Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event

Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event This report assesses the observed risk of PML in patients treated with the anti-CD20 monoclonal antibody rituximab in the regulatory authority-approved autoimmune indications rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). This was a cumulative analysis of confirmed PML cases in patients receiving rituximab for RA or GPA/MPA from both spontaneous reports and clinical trial sources, as captured in the manufacturer global company safety and clinical databases. Overall reporting rates were calculated and patient case details were summarized. As of 17 November 2015, there were nine confirmed PML cases among patients who had received rituximab for RA and two for GPA. Corresponding estimated reporting rates were 2.56 per 100,000 patients with RA (estimated exposure ≈ 351,396 patients) and < 1 per 10,000 patients with GPA/MPA (estimated exposure 40,000–50,000 patients). In all cases, patients had ≥ 1 potential risk factor for PML independent of rituximab treatment. In the RA population, the estimated reporting rate of PML generally remained stable and low since 2009 despite increasing rituximab exposure. There was no pattern of latency from time of rituximab initiation to PML development and no association of PML with the number of rituximab courses. Global post-marketing safety and clinical trial data demonstrated that the occurrence of PML is very rare among rituximab-treated patients with RA or GPA/MPA and has remained stable over time. . . . . Keywords Rituximab Progressive multifocal leukoencephalopathy Rheumatoid arthritis Granulomatosis with polyangiitis Microscopic polyangiitis The original version of this article was revised due to a retrospective Open Access order. Introduction Statistical analysis conducted by Stuart Lacey, MSc, Roche Products Ltd. Treatment with immunosuppressive biological agents has been reported as a potential risk factor for progressive multi- * Joseph R. Berger joseph.berger@uphs.upenn.edu focal leukoencephalopathy (PML), a rare, often fatal demye- linating disease of the central nervous system caused by the Vineeta Malik John Cunningham virus. vineeta.malik@parexel.com Rituximab is a chimeric anti-CD20 monoclonal antibody Stuart Lacey that targets and depletes CD20+ B cells. Initially approved stuart.lacey@roche.com worldwide to treat non-Hodgkin lymphoma and chronic lym- Paul Brunetta phocytic leukemia, rituximab was subsequently approved in paul.brunetta@junotherapeutics.com combination with methotrexate (MTX) for the treatment of adult patients with moderate to severely active rheumatoid Patricia B. Lehane patricia.lehane@roche.com arthritis (RA) who have had an inadequate response to ≥ 1 tumor necrosis factor inhibitor therapies. Rituximab later Department of Neurology, Perelman School of Medicine, University achieved global regulatory approval in combination with glu- of Pennsylvania, 3400 Convention Avenue, Room 765, cocorticoids for induction of remission in the anti-neutrophil Philadelphia, PA 19104, USA cytoplasmic autoantibody (ANCA)-associated vasculitides: F. Hoffmann-La Roche, Ltd., Basel, Switzerland granulomatosis with polyangiitis (GPA) and microscopic po- Roche Products Ltd., Welwyn Garden City, UK lyangiitis (MPA) (Fig. 1) (Rituxan PI 2014, MabThera Genentech, Inc, South San Francisco, USA PI 2016). Although PML in patients receiving rituximab is 324 J. Neurovirol. (2018) 24:323–331 Fig. 1 History of rituximab and PML in patients with RA or GPA/MPA. EMA, European Medicines Agency, FDA, Food and Drug References: 2006 SLE cases (Rituxan warning 2007); 2009 RA case Administration, GPA, granulomatosis with polyangiitis, MPA, microscop- (Fleischmann 2009); 2011 RA cases (Clifford et al. 2011); US FDA alert. ic polyangiitis, NHL, non-Hodgkin lymphoma, PML, progressive multi- SLE is not an approved indication for rituximab; two initial cases focal leukoencephalopathy, RA, rheumatoid arthritis, SLE, systemic lupus prompted an FDA warning on PML risk following rituximab treatment. erythematosus well-described in the oncology setting (non-Hodgkin the manufacturer global company safety and clinical databases lymphoma or chronic lymphocytic leukemia) (Carson et al. was undertaken. 2009), these diseases are themselves well-known PML risk A confirmed PML diagnosis was defined according to clin- factors. The case reports of patients with autoimmune disor- ical features, characteristic changes on magnetic resonance ders who developed PML after exposure to rituximab sug- imaging or computed tomography scans, and confirmation gested a potential association with rituximab; (2007; Clifford of the presence of JCV as detected by in situ hybridization et al. 2011; Fleischmann 2009;Molloy and Calabrese 2012) from brain tissue biopsy, by polymerase chain reaction in however, these patients all had confounding factors, including CSF, or in postmortem autopsy findings. predisposing comorbidities and past and concomitant therapies. Analysis of the rituximab (MabThera®/Rituxan®) To better describe the apparent association between rituxi- global safety database mab and PML in the autoimmune setting, this report presents a summary of confirmed PML cases and corresponding crude This global safety database includes serious adverse events reporting rates among patients who received rituximab for the documented in the rituximab clinical trial programs for RA regulatory authority-approved autoimmune indications RA and GPA/MPA, as well as all spontaneously reported adverse and GPA/MPA, as captured from both the manufacturer global events for which rituximab was considered a suspect drug. A clinical trial and safety databases (including post-marketing search of PML events and PML confirmatory tests was carried spontaneous reports). out using MedDRAVersion 18.1. The search period was from 2002 (to cover first exposure to rituximab in RA clinical trials) until the data cutoff, 17 November 2015. Potential cases were Patients and methods medically reviewed, and only confirmed PML cases (as de- fined in BOverall Strategy^) were included in this analysis. Overall strategy Only events occurring in the autoimmune indications ap- proved for rituximab (RA and GPA/MPA) were included, as A cumulative analysis of reported cases of confirmed PML in the overall exposure, as numbers of patients treated, could be patients receiving rituximab for RA or GPA/MPA, drawing more accurately tracked and estimated based on prescriptions from both spontaneous reports and clinical trial sources from for these approved indications. J. Neurovirol. (2018) 24:323–331 325 Rituximab (MabThera®/Rituxan®) clinical trial 2.56 cases per 100,000 patients, based on an estimated expo- program for RA and GPA/MPA sure of ≈ 351,396 unique patients treated with rituximab be- tween 2006 (first approval in RA) and 2015. The change in The RA clinical trial database includes safety data from pa- this reporting rate over time is captured in Fig. 2. A peak in tients with moderate to severe, active RA who were treated reporting rate was observed in 2010, due to most of the PML with rituximab plus MTX within a global clinical trial pro- events to date being reported from 2008 to 2010 (6 out of 9; gram (eight randomized clinical trials, two long-term open- see Table 1); there has been a trend of decreasing estimated label extensions, and one open-label prospective study were reporting rates since then, stabilizing around their current level included) (Emery et al. 2010; Edwards et al. 2004; Emery in recent years. One of the nine reported cases was from the et al. 2006; Cohen et al. 2006;Keystoneet al. 2007; RA clinical trial program, previously published in 2009 (case Rubbert-Roth et al. 2010; Mease et al. 2010; Tak et al. 2011; recorded in 2008; Table 1, case 1) and occurred 5 years after Bingham 3rd et al. 2010; van Vollenhoven et al. 2013). the first rituximab dose and 18 months since the last dose, in a Altogether, 3595 patients had received a mean of four courses patient with a history of malignancy (Fleischmann 2009). No (range 1–20) of rituximab over an observation period of cases of PML occurred in the double-blind treatment period or 11 years (14,816 patient-years’ exposure) (van Vollenhoven control arms of the RA clinical trial program. Eight cases were et al. 2015). Eligibility criteria, study designs, and treatment from spontaneous post-marketing reports (2007; Roche regimens for these trials have been previously published 2015). Further details of all cases are in Table 1. (Emery et al. 2010; Edwards et al. 2004; Emery et al. 2006; There were two confirmed PML cases in patients with Cohen et al. 2006;Keystone et al. 2007; Rubbert-Roth et al. GPA, both from