María José Magraner Francisco Coret Arantxa Navarré Isabel Boscá María Simó Matilde Escutia Ana Bernad Laura Navarro Bonaventura Casanova

Transcription

1 DOI /s ORIGINAL COMMUNICATION Pulsed steroids followed by glatiramer acetate to prevent inflammatory activity after cessation of natalizumab therapy: a prospective, 6-month observational study María José Magraner Francisco Coret Arantxa Navarré Isabel Boscá María Simó Matilde Escutia Ana Bernad Laura Navarro Bonaventura Casanova Received: 31 January 2011 / Revised: 15 March 2011 / Accepted: 18 March 2011 Ó Springer-Verlag 2011 Abstract In this study, the tolerability and safety of treatment with pulsed steroids and glatiramer acetate and the occurrence of clinical and radiological activity after natalizumab (NTZ) cessation in multiple sclerosis (MS) patients were assessed. MS patients with NTZ were discontinued after 2 years of treatment, or if adverse events or disease progressed during NTZ. They were offered as alternative treatment 1 g methylprednisolone per month during 3 months followed by daily 20 mcg glatiramer acetate and were prospectively studied. Adverse events, occurrence of immune reconstitution inflammatory syndrome, clinical exacerbations, and gadolinium-enhancing lesions in MRI performed at 3 and 6 months after NTZ cessation were recorded. EDSS change during follow-up was also recorded. A total of 18 MS patients entered the study and were followed up for a mean of 10 months (range 6 18 months). There were no significant adverse events. At month 3, no patient had clinical or radiological disease activity. At month 6, 16.6% of patients had had a relapse and 55.5% of patients showed gadoliniumenhancing lesions in the MRI. After 6 months, 33.3% of patients had a further relapse. There was no IRIS, severe relapses, or significant difference between EDSS at NTZ discontinuation and after follow-up. The alternative M. J. Magraner (&) I. Boscá M. Simó M. Escutia L. Navarro B. Casanova Multiple Sclerosis Unit, Hospital Universitari I Politècnic La Fe, Valencia, Bulevar Sur s/n, Valencia, Spain majomagbe@ono.com F. Coret A. Navarré A. Bernad Multiple Sclerosis Unit, Hospital Clínico Valencia, Valencia, Spain treatment with monthly prednisolone followed by GA prevents the development of IRIS, but not the return to previous inflammatory activity, which occurs between 5 and 6 months after NTZ withdrawal. Keywords Natalizumab Drug holidays Pulses of steroids Introduction Natalizumab (NTZ) is a humanized monoclonal antibody that binds to a4b1 and a4b7 integrins and prevents lymphocyte transmigration in relapsing remitting multiple sclerosis (RRMS), based on the results of two phase III clinical trials [1, 2]. Natalizumab was approved by the Food and Drug Administration (FDA) for the treatment of MS in Despite the high efficacy of NTZ to prevent relapses, the presentation of three cases of progressive multifocal leukoencephalopathy (PML) motivated the withdrawal of NTZ. After revising the risk, the US Federal Drug Administration (FDA) and the European Medicament Agency (EMEA) approved NTZ as a second-line treatment in monotherapy. Nevertheless, the risk of PML is nowadays known to be higher than originally thought. In addition, the risk is related to the time of exposure to NTZ, being higher after 2 years of treatment. In December 2010, 82 cases of PML have been reported out of 26,000 patients treated for more than 2 years [3]. On the other hand, there are several reasons to withdraw NTZ, e.g., desire of pregnancy, secondary effects, or progression in the disability. However, NTZ withdrawal can be follow by an uncontrolled inflammatory response in the central nervous system (immune reconstitution syndrome, IRIS) [4, 5], a potential life-threatening condition due to a

