophosphamide, prior to the era of disease modifying therapies (DMTs) in 1993, no cases of PML in MS had been observed until 2005 when two individuals who had received both natalizumab and interferon-β1a in a pivotal trial of natalizumab were described (Kleinschmidt-DeMasters and Tyler, 2005, Langer-Gould et al., 2005). Subsequently, it was recognized that natalizumab alone was sufficient to cause PML. As of September 7, 2016, 685 cases of natalizumab-associated PML have been reported (Biogen, 2016a and Biogen, 2016b). The ability of natalizumab to prevent effective CNS immunosurveillance was initially considered to be the underlying explanation for the occurrence of PML with this agent (Berger and Koralnik, 2005); however, subsequent studies suggested that the explanation for PML with natalizumab may be more complex.

Until the recognition of PML with other DMTs, namely, fingolimod and dimethyl fumarate, the disorder was considered to be a unique adverse event occurring only with natalizumab in the MS population. Following the observation that DMTs other than natalizumab can result in PML, physicians have had to explain the nature of the disorder and contextualize the risk of PML to patients in whom the use of these and other DMTs are contemplated for use in the treatment of their MS. The initial effort to catalogue the risk of PML with immunosuppressive agents was predicated on using three criteria, specifically, whether the underlying condition being treated predisposes to PML in the absence of the drug, the latency from initiation of the drug to the development of PML, and the frequency with which PML is observed (Zaheer and Berger, 2012). This initial categorization of PML risk with immunosuppressive therapy occurred before the recognition of PML with DMTs other than natalizumab. A subsequent iteration of the PML risk table included fingolimod and dimethyl fumarate (Chahin and Berger, 2015), but the available data for each of the criteria employed for classification was limited. The increased experience with DMT-associated PML permits a recalculation of this categorization of the PML risk.

2. Methods

The criteria used for the table includes: 1) whether the underlying condition being treated predisposes to PML in the absence of the drug; 2) the latency from initiation of the drug to the development of PML; and 3) the frequency with which PML is observed. The rationale for employing these specific criteria include the following. First, if PML occurs with a specific therapeutic agent in the treatment of a disease, such as, MS, with which no prior cases of PML had been previously reported, it heightens concern that the therapy was responsible for the PML rather than immune dysfunction or other reasons related to the underlying disorder. An increased risk of PML with certain disorders, such as, B cell malignancies, systemic lupus erythematosus, and sarcoidosis, irrespective of their treatment, has been well recognized (Brooks and Walker, 1984). The underlying mechanisms responsible for the association of these disorders with PML remain poorly understood. It has been suggested that in these disorders, activated B cells which harbor JCV and promote viral replication and neurotropism via genetic transformation contribute to the heightened risk of PML (Major et al., 1992, Major, 2010). Second, it was reasoned that in light of the ubiquitous presence of JCV in the otherwise normal population (Knowles et al, 2003, Berger et al, 2013, and Plavina et al, 2014), that there are likely multiple, relatively high barriers to the development of PML. If a therapeutic agent is responsible for setting in motion the events that lead to PML, a period of time needs to elapse to permit the barriers to the development of the disorder to occur. Among the sequence of events that have been proposed as being altered by therapy include evolution of a neurotropic variant of JCV, increased viral expression, facilitation of brain entry and glial cell infection, and failure of immunosurveillance. These events seem unlikely to occur in a period days or weeks, but likely require many months. Third, logic dictates that a high incidence rate of PML with a DMD represents a very different risk than an incidence rate that is many orders of magnitude lower, such as, with fingolimod and dimethyl fumarate.

3. Results

The table employs the three classifications for PML risk, I-high risk; II-low risk; and III – very low or no risk. The only Class I agent is natalizumab. Class II agents include dimethyl fumarate and fingolimod which are regarded to have a low, but real, risk for PML with incidence rates above 1:10,000. Class III agents, alemtuzumab, mitoxantrone, rituximab, and teriflunomide, possess a potential risk of PML, though no cases of PML have been observed in the MS population with their use. Drugs in this class have either been associated with PML when used in other contexts or have a related compound with which PML has been observed. Class IV agents, including glatiramer acetate and the interferon-βs, have no association with PML.