spontaneous post-marketing reports (Roche 2010; Mease et al. 2010; Tak et al. 2011; Bingham 3rd et al. 2015). No cases have been reported in patients with MPA. 2010; van Vollenhoven et al. 2013). The GPA/MPA clinical Due to imprecision in the patient exposure estimate in this trial database included 97 patients with GPA/MPA receiving very rare indication and the low number of confirmed cases concomitant glucocorticoids in the pivotal trial BRituximab in of PML reported overall in patients with GPA, a precise ANCA-Associated Vasculitis^ (RAVE), for which eligibility reporting rate could not be calculated. However, based on criteria, study design, and treatment regimen have been de- the estimated cumulative exposure (40,000–50,000 patients), scribed previously (Stone et al. 2010). The reporting window the rate of PML in ANCA-associated vasculitis remains < 1 in covers the primary RAVE trial period and ≥ 18 months of 10,000 patients. There are currently no reported cases of PML follow-up, up to a maximum of 5 years (Stone et al. 2010). in the GPA/MPA clinical trial program in patients in either the Each database was searched for reports of confirmed PML rituximab or the control arms. cases. All studies were previously reported and were in com- pliance with the Helsinki Declaration; local institutional re- Summaries of PML cases in patients with RA view board approval was given at each participating site. or GPA/MPA treated with rituximab Statistical analysis Table 1 provides a summary of the confirmed PML cases in patients who received rituximab for RA. Eight of the nine Due to the small number of PML cases, no statistical analysis cases were in women (which is representative of the general was performed. Cumulative reporting rates of PML were cal- RA patient population, which typically has three times more culated (number of confirmed PML cases per estimated women than men). The overall mean age of the nine patients patient-market exposure), and details of individual case re- with PML was 65 years (range, 50–83 years) compared with a ports were summarized. mean age of 52 years (range, 18–81 years) in the RA clinical trial program of 3595 patients. Differences between the over- all estimated number of patients exposed (≈ 351,396 unique Results patients) and the low numbers of patients with PML should be considered when interpreting these data. All nine patients with Reported cases of confirmed PML in patients with RA PML had a diagnosis of RA for ≥ 3 years and were HIV- or GPA/MPA treated with rituximab negative. Additionally, they all had ≥ 1 known risk factor for PML independent of rituximab treatment. These included a From the first rituximab exposure in RA clinical trials in 2002 history for Sjögren syndrome (n = 4), a history of malignancy up to a cutoff date of 17 November 2015, the company global (n = 2), prior and concomitant therapy with disease-modifying safety database contained 11 confirmed PML cases in autoim- anti-rheumatic drugs with established risk for PML (Molloy mune disorders approved for rituximab treatment (9 in RA and Calabrese 2012)(n = 9; the most common of which was and 2 in GPA/MPA; Fig. 1). The 9 confirmed PML cases in MTX), and treatment with ≥ 2 prior TNF inhibitors (n =4). patients with RA correspond to an estimated reporting rate of Six of the nine patients died due to PML, and the outcome for 326 J. Neurovirol. (2018) 24:323–331 Fig. 2 Reporting rates over time of confirmed PML cases per 100,000 patients with RA who received rituximab. Reporting rates of PML are based on estimated unique patient exposure. PML progressive multifocal leukoencephalopathy, RA rheumatoid arthritis one patient is unknown. The two patients who were reported with RA (n =9) or GPA (n = 2). There was also no association at the time of the data cutoff (17 November, 2015) as recov- between the number of courses of rituximab and the occur- ering were treated for PML with mirtazapine and mefloquine. rence of PML in patients with RA (range, 1–9; Table 1). For The number of rituximab courses ranged from 1 to 9. patients with GPA, the number of rituximab courses was un- Table 2 provides a summary of the confirmed PML cases in specified (Table 2). patients who received rituximab for GPA/MPA. The mean age of the 2 patients with PML was 66 years (range, 62–70 years), compared with a mean age of 56 years (range, 19–89 years) in Discussion the 97 patients in the GPA/MPA clinical trial program. Both patients with PML had GPA for 8 years and were HIV-nega- tive. Both also had ≥ 1 known risk factor for PML indepen- This report provides a comprehensive global safety and clin- dent of rituximab treatment. Patient 1 had a history of breast ical database analysis of confirmed PML cases occurring in cancer and treatment with chemotherapy, as well as immuno- patients exposed to rituximab for the autoimmune indications globulin deficiency. Both patients had previously received of RA and GPA/MPA. The observation period spans the first cyclophosphamide, azathioprine, and corticosteroids, and pa- exposure to rituximab in clinical trials (from 2002 for RA and tient 1 was receiving concomitant azathioprine. Importantly, 2009 for GPA/MPA) until the data cutoff date of 17 November Patient 1 showed signs of PML prior to the start of rituximab 2015. Our findings indicate: (1) the reported occurrence of treatment, including deficits in higher cognitive functions PML is very rare in both populations (2.56 cases per (speech, language, memory, and abstraction ability). Both pa- 100,000 patients in RA and < 1 case per 10,000 in GPA/ MPA); (2) in the RA population, the estimated reporting rate tients were treated for PML with mefloquine, mirtazapine, and/or cytarabine and cidofovir, and, at the time of the data of PML appears to have generally decreased since 2010 and cutoff, both were reported as recovering. stabilized despite increasing rituximab exposure in patients with RA receiving multiple treatment courses over time; and (3) all confirmed PML cases were associated with other risk Latency of PML after rituximab treatment factors, independent of rituximab treatment. Widespread use and duration of rituximab treatment of rituximab for RA only began following its regulatory ap- proval in 2006. The reduction and stabilization of PML cases No pattern of latency was detected between the first dose of in patients with RA after 2010 may perhaps be explained by rituximab and confirmed diagnosis of PML for the patients an increased use of rituximab as opposed to other J. Neurovirol. (2018) 24:323–331 327 Table 1 Cases of confirmed PML in patients with RA Characteristic Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 (Fleischmann (Clifford (Clifford (Clifford (Clifford 2009) et al. 2011) et al. 2011) et al. 2011) et al. 2011) Age, years 50 72 72 62 71 56 58 60 83 Sex F F F FF FM F F Country USA USA USA Australia Sweden USA Netherlands USA Germany Date PML confirmed May 2008 Nov. 2008 Sept. 2009 Oct. 2009 Nov. 2009 March 2010 Not specified Aug. 2012 Nov. 2014 Duration of RA, years 14 30 3 20 3 6 11 5 7 Relevant medical Radiation, Sjögren syndrome Sjögren Sjögren Leukopenia Lymphopenia at None reported SLE, ANA and SLE None reported history with lymphopenia, syndrome syndrome baseline, anti-DNA anti- undetectable complement secondary bodies positive, and CD4, Sjögren opportunistic in- lymphadenopathy syndrome, fections radiation History of Yes No No No Yes No No No No malignancy a, b Prior nonbiologics MTX, steroids, HCQ, etodolac MTX, steroids Steroids, Leflunomide, MTX, steroids Leflunomide MTX, steroids, Azathioprine, MTX, MTX, Steroids leflunomi- sulfasalazine, MTX sulfasalazine, CYC, HCQ de, HCQ gold, HCQ, HCQ steroids Prior biologics Infliximab Adalimumab, None Adalimumab, None Adalimumab, Etanercept, None Denosumab etanercept etanercept, etanercept infliximab anakinra a, b Concomitant drug MTX, steroids MTX, steroids Steroids, MTX HCQ, steroids MTX, steroids, MTX, steroids Steroids, MMF MTX, steroids leflunomi- leflunomide de, HCQ Rituximab treatment,45 1 ≈42 3 4 9 unspecified no. of coursesb Latency distribution 5 years from first dose and ≈ 26 months ≈7months ≈ 18 months ≈ 15 months from ≈ 23 months ≈ 28 months from ≈ 56 months from first ≈ 57 months from first (time from first 18 months from last dose after first dose from first dose first dose. Not from first dose first dose and rituximab dose and rituximab dose and rituximab infusion and and specified and ≈2months from ≈ 6 months from last ≈8monthsfromlast to PML diagnosis) ≈2months ≈ 3 months relative to last ≈ 6 months last dose rituximab dose rituximab dose from last dose from last dose dose from last dose PML treatment None reported Mefloquine Mefloquine Mirtazapine and Mirtazapine and Plasmapheresis Mirtazapine and None