2 massive CD8? lymphocytes infiltration of the CNS with demyelization and axonal damage [6], and the return to previous inflammatory activity [7]. In order to prevent PML, some experts have argued that planned dosage interruption could decrease the risk of PML [8]. The duration of these drug holidays should last from 3 6 months, which is the time to recover the immune surveillance of the brain. This recommendation is based on two indirect observations. One arises from the NTZ phase II trial [9, 10], in which the return to the inflammatory activity measured by the number of gadolinium-enhanced lesions (GEL) in the MRI at 3 months after NTZ withdrawal was equivalent to the placebo group. Second, a recent study showed an increase of intrathecal gammaglobulin synthesis 6 months after NTZ interruption [11]. However, several studies of NTZ discontinuation have reported the early presentation of an immune reconstitution inflammatory syndrome (IRIS) as a result of a rebound in the inflammatory activity after NTZ withdrawal, and a return to the inflammatory activity present before NTZ treatment [4, 5]. For these reasons, NTZ drug holidays are not recommended without an alternative treatment; however, to date no specific strategies have been proposed to prevent these from occurring [12, 13]. We report our experience of NTZ interruption with an alternative treatment: monthly 1 g oral methylprednisolone for 3 months followed by daily 20 lg subcutaneous glatiramer acetate. This protocol aimed to prevent the presentation of IRIS [14] and to control the inflammatory activity increase after NTZ discontinuation [7]. The main objective was to study safety and tolerability of the alternative treatment. A second objective was the description of the clinical and radiological activity during follow-up. Methods The prospective observational study was performed in the MS Units of the Hospital Politécnic i Universitari La Fe and the Hospital Clínic Universitari in Valencia. Patients with RRMS treated with NTZ following European regulatory agency indications were offered NTZ interruption after 2 years of treatment, or if adverse events related to NTZ occurred or disease progressed during NTZ (defined as at least one point sustained increase in the EDSS) with the alternative treatment aiming to prevent IRIS and MS reactivation. IRIS has been defined as a severe neurological syndrome that is characterized by dramatic clinical and radiological worsening, which appears soon after NTZ therapy discontinuation. It is due to the massive and accelerated lymphocyte and quimocine trafficking into the brain. Patients developing IRIS suffer fulminant disease progression. MRI shows both atypical radiological presentation, high lesional activity, and diffuse leukoencephalopathy, indicated an unusual inflammatory process affecting the entire brain. IRIS occurs soon after NTZ withdrawal (between 2 and 3 months afterwards) and can clinically present as an acute syndrome with seizures, cognitive and language disturbance, and other symptoms different from relapses [6]. MS reactivation has been defined as the apparition of gadolinium-enhancing lesions or clinical relapse that can occurs between 3 and 6 months after NTZ withdrawal, as a consequence of NTZ plasma disappearance and unblocking of alfa integrins. Treatment after discontinuation was monthly 1 g oral methylprednisolone for 3 months followed by daily 20 lg subcutaneous glatiramer acetate. The protocol was approved by the ethical committee of Hospital Politécnic i Universitari La Fe. We decide to use glatiramer acetate by two reasons. The first reason was that all patients had had a poor response to IFN previous to NTZ treatment (in our country, one indication for natalizumab treatment is suboptimal response to interferon, which is defined as a patient having two or more relapses, or one relapse and one or more gadolinium-enhancing lesion per year, under beta interferon treatment). Second, 6 patients with suboptimal response to interferon (33%) developed neutralizing antibodies (Nabs). For these reasons, we assume that to return to IFN treatment after NTZ discontinuation could be an ineffective treatment alternative. The NTZ withdrawal protocol was as follows: after signing the informed consent, a lumbar puncture and MRI were performed at the moment of NTZ withdrawal. The