Daclizumab is a humanized monoclonal antibody that binds to CD25, the alpha subunit of the IL-2 receptor of T-cells. Though approved for use in MS only in 2016, it had been available for prophylaxis of renal transplant rejection in conjunction with corticosteroids and cyclosporine between 1999 and 2008 when it was withdrawn from the market for this indication. The precise mechanisms of action remain uncertain, but its salutary effect in MS has been postulated to be the consequence of shifting the immune balance in favor of regulatory cells and upregulating CD56bright NK cells (Weindl and Gross, 2013). To date, there have been no reported cases of PML with daclizumab either during its use in preventing acute renal transplant rejection or in the short time that it has been employed in treating MS.

4. Discussion

There are currently 13 DMTs that are FDA approved for MS. To date there are no reports of PML with glatiramer acetate. Among the five interferon-βs approved for treatment of MS, there is but one case reported with interferon-β1a intramuscular monotherapy in an MS patient; however, that patient was demonstrated to have a low CD4 lymphocyte count and decreased immunoglobulins consistent with common variable immunodeficiency, an disorder known to predispose to PML (Lehmann et al., 2015). Indeed, both interferon-α and interferon-β have been proposed as treatments for PML due to their antiviral activity. However, interferon-α failed to demonstrate any efficacy in AIDS-related PML (Berger et al., 1992). Interferon-β failed to have a detectable effect JC viruria in an MS population (Miller et al., 2012), although one study found a decrease in the frequency of JCV viremia (Delbue et al., 2007). Despite extensive use over two decades, there has been no signal for PML with either interferon-β or glatiramer acetate.

4.1. Class I Agents

Class I agents include only natalizumab. In prior versions of this chart (Zaheer and Berger, 2012 and Chahin and Berger, 2015), efalizumab, an anti-LFA 1 (CD11a), was also included in this class of agents; however, while contemplated as a possible treatment of MS, it was used only in psoriasis and removed from the market shortly after the observation of the association with PML. The incidence rate of PML in patients treated with natalizumab is very high. There have been 685 confirmed cases of PML with natalizumab as of September 7, 2016 (Biogen, 2016a and Biogen, 2016b). Considering all patients treated with natalizumab regardless of duration of therapy, presence of JCV antibody seropositivity, or prior immunosuppressive use, reveals that the incidence of PML exceeds one in 250 (4.22/1000 with confidence intervals of 3.91–4.51/1000) (Biogen, 2016a and Biogen, 2016b). The incidence of PML is very low with natalizumab in the first 12 months of infusion, though it has been observed within 8 months of drug initiation.(Biogen, 2016a and Biogen, 2016b; Prosperini et al., 2016) Curiously, the risk of developing PML early in the course of treatment with natalizumab may be higher in an older (>44 years) population (Prosperini et al., 2016). The age range of all natalizumab associated PML cases is 22–73 years (mean and median 45 years) compared to an age range of overall natalizumab use of 6–85 (mean and median 43 years). Using risk stratification measures that employ duration of therapy greater than 24 months, prior immunosuppressant use, and JCV antibody positivity fully implemented by January 2012 when the latter was added to the product label should have resulted in a significant decrease in the incidence of PML (Cutter and Stuve, 2014, Werner and Huang, 2016). Although there is an inflection of the PML incidence curve (Campagnolo et al., 2016) appears subtle. Additional methods to determine PML risk with natalizumab may increase sensitivity, such as, determining L-selectin expression on CD4 lymphocytes (Schwab et al., 2016) or assaying lipid-specific IgM bands in CSF (Villar et al., 2015), but these measures will require greater validation before they are widely implemented.