reported None reported mefloquine mefloquine and nitrofurantoin mefloquine Outcome Fatal Fatal Fatal Recovering Recovering Unknown Fatal Fatal Fatal ANA, antinuclear antibody; CYC, cyclophosphamide; F, female; HCQ, hydroxychloroquine; M, male; MMF, mycophenolate mofetil; MTX, methotrexate; PML, progressive multifocal leukoencephalopathy; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus MMF is a class 2 agent and adalimumab, azathioprine, CYC, etanercept, infliximab, and MTX are class 3 agents, with respect to known or possible risk for PML MMF had a PML risk signal, and azathioprine and CYC had possible PML risk signals in a disproportionality analysis of spontaneous PML reports (Chahin and Berger 2015) Per the rituximab label recommendations for RA, one treatment course consists of 2 × 1000 mg intravenous infusions separated by 2 weeks, with treatment courses repeated every 24 weeks based on clinical evaluation, but no sooner than every 16 weeks 328 J. Neurovirol. (2018) 24:323–331 immunosuppressive therapies that more widely employed pri- rituximab use from that seen with natalizumab (Chahin or to its approval for these indications which may have carried and Berger 2015). a higher risk of PML. Identifying the risk of PML in any individual patient As reported previously (2007; Clifford et al. 2011; receiving a given immunosuppressive biologic treatment Fleischmann 2009;Molloy and Calabrese 2012; Hashi et al. requires an improved understanding of the barriers to the 2008), cases of PML in patients with RA treated with rituxi- development of PML. Although evidence from patients mab are associated with confounding PML risk factors, in- with HIV suggests that cell-mediated immunity has a cen- cluding prior and concomitant therapies, a history of malig- tral role in controlling JCV (Koralnik et al. 2001), theroleof nancy, prior or concomitant SLE, and other immune disorders B cells is less clear: they may act as a potential viral reser- (leukopenia, lymphopenia). Notably, in four of the nine cases voir or contribute to the immune response controlling JCV reported here, the patient also had Sjögren syndrome. It is infection (Durali et al. 2015). Rituximab robustly achieves presently not possible to separate the contribution of these peripheral blood B cell depletion (Leandro et al. 2006) factors and any contribution of rituximab to the development while the risk for PML remains low, suggesting a minimal of PML in these cases. involvement of peripheral blood B cells in JCV reactivation. Immunosenescence, the gradual deterioration of the im- In addition, rituximab administration to a patient with PML mune system brought on by aging, has also been suggested neither aggravated the disease process nor prevented clear- as a contributor to PML occurrence in patients treated with ance of JCV despite a significant B cell depletion lasting immunomodulatory therapies, with patients ≥ 44 years show- 15 months, indicating that B cells are not essential for JCV ing a higher prevalence of Bearly onset^ natalizumab- clearance and recovery (Asztely et al. 2015). Future re- associated PML (defined as PML developed prior to complet- search should seek to better elucidate the factors resulting ing 24 natalizumab courses) than patients < 44 years old in the development of PML and how these might be affected (Prosperini et al. 2016). Of 9 patients developing PML with by specific immunosuppressive therapies—including de- fingolimod, another disease-modifying therapy for multiple veloping an improved understanding of the localities of per- sclerosis, all but one were older than 48 years (Berger 2017). sistent JCV, how the neurovirulent form of JCV arises dur- The mean age of patients reported herein who developed PML ing PML pathogenesis, and how JCV is regulated in white was relatively high compared both with the mean observed in blood cells (Wollebo et al. 2015). the RA and GPA/MPA global clinical trial programs and with PML should be ruled out in any patient displaying neuro- that in the general RA and GPA/MPA populations. However, logical deficits, e.g., patient 1, prior to rituximab initiation. the overall numbers of confirmed PML cases are low by com- Impaired cognitive functions in patients with RA or GPA/ parison, and therefore definitive conclusions on the effect of MPA who are receiving biologics may be more than a mani- age as a possible risk factor cannot be drawn. festation of aging. PML should be considered as a possible While natalizumab-associated PML usually occurs after diagnosis when patients treated with rituximab for autoim- a characteristic latency period of 18 to 24 months (Chahin mune conditions present with new onset neurological mani- and Berger 2015), the number of PML cases among festations, and consultation with a neurologist is advised as rituximab-treated patients with RA or GPA/MPA remains clinically indicated. On suspicion of PML, it is advised that too small to assess whether any such characteristic latency further dosing of immunosuppressive therapy, including ritux- period exists with rituximab for these indications. A corre- imab, be suspended until PML has been excluded. Upon di- lation between the number of courses of rituximab and PML agnosis of confirmed PML, rituximab must be permanently occurrence might be expected if rituximab were a main driv- discontinued and the case should be reported and followed up er of PML in these cases. However, the number of rituximab per standard pharmacovigilance practices (2014, 2016). courses was highly variable among the nine patients with Routine JCV antibody testing for virus exposure is not ap- RA and PML documented here (between one and nine proved, nor warranted, for patients with RA or GPA/MPA courses) and therefore does not provide any such evidence due to the rarity of PML in these populations (Borie and of causality. Similarly, there was no obvious pattern in PML Kremer 2015). To date, JCV antibody testing for PML risk latency in the cumulative confirmed PML cases where the reduction has been validated only with natalizumab because information was reported. In addition to the lack of an ap- the observed incidence of PML is sufficiently high enough to parent latent period from the time of first initiation of ritux- enable estimated risk stratification in patients with multiple imab to the development of PML, the occurrence of PML in sclerosis (Lee et al. 2013). patients whose autoimmune underlying diseases already predispose them to PML and the exceptionally low numbers Study limitations of observed cases in RA and GPA/MPA, despite widespread usage of the monoclonal antibody since regulatory authority Only reported and confirmed cases of PML in approved auto- approval, further distinguish reports of PML following immune indications (RA and GPA/MPA) are included in the J. Neurovirol. (2018) 24:323–331 329 Table 2 Cases of confirmed PML in patients with GPA Characteristic Case 1 Case 2 Age, years 70 62 Sex F M Country Germany Denmark Date PML confirmed July 2012 Sept. 2013 Duration of GPA, years Not specified 8 Relevant medical history Immunoglobulin deficiency, breast cancer, None reported diabetes mellitus, arterial hypertension, and chronic stage III renal insufficiency Prior treatments CYC, epirubicin, 5-FU, prednisolone, and CYC, azathioprine, and MTX high-dose glucocorticoids Concomitant drug Azathioprine None reported Rituximab treatment Aug. 2011–March 2012 for GPA; no. of 2011–Mar 2013 occasionally courses not specified as needed for GPA; no. of courses not specified Latency distribution (time from ≈ 11 months from first dose and ≈ 4 months ≈ 2 years from first dose and first rituximab infusion to from last dose, symptoms prior to the ≈ 6 months from the last PML diagnosis) start of rituximab dose PML treatment Immune apheresis to eliminate residual Mefloquine, mirtazapine, and rituximab, cidofovir, mefloquine, and cytarabine mirtazapine Outcome ≈ 1 year after PML diagnosis, the patient’s ≈ 3 months after PML diagnosis, condition had improved; however, she the patient’s condition had continued to experience cognitive deficits improved and JCV was still detected in her CSF 5-FU,fluorouracil; CSF, cerebrospinal fluid; CYC, cyclophosphamide; F,female; GPA, granulomatosis with polyangiitis; JCV, John Cunningham polyomavirus; M, male; MTX, methotrexate; PML, progressive multifocal leukoencephalopathy analysis and estimated reporting rates. The PML case reports patient-market rituximab exposure estimates, is very low, with were limited to available safety data as reported by clinicians an overall reporting rate of 2.56 confirmed PML cases per and may not, in all cases, contain all relevant information 100,000 patients. The observed reporting rate has generally concerning exposure to all