MRI study was repeated at months 3 and 6. Visits were scheduled monthly during the first 3 months and every 3 months afterwards. Rescue therapy with NTZ was preplanned in cases presenting with new severe relapses. A relapse was defined as the presentation of new signs of neurological disturbance or worsening in 2.0 points in a previously affected functional system sustained for more than 24 hours in the absence of fever. Treatment of Month NTZ-withdrawal Scheduled visits MRi Lumbar puncture MRi 6-MP 6-MP 6-MP Glatiramer Acetate MRi NTZ: natalizumab; MRI: Magnetic resonance imaging; 6-MP: Methyl-prednisolone (1 gr. a day each month for three months) Fig. 1 Diagram of the protocol for natalizumab withdrawal

3 relapses was planned with 1 g of oral methylprednisolone for 3 days, without tapering (Fig. 1). MRI studies were performed using a 1.5 T machine and included brain and cervical spinal cord T1- and T2- weighted images, brain FLAIR images, and spinal cord STIR images as well as brain and spinal cord T1-weighted images after the administration of 0.1 mmol of intravenous gadolinium. The study of the cerebrospinal fluid (CSF) included the determination of the JC virus by real time PCR (cut-off of 50 copies). Lumbar puncture was performed at the moment of NTZ discontinuation, prior to starting corticosteroid treatment. Oligoclonal bands of IgM and IgG were determined by isoelectrofocusing and immunodetection methods in paired samples of serum and CSF. Immunological studies in serum or CSF, e.g., CD4/CD8 count, were not performed. The main objective was to study safety and tolerability of pulsed methylprednisolone followed by glatiramer acetate after NTZ withdrawal. The secondary objectives were to explore the presentation of IRIS and occurrence of MRI and/or clinical disease activity during the 6 months after NTZ withdrawal. Finally, the outcome of patients after 6 months was also performed. The following variables were recorded at study onset: age; sex; evolution time; previous treatments; number of relapses in the year before, during, and after NTZ treatment withdrawal; EDSS at the beginning of NTZ treatment, at NTZ withdrawal, and 6 months after NTZ withdrawal, and number of gadolinium-enhanced lesions (GEL) at the beginning of NTZ treatment, at NTZ withdrawal, and at month 3 and 6 after NTZ withdrawal. Results At the moment of the ethical committee approval, 63 patients were receiving NTZ treatment at our hospitals. A total of 16 patients had reached 2 years of treatment and were offered information, of which 15 patients gave written, informed consent and entered the study. In addition, 3 other patients discontinued NTZ treatment for other reasons (1 patient experienced an anaphylaxis reaction, 1 patient had a systemic infection, and 1 patient discontinued NTZ therapy because of progression of disability) and consented to enter the study. Thus, a total of 18 patients entered the aforementioned study. The study group consisted of 83.3% females, with a mean age of 35 and a mean disease duration of 10 years. All patients had received immunomodulatory or immunosupressant therapy and had experienced a mean number of 2.0 relapses the year before NTZ, having a median number of 1.5 GEL and an EDSS of 3.5 at NTZ initiation. Before starting NTZ therapy, all patients had received one of the three beta interferon (IFN) medications approved for the treatment of MS. Four of them were switched to NTZ after only one immunomodulatory IFN treatment; three patients were switched to NTZ after two beta IFN, first IFN of low doses, followed by IFN of high doses. Five of the patients had still been treated with glatiramer acetate because IFN was not effective. Two patients were in treatment with IFN plus pulsed steroids, and finally, 4 patients had received some type of immunosupressant drugs: 2 daclizumab, 1 fingolimod, and 1 azathioprine. Thus, it can be noted that this group of patients had very active forms of MS, so we assume that the risk of return of previous activity disease after NTZ withdrawal without an