The pathophysiological mechanisms that underlie the development of PML with natalizumab remain poorly understood. Natalizumab is a humanized monoclonal antibody against α4β1 integrin and α4β7 integrin. It is the activity directed against α4β1 integrin that is responsible for its effect in MS as it prevents the entry of inflammatory cells into the CNS, whereas, that directed against α4β7 integrin accounts for its efficacy in inflammatory bowel disease by preventing the entry of these cells into the gut. To date, there have been no reported cases of PML with vedolizumab, a monoclonal antibody against α4β7 integrin, suggesting that the activity directed against α4β1 integrin is solely responsible for the high rate of PML. While impaired neuroimmunosurveillance almost certainly contributes to the development of PML in patients treated with natalizumab, the antibody has other effects that may predispose to the development of the disease. Other potential contributors to the high rate of PML with natalizumab include an effect on premature B cells (CD34+ cells) which may harbor the virus (Frohman et al., 2014), an increase in expression of the neurotropic variant of JCV under therapy (Dominguez-Mozo et al., 2016), and alterations in cellular transcription factor expression, e.g., NF-1x and Spi-B, that may increase risk (Marshall et al., 2014; Meira et al., 2016).

Efalizumab inhibits binding of LFA-1, a β2 integrin expressed on T cells (CD4 and CD8 lymphocytes) to ICAM (Jahn and Schmitt-Rau, 2007); therefore, it likely predisposes to PML in a fashion similar to natalizumab (Berger et al., 2009). This monoclonal antibody downregulates VLA4, inhibits T-cell activation, migration and reactivation and reduces the chemotactic properties of monocytes and neutrophils (Berger et al., 2009). However, its specific effects on immune trafficking in brain tissue and effects on B cells remains unexplored.

4.2. Class II agents

Two DMTs, dimethyl fumarate and fingolimod, are regarded as class II agents with a low, but real, risk of PML. In light of the observation of PML with the fumaric acid esters in the treatment of psoriasis (Dammeier et al, 2015 and Hoepner et al, 2015), a disease not recognized as increasing the risk of PML, the occurrence of PML with dimethyl fumarate in MS patients is not unexpected. As of September 1, 2016, there have been four cases of PML occurring in individuals with MS treated with dimethyl fumarate (Biogen, 2016a and Biogen, 2016b) of which three have been published in the literature (Rosenkranz et al., 2015, Baharnoori et al., 2016, Lehmann-Hornet al., 2016). The incidence rates are low, four cases with 215,000 patient exposures (Biogen, 2016a and Biogen, 2016b); the equivalent of 0.019 cases per 1000 patients. The affected patients’ ages ranged from 54 to 64 which are considerably higher than anticipated in the overall MS population. The duration of dimethyl fumarate therapy ranged from 18 to 54 months (Biogen, 2016a and Biogen, 2016b). Lymphocyte counts may be diminished during dimethyl fumarate therapy and a sustained reduction in CD8 lymphocytes has been observed in some patients (Khatri et al., 2015). Lymphopenia with counts below 500 cells/cu mm were observed in three of four patients and a recommendation has been advanced that sustained lymphopenia, i.e., lymphocyte counts <500 cells/cu mm over 6 months, should result in consideration of discontinuation of dimethyl fumarate. In addition to the potential risk of lymphopenia, in vitro studies of dimethyl fumarate have demonstrated a reduction of lymphocyte binding to vascular cell adhesion molecule-1 by 33% as well as to P-selectin and E-selectin (Rubant et al., 2008), perhaps mirroring the activity of natalizumab to some extent.

Fingolimod is a sphingosine-1-phospgate receptor that sequesters lymphocytes in lymph nodes. Through September 1, 2016, it has been associated with 8 cases of probable or definite PML in the absence of any prior natalizumab administration and a ninth patient three years after the administration of natalizumab was discontinued (Novartis, 2016). Despite the invariable decline in lymphocyte count observed with fingolimod, these cases of PML were not associated with sustained grade 4 (<300 cells/cu mm) lymphopenia (Novartis, 2016). All patients with probable or definite PML had been treated for at least 18 months 18–54 months) consistent with the possibility that fingolimod is mechanistically responsible for the PML. As with dimethyl fumarate, all but one were older with ages ranging from 49 to 63 years. The incidence rate of 9 cases per 160,000 patients or 368,000 patient-years of fingolimod exposure leads to an estimated risk of 0.056/1000 patients (CI 0.026,0.106) and 2.44/100,000 patient years (CI 1.12,4.63) (Novartis, 2016).