potential confounders. For example, declined over time and, in recent years (from 2013 onward), high-dose corticosteroids and other immunosuppressive agents has remained low and stable for the yearly company analysis are widely used in autoimmune disorders, but information on of reported safety data, despite increasing rituximab exposures duration of concomitant therapies was generally lacking. in patients with RA and increasing numbers of treatment In addition, the data discussed herein are largely based on courses received. In patients with GPA/MPA, the observed spontaneous reporting of PML cases over 11 years (for RA) reportingrateofPML between2009(firstcompany- and 5 years (for GPA/MPA), and the number of unreported sponsored clinical trials in GPA/MPA) and November 2015 cases during these time periods is unknown. Thus, this evalu- was also very low (< 1 case per 10,000 patients). Analysis of ation reveals the importance of physician vigilance, prompt PML cases in the RA and GPA/MPA patient populations reporting, and long-term/continued safety follow-up for an shows that multiple factors independent of rituximab treat- accurate prevalence estimation of very rare adverse events ment likely contributed to the development of PML. It should such as PML. also be noted that rituximab is indicated for patients with RA who concomitantly receive non-biologic immunosuppressive agents, and for patients with GPA/MPA who often receive cytotoxic immunomodulatory and immunosuppressant agents Conclusions and high-dose corticosteroid therapies. These are all known risk factors for PML. This analysis provides cumulative data The occurrence of confirmed PML in rituximab-treated pa- on PML estimated reporting rates over time and important tients with RA and GPA/MPA from spontaneous reporting previously unpublished information to healthcare profes- and clinical trial sources remains very rare (defined as an sionals prescribing rituximab for regulatory authority- incidence < 1 in 10,000) (CIOMS 1995). The risk of PML in approved autoimmune indications. patients with RA, as determined in this analysis based on 330 J. Neurovirol. (2018) 24:323–331 Acknowledgements Roche was involved in the design of the included Asztely F, Gilland E, Wattjes MP, Lycke J (2015) Rituximab treatment clinical studies; the collection, analysis, and interpretation of the clinical did not aggravate ongoing progressive multifocal and post-marketing safety data; writing of the report; and the decision to leukoencephalopathy in a patient with multiple sclerosis. J Neurol submit the paper for publication. Sci 353:155–157 Editorial support (in the form of collating and incorporating author Berger JR (2017) Classifying PML risk with disease modifying therapies. comments on all drafts, grammatical editing, and referencing) was pro- Mult Scler Relat Disord 12:59–63 vided by Neil Burton and Susan Parker of Fishawack Group of Bingham CO 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M, Companies, and Ellen Mercado of Health Interactions, funded by Roche. Codding C et al (2010) Immunization responses in rheumatoid ar- thritis patients treated with rituximab: results from a controlled clin- ical trial. Arthritis Rheum 62:64–74 Author contributions Joseph R. Berger study concept and design, inter- Borie D, Kremer JM (2015) Considerations on the appropriateness of the pretation of data, manuscript development, and review and critical John Cunningham virus antibody assay use in patients with rheu- revision. Vineeta Malik study concept and design, acquisition of data, analysis matoid arthritis. Semin Arthritis Rheum 45:163–166 and interpretation of data, manuscript development, and review and crit- (2007) Rituxan warning. FDA Consumer 41:3. ical revision. Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymore Stuart Lacey study concept and design, acquisition of data, analysis JF et al (2009) Progressive multifocal leukoencephalopathy after and interpretation of data, manuscript development, and review and crit- rituximab therapy in HIV-negative patients: a report of 57 cases from ical revision. the research on adverse drug events and reports project. Blood 113: Paul Brunetta study concept and design, interpretation of data, study 4834–4840 supervision, manuscript development, and review and critical revision. Chahin S, Berger JR (2015) A risk classification for immunosuppressive Patricia Lehane study concept and design, interpretation of data, study treatment-associated progressive multifocal leukoencephalopathy. J supervision, manuscript development, and review and critical revision Neurovirol 21:623–631 CIOMS (1995) Report of CIOMS (Council of International Funding This study was funded by F. Hoffmann-La Roche, the market- Organizations of Medical Sciences) Working Group III. ing authorization holder for rituximab (MabThera®/Rituxan®). Guidelines for Preparing Core Clinical-Safety Information on Drugs, Geneva Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson M, Compliance with ethical standards Parks D et al (2011) Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol 68: All studies were previously reported and were in compliance with the 1156–1164 Helsinki Declaration; local institutional review board approval was given Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese at each participating site. MC et al (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, random- Conflict of interest Joseph R. Berger has received personal fees as a ized, double-blind, placebo-controlled, phase III trial evaluating pri- consultant to Genentech and Roche. He reports grants from Biogen, dur- mary efficacy and safety at twenty-four weeks. Arthritis Rheum 54: ing the conduct of the study; personal fees from Amgen; personal fees 2793–2806 from Astra-Zeneca; personal fees from Janssen; personal fees from Durali D, de Goër de Herve MG, Gasnault J, Taoufik Y (2015) B cells Millennium/Takeda; personal fees from Novartis; personal fees from and progressive multifocal leukoencephalopathy: search for the Biogen; personal fees from Genzyme/Sanofi; personal fees from missing link. Front Immunol 6:241 Inhibikase; personal fees from Forward Pharma; personal fees from Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Johnson and Johnson; personal fees from Pfizer; and personal fees from Emery P, Close DR et al (2004) Efficacy of B-cell-targeted therapy Eisai, outside the submitted work. with rituximab in patients with rheumatoid arthritis. N Engl J Med Vineeta Malik was an employee of Roche at the time of this study. 350:2572–2581 Stuart Lacey is an employee of Roche. Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Paul Brunetta was an employee of Genentech at the time of this study. Szczepanski L, Kavanaugh A et al (2006) The efficacy and safety Patricia Lehane is an employee of Roche. of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double- Open Access This article is distributed under the terms of the Creative blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 54: Commons Attribution 4.0 International License (http:// 1390–12400 creativecommons.org/licenses/by/4.0/), which permits use, duplication, Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ et al adaptation, distribution and reproduction in any medium or format, as (2010) Efficacy and safety of different doses and retreatment of long as you give appropriate credit to the original author(s) and the rituximab: a randomised, placebo-controlled trial in patients who source, provide a link to the Creative Commons license, and indicate if are biological naive with active rheumatoid arthritis and an inade- changes were made. quate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis 69:1629–1635 Fleischmann RM (2009) Progressive multifocal leukoencephalopathy following rituximab treatment in a patient with rheumatoid arthritis. 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Rheumatology Lee P, Plavina T, Castro A, Berman M, Jaiswal D, Rivas S et al (2013) A (Oxford) 49:1683–1693 second-generation ELISA (STRATIFY JCV DxSelect) for detection Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS et al of JC virus antibodies in human serum and plasma to support pro- (2010) Rituximab versus cyclophosphamide for ANCA-associated gressive multifocal leukoencephalopathy risk stratification. J Clin vasculitis. N Engl J Med 363:221–232 Virology 57:141–146 Tak PP, Rigby WF, Rubbert-Roth A, Peterfy C, van Vollenhoven RF, Mease PJ, Cohen S, Gaylis NB, Chubick A, Kaell AT, Greenwald M et al Stohl W et al (2011) Inhibition of joint damage and improved clin- (2010) Efficacy and safety of retreatment in patients with rheuma- ical outcomes with rituximab plus methotrexate in early active rheu- toid arthritis with previous inadequate response to tumor necrosis matoid arthritis: the IMAGE trial. 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J Rheumatol 42: cofactor for developing early onset progressive multifocal 1761–1766 leukoencephalopathy. European Committe for Treatment and Wollebo HS, White MK, Gordon J, Berger JR, Khalili K (2015) Research in Multiple Sclerosis; September 14–17; London, UK [ab- Persistence and pathogenesis of the neurotropic polyomavirus JC. stract P1598]. http://onlinelibrary.ectrims-congress.eu/ectrims/2016/ Ann Neurol 77:560–570 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of NeuroVirology Springer Journals

Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event

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Biomedicine; Neurosciences; Virology; Infectious Diseases; Immunology; Neurology
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Abstract

This report assesses the observed risk of PML in patients treated with the anti-CD20 monoclonal antibody rituximab in the regulatory authority-approved autoimmune indications rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). This was a cumulative analysis of confirmed PML cases in patients receiving rituximab for RA or GPA/MPA from both spontaneous reports and clinical trial sources, as captured in the manufacturer global company safety and clinical databases. Overall reporting rates were calculated and patient case details were summarized. As of 17 November 2015, there were nine confirmed PML cases among patients who had received rituximab for RA and two for GPA. Corresponding estimated reporting rates were 2.56 per 100,000 patients with RA (estimated exposure ≈ 351,396 patients) and < 1 per 10,000 patients with GPA/MPA (estimated exposure 40,000–50,000 patients). In all cases, patients had ≥ 1 potential risk factor for PML independent of rituximab treatment. In the RA population, the estimated reporting rate of PML generally remained stable and low since 2009 despite increasing rituximab exposure. There was no pattern of latency from time of rituximab initiation to PML development and no association of PML with the number of rituximab courses. Global post-marketing safety and clinical trial data demonstrated that the occurrence of PML is very rare among rituximab-treated patients with RA or GPA/MPA and has remained stable over time. . . . . Keywords Rituximab Progressive multifocal leukoencephalopathy Rheumatoid arthritis Granulomatosis with polyangiitis Microscopic polyangiitis The original version of this article was revised due to a retrospective Open Access order. Introduction Statistical analysis conducted by Stuart Lacey, MSc, Roche Products Ltd. Treatment with immunosuppressive biological agents has been reported as a potential risk factor for progressive multi- * Joseph R. Berger joseph.berger@uphs.upenn.edu focal leukoencephalopathy (PML), a rare, often fatal demye- linating disease of the central nervous system caused by the Vineeta Malik John Cunningham virus. vineeta.malik@parexel.com Rituximab is a chimeric anti-CD20 monoclonal antibody Stuart Lacey that targets and depletes CD20+ B cells. Initially approved stuart.lacey@roche.com worldwide to treat non-Hodgkin lymphoma and chronic lym- Paul Brunetta phocytic leukemia, rituximab was subsequently approved in paul.brunetta@junotherapeutics.com combination with methotrexate (MTX) for the treatment of adult patients with moderate to severely active rheumatoid Patricia B. Lehane patricia.lehane@roche.com arthritis (RA) who have had an inadequate response to ≥ 1 tumor necrosis factor inhibitor therapies. Rituximab later Department of Neurology, Perelman School of Medicine, University achieved global regulatory approval in combination with glu- of Pennsylvania, 3400 Convention Avenue, Room 765, cocorticoids for induction of remission in the anti-neutrophil Philadelphia, PA 19104, USA cytoplasmic autoantibody (ANCA)-associated vasculitides: F. Hoffmann-La Roche, Ltd., Basel, Switzerland granulomatosis with polyangiitis (GPA) and microscopic po- Roche Products Ltd., Welwyn Garden City, UK lyangiitis (MPA) (Fig. 1) (Rituxan PI 2014, MabThera Genentech, Inc, South San Francisco, USA PI 2016). Although PML in patients receiving rituximab is 324 J. Neurovirol. (2018) 24:323–331 Fig. 1 History of rituximab and PML in patients with RA or GPA/MPA. EMA, European Medicines Agency, FDA, Food and Drug References: 2006 SLE cases (Rituxan warning 2007); 2009 RA case Administration, GPA, granulomatosis with polyangiitis, MPA, microscop- (Fleischmann 2009); 2011 RA cases (Clifford et al. 2011); US FDA alert. ic polyangiitis, NHL, non-Hodgkin lymphoma, PML, progressive multi- SLE is not an approved indication for rituximab; two initial cases focal leukoencephalopathy, RA, rheumatoid arthritis, SLE, systemic lupus prompted an FDA warning on PML risk following rituximab treatment. erythematosus well-described in the oncology setting (non-Hodgkin the manufacturer global company safety and clinical databases lymphoma or chronic lymphocytic leukemia) (Carson et al. was undertaken. 2009), these diseases are themselves well-known PML risk A confirmed PML diagnosis was defined according to clin- factors. The case reports of patients with autoimmune disor- ical features, characteristic changes on magnetic resonance ders who developed PML after exposure to rituximab sug- imaging or computed tomography scans, and confirmation gested a potential association with rituximab; (2007; Clifford of the presence of JCV as detected by in situ hybridization et al. 2011; Fleischmann 2009;Molloy and Calabrese 2012) from brain tissue biopsy, by polymerase chain reaction in however, these patients all had confounding factors, including CSF, or in postmortem autopsy findings. predisposing comorbidities and past and concomitant therapies. Analysis of the rituximab (MabThera®/Rituxan®) To better describe the apparent association between rituxi- global safety database mab and PML in the autoimmune setting, this report presents a summary of confirmed PML cases and corresponding crude This global safety database includes serious adverse events reporting rates among patients who received rituximab for the documented in the rituximab clinical trial programs for RA regulatory authority-approved autoimmune indications RA and GPA/MPA, as well as all spontaneously reported adverse and GPA/MPA, as captured from both the manufacturer global events for which rituximab was considered a suspect drug. A clinical trial and safety databases (including post-marketing search of PML events and PML confirmatory tests was carried spontaneous reports). out using MedDRAVersion 18.1. The search period was from 2002 (to cover first exposure to rituximab in RA clinical trials) until the data cutoff, 17 November 2015. Potential cases were Patients and methods medically reviewed, and only confirmed PML cases (as de- fined in BOverall Strategy^) were included in this analysis. Overall strategy Only events occurring in the autoimmune indications ap- proved for rituximab (RA and GPA/MPA) were included, as A cumulative analysis of reported cases of confirmed PML in the overall exposure, as numbers of patients treated, could be patients receiving rituximab for RA or GPA/MPA, drawing more accurately tracked and estimated based on prescriptions from both spontaneous reports and clinical trial sources from for these approved indications. J. Neurovirol. (2018) 24:323–331 325 Rituximab (MabThera®/Rituxan®) clinical trial 2.56 cases per 100,000 patients, based on an estimated expo- program for RA and GPA/MPA sure of ≈ 351,396 unique patients treated with rituximab be- tween 2006 (first approval in RA) and 2015. The change in The RA clinical trial database includes safety data from pa- this reporting rate over time is captured in Fig. 2. A peak in tients with moderate to severe, active RA who were treated reporting rate was observed in 2010, due to most of the PML with rituximab plus MTX within a global clinical trial pro- events to date being reported from 2008 to 2010 (6 out of 9; gram (eight randomized clinical trials, two long-term open- see Table 1); there has been a trend of decreasing estimated label extensions, and one open-label prospective study were reporting rates since then, stabilizing around their current level included) (Emery et al. 2010; Edwards et al. 2004; Emery in recent years. One of the nine reported cases was from the et al. 2006; Cohen et al. 2006;Keystoneet al. 2007; RA clinical trial program, previously published in 2009 (case Rubbert-Roth et al. 2010; Mease et al. 2010; Tak et al. 2011; recorded in 2008; Table 1, case 1) and occurred 5 years after Bingham 3rd et al. 2010; van Vollenhoven et al. 2013). the first rituximab dose and 18 months since the last dose, in a Altogether, 3595 patients