4.3. Class III agents

Alemtuzumab, an anti-CD52 antibody, rapidly depletes both B and T cells with mean recovery time for B cells of 7.1 months, but CD4 and CD8 T lymphocyte mean recovery lagging 35 and 20 months, respectively, in patients treated for MS (Hill-Cawthorne et al., 2012). One might anticipate that this immunological scenario with a return of immature B cells and a relative absence of cytotoxic JCV specific T cells would be an ideal set up for the development of PML. While PML has been observed in patients on alemtuzumab, virtually all have been patients with chronic lymphocytic leukemia or, more rarely, transplant patients (Martin et al., 2006; Waggoner et al., 2009; Keene et al., 2011; Isidoro et al., 2014) namely, underlying conditions well known to predispose to PML. No cases of PML have been seen to date in the clinical development program that involved nearly 1,500 patients worldwide and 5,400 patient-years of follow-up or in the approximately 9,200 patients who have been treated with alemtuzumab for MS worldwide (Genzyme, 2016). Yet the potential risk of PML with this agent cannot be dismissed in light of the association of this monoclonal antibody with PML in other contexts and the relatively small number of MS patients who have been exposed. Therefore, it is included as a class III agent.

The risk of PML with natalizumab therapy has been recognized to be increased by prior treatment of MS with immunosuppressant therapy, including mitoxantrone (Bloomgren et al., 2012). However, even in the setting of underlying lymphoid malignancies, mitoxantrone has only rarely been associated with PML. There have been no cases reported of PML in patients with MS treated with mitoxantrone and it is therefore listed as a class III agent. Mitoxantrone is a type II topoisomerase inhibitor; it disrupts DNA synthesis and DNA repair and results in a sustained reduction of neutrophils and lymphocytes with the exception of naïve and activated T lymphocytes within 2 weeks of administration (Gbadamosi et al., 2003). No change in CD4/8 ratios or immunoglobulin levels occurs with mitoxantrone (Gbadamosi et al., 2003). PML in mitoxantrone treated patients has been observed only in persons with predisposing illnesses for the disorder, such as, non-Hodgkins lymphoma and leukemia who had also received other immunosuppressive therapies (Daibata et al., 2001).

Rituximab has not been approved for use in MS, but has been used off label widely, particularly since the phase 2 study reported by Hauser in 2008 (Hauser et al., 2008). Despite widespread use in neurological conditions, such as, chronic inflammatory polyradiculoneuropathy, myasthenia gravis, neuromyelitis optica, rituximab has not been associated with PML in these conditions. Even when administered for conditions in which there exists a predisposing risk of PML, such as, chronic lymphocytic leukemia, lymphoma, rheumatoid arthritis, and ANCA positive vasculitis, the risk of PML is calculated to be about 1 in 30,000. The appearance of PML after its administration is quite variable and seems to be stochastic with an average latency of 4 months, but latencies as short as 2 weeks reported. At least one person who developed unsuspected PML following natalizumab therapy failed to worsen with B cell depletion after treatment with rituximab (Asztely et al., 2015). To date, no cases of PML have been observed with humanized versions of anti-CD20 monoclonal antibodies, ocrelizumab and ofatumumab, in the extensive pre-marketing experience.