had received a mean of four courses patient with a history of malignancy (Fleischmann 2009). No (range 1–20) of rituximab over an observation period of cases of PML occurred in the double-blind treatment period or 11 years (14,816 patient-years’ exposure) (van Vollenhoven control arms of the RA clinical trial program. Eight cases were et al. 2015). Eligibility criteria, study designs, and treatment from spontaneous post-marketing reports (2007; Roche regimens for these trials have been previously published 2015). Further details of all cases are in Table 1. (Emery et al. 2010; Edwards et al. 2004; Emery et al. 2006; There were two confirmed PML cases in patients with Cohen et al. 2006;Keystone et al. 2007; Rubbert-Roth et al. GPA, both from spontaneous post-marketing reports (Roche 2010; Mease et al. 2010; Tak et al. 2011; Bingham 3rd et al. 2015). No cases have been reported in patients with MPA. 2010; van Vollenhoven et al. 2013). The GPA/MPA clinical Due to imprecision in the patient exposure estimate in this trial database included 97 patients with GPA/MPA receiving very rare indication and the low number of confirmed cases concomitant glucocorticoids in the pivotal trial BRituximab in of PML reported overall in patients with GPA, a precise ANCA-Associated Vasculitis^ (RAVE), for which eligibility reporting rate could not be calculated. However, based on criteria, study design, and treatment regimen have been de- the estimated cumulative exposure (40,000–50,000 patients), scribed previously (Stone et al. 2010). The reporting window the rate of PML in ANCA-associated vasculitis remains < 1 in covers the primary RAVE trial period and ≥ 18 months of 10,000 patients. There are currently no reported cases of PML follow-up, up to a maximum of 5 years (Stone et al. 2010). in the GPA/MPA clinical trial program in patients in either the Each database was searched for reports of confirmed PML rituximab or the control arms. cases. All studies were previously reported and were in com- pliance with the Helsinki Declaration; local institutional re- Summaries of PML cases in patients with RA view board approval was given at each participating site. or GPA/MPA treated with rituximab Statistical analysis Table 1 provides a summary of the confirmed PML cases in patients who received rituximab for RA. Eight of the nine Due to the small number of PML cases, no statistical analysis cases were in women (which is representative of the general was performed. Cumulative reporting rates of PML were cal- RA patient population, which typically has three times more culated (number of confirmed PML cases per estimated women than men). The overall mean age of the nine patients patient-market exposure), and details of individual case re- with PML was 65 years (range, 50–83 years) compared with a ports were summarized. mean age of 52 years (range, 18–81 years) in the RA clinical trial program of 3595 patients. Differences between the over- all estimated number of patients exposed (≈ 351,396 unique Results patients) and the low numbers of patients with PML should be considered when interpreting these data. All nine patients with Reported cases of confirmed PML in patients with RA PML had a diagnosis of RA for ≥ 3 years and were HIV- or GPA/MPA treated with rituximab negative. Additionally, they all had ≥ 1 known risk factor for PML independent of rituximab treatment. These included a From the first rituximab exposure in RA clinical trials in 2002 history for Sjögren syndrome (n = 4), a history of malignancy up to a cutoff date of 17 November 2015, the company global (n = 2), prior and concomitant therapy with disease-modifying safety database contained 11 confirmed PML cases in autoim- anti-rheumatic drugs with established risk for PML (Molloy mune disorders approved for rituximab treatment (9 in RA and Calabrese 2012)(n = 9; the most common of which was and 2 in GPA/MPA; Fig. 1). The 9 confirmed PML cases in MTX), and treatment with ≥ 2 prior TNF inhibitors (n =4). patients with RA correspond to an estimated reporting rate of Six of the nine patients died due to PML, and the outcome for 326 J. Neurovirol. (2018) 24:323–331 Fig. 2 Reporting rates over time of confirmed PML cases per 100,000 patients with RA who received rituximab. Reporting rates of PML are based on estimated unique patient exposure. PML progressive multifocal leukoencephalopathy, RA rheumatoid arthritis one patient is unknown. The two patients who were reported with RA (n =9) or GPA (n = 2). There was also no association at the time of the data cutoff (17 November, 2015) as recov- between the number of courses of rituximab and the occur- ering were treated for PML with mirtazapine and mefloquine. rence of PML in patients with RA (range, 1–9; Table 1). For The number of rituximab courses ranged from 1 to 9. patients with GPA, the number of rituximab courses was un- Table 2 provides a summary of the confirmed PML cases in specified (Table 2). patients who received rituximab for GPA/MPA. The mean age of the 2 patients with PML was 66 years (range, 62–70 years), compared with a mean age of 56 years (range, 19–89 years) in Discussion the 97 patients in the GPA/MPA clinical trial program. Both patients with PML had GPA for 8 years and were HIV-nega- tive. Both also had ≥ 1 known risk factor for PML indepen- This report provides a comprehensive global safety and clin- dent of rituximab treatment. Patient 1 had a history of breast ical database analysis of confirmed PML cases occurring in cancer and treatment with chemotherapy, as well as immuno- patients exposed to rituximab for the autoimmune indications globulin deficiency. Both patients had previously received of RA and GPA/MPA. The observation period spans the first cyclophosphamide, azathioprine, and corticosteroids, and pa- exposure to rituximab in clinical trials (from 2002 for RA and tient 1 was receiving concomitant azathioprine. Importantly, 2009 for GPA/MPA) until the data cutoff date of 17 November Patient 1 showed signs of PML prior to the start of rituximab 2015. Our findings indicate: (1) the reported occurrence of treatment, including deficits in higher cognitive functions PML is very rare in both populations (2.56 cases per (speech, language, memory, and abstraction ability). Both pa- 100,000 patients in RA and < 1 case per 10,000 in GPA/ MPA); (2) in the RA population, the estimated reporting rate tients were treated for PML with mefloquine, mirtazapine, and/or cytarabine and cidofovir, and, at the time of the data of PML appears to have generally decreased since 2010 and cutoff, both were reported as recovering. stabilized despite increasing rituximab exposure in patients with RA receiving multiple treatment courses over time; and (3) all confirmed PML cases were associated with other risk Latency of PML after rituximab treatment factors, independent of rituximab treatment. Widespread use and duration of rituximab treatment of rituximab for RA only began following its regulatory ap- proval in 2006. The reduction and stabilization of PML cases No pattern of latency was detected between the first dose of in patients with RA after 2010 may perhaps be explained by rituximab and confirmed diagnosis of PML for the patients an increased use of rituximab as opposed to other J. Neurovirol. (2018) 24:323–331 327 Table 1 Cases of confirmed PML in patients with RA Characteristic Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 (Fleischmann (Clifford (Clifford (Clifford (Clifford 2009) et al. 2011) et al. 2011) et al. 2011) et al. 2011) Age, years 50 72 72 62 71 56 58 60 83 Sex F F F FF FM F F Country USA USA USA Australia Sweden USA Netherlands USA Germany Date PML confirmed May 2008 Nov. 2008 Sept. 2009 Oct. 2009 Nov. 2009 March 2010 Not specified Aug. 2012 Nov. 2014 Duration of RA, years 14 30 3 20 3 6 11 5 7 Relevant medical Radiation, Sjögren syndrome Sjögren Sjögren Leukopenia Lymphopenia at None reported SLE, ANA and SLE None reported history with lymphopenia, syndrome syndrome baseline, anti-DNA anti- undetectable complement secondary bodies positive, and CD4, Sjögren opportunistic in- lymphadenopathy syndrome, fections radiation History of Yes No No No Yes No No No No malignancy a, b Prior nonbiologics MTX, steroids, HCQ, etodolac MTX, steroids Steroids, Leflunomide, MTX, steroids Leflunomide MTX, steroids, Azathioprine, MTX, MTX, Steroids leflunomi- sulfasalazine, MTX sulfasalazine, CYC, HCQ de, HCQ gold, HCQ, HCQ steroids Prior biologics Infliximab Adalimumab, None Adalimumab, None Adalimumab, Etanercept, None Denosumab etanercept etanercept, etanercept infliximab anakinra a, b Concomitant drug MTX, steroids MTX, steroids Steroids, MTX HCQ, steroids MTX, steroids, MTX, steroids Steroids, MMF MTX, steroids leflunomi- leflunomide de, HCQ Rituximab treatment,45 1 ≈42 3 4 9 unspecified no. of coursesb Latency distribution 5 years from first dose and ≈ 26 months ≈7months ≈ 18 months ≈ 15 months from ≈ 23 months ≈ 28 months from ≈ 56 months from first ≈ 57 months from first (time from first 18 months from last dose after first dose from first dose first dose. Not from first dose first dose and rituximab dose and rituximab dose and rituximab infusion and and specified and ≈2months from ≈ 6 months from last ≈8monthsfromlast to PML diagnosis) ≈2months ≈ 3 months relative to last ≈ 6 months last dose rituximab dose rituximab dose from last dose from last dose dose from last dose PML treatment None reported Mefloquine Mefloquine Mirtazapine and Mirtazapine and Plasmapheresis Mirtazapine and None reported None reported mefloquine mefloquine and nitrofurantoin mefloquine Outcome Fatal Fatal Fatal Recovering Recovering Unknown Fatal Fatal Fatal ANA, antinuclear antibody; CYC, cyclophosphamide; F, female; HCQ, hydroxychloroquine; M, male; MMF, mycophenolate mofetil; MTX, methotrexate; PML, progressive multifocal leukoencephalopathy; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus MMF is a class 2 agent and adalimumab, azathioprine, CYC, etanercept, infliximab, and MTX are class 3 agents, with respect to known or possible risk for PML MMF had a PML risk signal, and azathioprine and CYC had possible PML risk signals in a disproportionality analysis of spontaneous PML reports (Chahin and Berger 2015) Per the rituximab label recommendations for RA, one treatment course consists of 2 × 1000 mg intravenous infusions separated by 2 weeks, with treatment courses repeated every 24 weeks based on clinical evaluation, but no sooner than every 16 weeks 328 J. Neurovirol. (2018) 24:323–331 immunosuppressive therapies that more widely employed pri- rituximab use from that seen with natalizumab (Chahin or to its approval for these indications which may have carried and Berger 2015). a higher risk of PML. Identifying the risk of PML in any individual patient As reported previously (2007; Clifford et al. 2011; receiving a given immunosuppressive biologic treatment Fleischmann 2009;Molloy and Calabrese 2012; Hashi et al. requires an improved understanding of the barriers to the 2008), cases of PML in patients with RA treated with rituxi- development of PML. Although evidence from patients mab are associated with confounding PML risk factors, in- with HIV suggests that cell-mediated immunity has a cen- cluding prior and concomitant therapies, a history of malig- tral role in controlling JCV (Koralnik et al. 2001), theroleof nancy, prior or concomitant SLE, and other immune disorders B cells is less clear: they may act as a potential viral reser- (leukopenia, lymphopenia). Notably, in four of the nine cases voir or contribute to the immune response controlling JCV reported here, the patient also had Sjögren syndrome. It is infection (Durali et al. 2015). Rituximab robustly achieves presently not possible to separate the contribution of these peripheral blood B cell depletion (Leandro et al. 2006) factors and any contribution of rituximab to the development while the risk for PML remains low, suggesting a minimal of PML in these cases. involvement of peripheral blood B cells in JCV reactivation. Immunosenescence, the gradual deterioration of the im- In addition, rituximab administration to a patient with PML mune system brought on by aging, has also been suggested neither aggravated the disease process nor prevented clear- as a contributor to PML occurrence in patients treated with ance of JCV despite a significant B cell depletion lasting immunomodulatory therapies, with patients ≥ 44 years show- 15 months, indicating that B cells are not essential for JCV ing a higher prevalence of Bearly onset^ natalizumab- clearance and recovery (Asztely et al. 2015). Future re- associated PML (defined as PML developed prior to complet- search should seek to better elucidate the factors resulting ing 24 natalizumab courses) than patients < 44 years old in the development of PML and how these might be affected (Prosperini et al. 2016). Of 9 patients developing PML with by specific immunosuppressive therapies—including de- fingolimod, another disease-modifying therapy for multiple veloping an improved understanding of the localities of per- sclerosis, all but one were older than 48 years (Berger 2017). sistent JCV, how the neurovirulent form of JCV arises dur- The mean age of patients reported herein who developed PML ing PML pathogenesis, and how JCV is regulated in white was relatively high compared both with the mean observed in blood cells (Wollebo et al. 2015). the RA and GPA/MPA global clinical trial programs and with PML should be ruled out in any patient displaying neuro- that in the general RA and GPA/MPA populations. However, logical deficits, e.g., patient 1, prior to rituximab initiation. the overall numbers of confirmed PML cases are low by com- Impaired cognitive functions in patients with RA or GPA/ parison, and therefore definitive conclusions on the effect of MPA who are receiving biologics may be more than a mani- age as a possible risk factor cannot be drawn. festation of aging. PML should be considered as a possible While natalizumab-associated PML usually occurs after diagnosis when patients treated with rituximab for autoim- a characteristic latency period of 18 to 24 months (Chahin mune conditions present with new onset neurological mani- and Berger 2015), the number of PML cases among festations, and consultation with a neurologist is advised as rituximab-treated patients with RA or GPA/MPA remains clinically indicated. On suspicion of PML, it is advised that too small to assess whether any such characteristic latency further dosing of immunosuppressive therapy, including ritux- period exists with rituximab for these indications. A corre- imab, be suspended until PML has been excluded. Upon di- lation between the number of courses of rituximab and PML agnosis of confirmed PML, rituximab must be permanently occurrence might be expected if rituximab were a main driv- discontinued and the case should be reported and followed up er of PML in these cases. However, the number of rituximab per standard pharmacovigilance practices (2014, 2016). courses was highly variable among the nine patients with Routine JCV antibody testing for virus exposure is not ap- RA and PML documented here (between one and nine proved, nor warranted, for patients with RA or GPA/MPA courses) and therefore does not provide any such evidence due to the rarity of PML in these populations (Borie and of causality. Similarly, there was no obvious pattern in PML Kremer 2015). To date, JCV antibody testing for PML risk latency in the cumulative confirmed PML cases where the reduction has been validated only with natalizumab because information was reported. In addition to the lack of an ap- the observed incidence of PML is sufficiently high enough to parent latent period from the time of first initiation of ritux- enable estimated risk stratification in patients with multiple imab to the development of PML, the occurrence of PML in sclerosis (Lee et al. 2013). patients whose autoimmune underlying diseases already predispose them to PML and the exceptionally low numbers Study limitations of observed cases in RA and GPA/MPA, despite widespread usage of the monoclonal antibody since regulatory authority Only reported and confirmed cases of PML in approved auto- approval, further distinguish reports of PML following immune indications (RA and GPA/MPA) are included in the J. Neurovirol. (2018) 24:323–331 329 Table 2 Cases of confirmed PML in patients with GPA Characteristic Case 1 Case 2 Age, years 70 62 Sex F M Country Germany Denmark Date PML confirmed July 2012 Sept. 2013 Duration of GPA, years Not specified 8 Relevant medical history Immunoglobulin deficiency, breast cancer, None reported diabetes mellitus, arterial hypertension, and chronic stage III renal insufficiency Prior treatments CYC, epirubicin, 5-FU, prednisolone, and CYC, azathioprine, and MTX high-dose glucocorticoids Concomitant drug Azathioprine None reported Rituximab treatment Aug. 2011–March 2012 for GPA; no. of 2011–Mar 2013 occasionally courses not specified as needed for GPA; no. of courses not specified Latency distribution (time from ≈ 11 months from first dose and ≈ 4 months ≈ 2 years from first dose and first rituximab infusion to from last dose, symptoms prior to the ≈ 6 months from the last PML diagnosis) start of rituximab dose PML treatment Immune apheresis to eliminate residual Mefloquine, mirtazapine, and rituximab, cidofovir, mefloquine, and cytarabine mirtazapine Outcome ≈ 1 year after PML diagnosis, the patient’s ≈ 3 months after PML diagnosis, condition had