PML has not been reported with teriflunomide either in the trials for MS or after marketing with 55,000 patients treated as of April 2016 and a total exposure to the 14 mg dose approaching 70,000 patient years (Coyle et al., 2016). As teriflunomide is the active metabolite of leflunomide, a drug with which rare instances of PML have been observed, it has been included in the class III category. In a univariate analysis of relationship of immunosuppressant drugs to PML obtained from the U.S. Adverse Event Reporting System (AERS), leflunomide was one of 11 agents identified, but this signal was lost after multivariate analysis (Schmedt et al., 2012). PML with leflunomide typically occurs in patients with underlying predisposing diseases and in association with treatment of other immunosuppressants (Rahmlow et al., 2008). Leflunomide has been used preferentially as an immunosuppressant in individuals with PML developing after kidney transplantation based on the rationale that it exhibits activity against other polyoma viruses (Epker et al., 2009; Sanders et al., 2012).

5. Conclusion

This table is an attempt to stratify risks of PML with the various DMTs. Increased experience will almost certainly necessitate a modification of the table with a re-classification of the DMTs and introduction of those not be currently listed. With improvements in our understanding of the pathogenesis of PML, such as, the contribution of host genetic factors (Brassat, 2016), and potential therapies for eliminating JCV, such as, CRISPR-Cas9 (Wollebo et al., 2015), the possibility exists that the risk of PML with DMTs may be eliminated (Table 1).

Table 1

A PML risk stratification table for disease modifying therapies.

 

Therapeutic Agent Treated condition predisposes to PML? Latency from time of drug initiation to PML Frequency/Incidence of PML Year drug introduced into U.S. and European markets Patients/patient-year (PY) exposure#
Class I – high potential risk of PML No Yes High
Natalizumab MS and Crohn's disease None<8 months; >85% of cases >24 months 1/100–1/1000 U.S.- approved 2004; withdrawn Feb 2005; reintroduced Jun 2006 161,300 patients
~527,159 PY (September 30, 2016)
EUR – Apr 2006
Class II – low potential risk of PML No Yes Low/infrequent
 
Dimethyl fumarate MS and psoriasis 18–54 months ~1/50,000 U.S. – Mar 2013 224,542 patients
Europe – Feb 2014 308,732 PY
Fingolimod MS 18–54 months* ~1/18,000 U.S.- Sep 2010 160,000 patients 368,000 PY
EUR-Mar 2011
Class III – no or very low potential risk of PML Yes No Very low or evident only with related drug
 
Alemtuzumab Hematological malignancies, transplantation Unknown; no cases with MS U.S. – Nov 2014 ~11,000 patients
EUR – Sep 2013 ~6000 PY
Rituximab Lymphoproliferative disorders, rheumatoid arthritis, ANCA-associated vasculitis, SLE 1/30,000 MS – unapproved indication No data
Mitoxantrone Non-Hodgkins lymphoma and leukemia U.S.-Oct 2000 No data
EUR-divergent dates
Teriflunomide No PML observed with teriflunomide but with related leflunomide U.S.-Sep 2012 68,952 patients
96,909 PY
EUR-Aug 2013
Daclizumab No PML observed with MS or as prophylaxis for renal transplant U.S.-May 2016 1516 patients
EUR-Jul 2016 3744 PY

Legend PY - Patient year exposure.

U.S. – United States.

EUR - Europe.

# - Data on file with respective manufacturer as of submission date.

Author contributions

JRB was responsible for conception and design of the study and drafting and submitting the manuscript.

Potential conflict of interests

None.

Authors' conflict of interests

Dr. Joseph R. Berger reports grants from Biogen, during the conduct of the study; personal fees from Amgen, personal fees from Astra-Zeneca, personal fees from Janssen, personal fees from Millennium/Takeda, personal fees from Novartis, personal fees from Biogen, personal fees from Roche, personal fees from Genentech, personal fees from Genzyme/Sanofi, personal fees from Inhibikase, personal fees from Forward Pharma, personal fees from Johnson and Johnson, personal fees from Pfizer, personal fees from Eisai, outside the submitted work.

Acknowledgements

There was no support for this study.

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Footnotes

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Gates 3W, Philadelphia, PA 19104, USA