improved; however, she the patient’s condition had continued to experience cognitive deficits improved and JCV was still detected in her CSF 5-FU,fluorouracil; CSF, cerebrospinal fluid; CYC, cyclophosphamide; F,female; GPA, granulomatosis with polyangiitis; JCV, John Cunningham polyomavirus; M, male; MTX, methotrexate; PML, progressive multifocal leukoencephalopathy analysis and estimated reporting rates. The PML case reports patient-market rituximab exposure estimates, is very low, with were limited to available safety data as reported by clinicians an overall reporting rate of 2.56 confirmed PML cases per and may not, in all cases, contain all relevant information 100,000 patients. The observed reporting rate has generally concerning exposure to all potential confounders. For example, declined over time and, in recent years (from 2013 onward), high-dose corticosteroids and other immunosuppressive agents has remained low and stable for the yearly company analysis are widely used in autoimmune disorders, but information on of reported safety data, despite increasing rituximab exposures duration of concomitant therapies was generally lacking. in patients with RA and increasing numbers of treatment In addition, the data discussed herein are largely based on courses received. In patients with GPA/MPA, the observed spontaneous reporting of PML cases over 11 years (for RA) reportingrateofPML between2009(firstcompany- and 5 years (for GPA/MPA), and the number of unreported sponsored clinical trials in GPA/MPA) and November 2015 cases during these time periods is unknown. Thus, this evalu- was also very low (< 1 case per 10,000 patients). Analysis of ation reveals the importance of physician vigilance, prompt PML cases in the RA and GPA/MPA patient populations reporting, and long-term/continued safety follow-up for an shows that multiple factors independent of rituximab treat- accurate prevalence estimation of very rare adverse events ment likely contributed to the development of PML. It should such as PML. also be noted that rituximab is indicated for patients with RA who concomitantly receive non-biologic immunosuppressive agents, and for patients with GPA/MPA who often receive cytotoxic immunomodulatory and immunosuppressant agents Conclusions and high-dose corticosteroid therapies. These are all known risk factors for PML. This analysis provides cumulative data The occurrence of confirmed PML in rituximab-treated pa- on PML estimated reporting rates over time and important tients with RA and GPA/MPA from spontaneous reporting previously unpublished information to healthcare profes- and clinical trial sources remains very rare (defined as an sionals prescribing rituximab for regulatory authority- incidence < 1 in 10,000) (CIOMS 1995). The risk of PML in approved autoimmune indications. patients with RA, as determined in this analysis based on 330 J. Neurovirol. (2018) 24:323–331 Acknowledgements Roche was involved in the design of the included Asztely F, Gilland E, Wattjes MP, Lycke J (2015) Rituximab treatment clinical studies; the collection, analysis, and interpretation of the clinical did not aggravate ongoing progressive multifocal and post-marketing safety data; writing of the report; and the decision to leukoencephalopathy in a patient with multiple sclerosis. J Neurol submit the paper for publication. Sci 353:155–157 Editorial support (in the form of collating and incorporating author Berger JR (2017) Classifying PML risk with disease modifying therapies. comments on all drafts, grammatical editing, and referencing) was pro- Mult Scler Relat Disord 12:59–63 vided by Neil Burton and Susan Parker of Fishawack Group of Bingham CO 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M, Companies, and Ellen Mercado of Health Interactions, funded by Roche. Codding C et al (2010) Immunization responses in rheumatoid ar- thritis patients treated with rituximab: results from a controlled clin- ical trial. Arthritis Rheum 62:64–74 Author contributions Joseph R. Berger study concept and design, inter- Borie D, Kremer JM (2015) Considerations on the appropriateness of the pretation of data, manuscript development, and review and critical John Cunningham virus antibody assay use in patients with rheu- revision. Vineeta Malik study concept and design, acquisition of data, analysis matoid arthritis. Semin Arthritis Rheum 45:163–166 and interpretation of data, manuscript development, and review and crit- (2007) Rituxan warning. FDA Consumer 41:3. ical revision. Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymore Stuart Lacey study concept and design, acquisition of data, analysis JF et al (2009) Progressive multifocal leukoencephalopathy after and interpretation of data, manuscript development, and review and crit- rituximab therapy in HIV-negative patients: a report of 57 cases from ical revision. the research on adverse drug events and reports project. Blood 113: Paul Brunetta study concept and design, interpretation of data, study 4834–4840 supervision, manuscript development, and review and critical revision. Chahin S, Berger JR (2015) A risk classification for immunosuppressive Patricia Lehane study concept and design, interpretation of data, study treatment-associated progressive multifocal leukoencephalopathy. J supervision, manuscript development, and review and critical revision Neurovirol 21:623–631 CIOMS (1995) Report of CIOMS (Council of International Funding This study was funded by F. Hoffmann-La Roche, the market- Organizations of Medical Sciences) Working Group III. ing authorization holder for rituximab (MabThera®/Rituxan®). Guidelines for Preparing Core Clinical-Safety Information on Drugs, Geneva Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson M, Compliance with ethical standards Parks D et al (2011) Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol 68: All studies were previously reported and were in compliance with the 1156–1164 Helsinki Declaration; local institutional review board approval was given Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese at each participating site. MC et al (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, random- Conflict of interest Joseph R. Berger has received personal fees as a ized, double-blind, placebo-controlled, phase III trial evaluating pri- consultant to Genentech and Roche. He reports grants from Biogen, dur- mary efficacy and safety at twenty-four weeks. Arthritis Rheum 54: ing the conduct of the study; personal fees from Amgen; personal fees 2793–2806 from Astra-Zeneca; personal fees from Janssen; personal fees from Durali D, de Goër de Herve MG, Gasnault J, Taoufik Y (2015) B cells Millennium/Takeda; personal fees from Novartis; personal fees from and progressive multifocal leukoencephalopathy: search for the Biogen; personal fees from Genzyme/Sanofi; personal fees from missing link. Front Immunol 6:241 Inhibikase; personal fees from Forward Pharma; personal fees from Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Johnson and Johnson; personal fees from Pfizer; and personal fees from Emery P, Close DR et al (2004) Efficacy of B-cell-targeted therapy Eisai, outside the submitted work. with rituximab in patients with rheumatoid arthritis. N Engl J Med Vineeta Malik was an employee of Roche at the time of this study. 350:2572–2581 Stuart Lacey is an employee of Roche. Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Paul Brunetta was an employee of Genentech at the time of this study. Szczepanski L, Kavanaugh A et al (2006) The efficacy and safety Patricia Lehane is an employee of Roche. of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double- Open Access This article is distributed under the terms of the Creative blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 54: Commons Attribution 4.0 International License (http:// 1390–12400 creativecommons.org/licenses/by/4.0/), which permits use, duplication, Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ et al adaptation, distribution and reproduction in any medium or format, as (2010) Efficacy and safety of different doses and retreatment of long as you give appropriate credit to the original author(s) and the rituximab: a randomised, placebo-controlled trial in patients who source, provide a link to the Creative Commons license, and indicate if are biological naive with active rheumatoid arthritis and an inade- changes were made. quate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis 69:1629–1635 Fleischmann RM (2009) Progressive multifocal leukoencephalopathy following rituximab treatment in a patient with rheumatoid arthritis. 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Journal of NeuroVirologySpringer Journals

Published: Mar 5, 2018

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