alternative regimen of treatment with corticosteroids was too high. Patients received NTZ treatment during a mean of 23 months. The annualized relapse rate under NTZ treatment was 0.1, the percent of relapse-free patients under NTZ treatment was 66.6% (12/18), and the reduction of the annualized relapse rate was 83.8% (Fig. 2). The EDSS decreased significantly to 3.0 at the end of NTZ treatment (p = 0.02) and increased to 3.3 at month 6 after NTZ withdrawal; this increase was compared to the EDSS at the beginning or the end of NTZ treatment (Fig. 3). The median number of cumulated GEL at the end of treatment was 0.05 and increased to 1.5 at month 6 after NTZ withdrawal. There were significant differences in the reduction of GEL compared with the median GEL at baseline and 6 month after NTZ withdrawal, but not between the median number of GEL at month 6 and the baseline (Table 1, Fig. 4). The patients were followed after NTZ withdrawal for a mean time of 10 months (range 6 18). Methylprednisolone and glatiramer acetate were well tolerated, and no significant adverse events were reported. Annualized Relapses Rate p= p= Reduction of the ARR 83.8% 0.1 year before NTZ under NTZ 6 month after NTZ Fig. 2 Annualized relapses rate in the year before NTZ treatment, under NTZ, and 6 months after NTZ withdrawal and under the alternative protocol studied (mean and standard deviation) 0.3

4 Regarding the MRI inflammatory activity, at month 3 no patients showed GEL in the MRI and 10 (55.5%) at month 6. The median number of GEL at month 6 was 1.5 (range 0 18) with no significant differences compared to the number of GEL in the MRI prior to starting NTZ therapy (median 1.0; SD 1.8; p = 0.61) (Wilcoxon test). With respect to clinical activity, at month 3 no patient had any relapse, while 3 patients (16.6%) had had a relapse by month 6. After 6 months, 6 more patients (33.3%) experienced a relapse; all of them had radiological activity present at month 6 (Table 2). There was no significant difference between mean EDSS at NTZ discontinuation and after 6 months (3.0 vs. 3.3, p [ 0.05). A total of 9 patients (50%) returned to NTZ treatment after 6 months due to disease activity. 2.0 p= p= p= Mean EDSS Basal EDSS EDSS at the end of NTZ EDSS 6 month after NTZ 0.0 Basal On NTZ treatment 3 month after NTZ 6 months after NTZ Fig. 3 EDSS evolution: at the moment of beginning NTZ, at the end of NTZ treatment, and 6 months after TNZ withdrawal (mean and standard deviation) Fig. 4 Median gadolinium-enhanced lesions at the beginning of NTZ, at the end of NTZ (cumulated GEL), at 3 months after NTZ withdrawal, and 6 months after finishing NTZ treatment Table 1 Clinical and demographic characteristics of the patients included in the study Case no. Age Sex MS duration (y) Previous treatments Relapses prev. year Basal EDSS Basal GEL Time on NTZ (m) Relapses during NTZ EDSS at NTZ end GEL at NTZ end 1 28 F 10 AV? 6MP Yes F 3 AV Yes F 5 REB, DCL Yes F 4 GA, REB Yes F 8 REB, GA Yes M 18 MTZ Yes F 17 BET? DCL No F 20 BET No M 16 REB No F 18 AV, REB, GA, No BET M 16 REB No F 12 REB? AZA No F 3 AV, REB No F 17 REB, MTZ, GA No F 8 REB, FGM, GA No F 10 GA, REB No F 7 BET, CP No M 5 BET No Mean range (%) 35.3 (23 54) 3/15 83% 10.9 (3 20) 2.06 (1 5) 3.5 ( ) 1.5 (0 9) 23.6 (12 28) 6/18 (33.3%) 3.0 ( ) (1/18) Case no. case number, y years, m months, GEL gadolinium-enhancing lesions, NTZ natalizumab, AV avonex, 6MP pulses of 6 methylprednisolone, GA copaxone, REB rebif, MTZ mitoxantrone, DCL daclizumab, BET betaferon, FGM fingolimod

5 No patients experienced IRIS. Two patients had a high numberofgelinthe6 monthmri(14and18gel),butiris was ruled out as these lesions were typical of MS (Fig. 5), and patients were neurologically stable at the moment of MRI [15]. Moderate relapses occurred in both patients during the following month, which responded well to steroids (Table 2). JCV in the CSF was detected in only one patient. This patient did not experience any clinical or radiological sings Fig. 5 Gadolinium-enhancing lesions in cases 11 (a) and 12 (b), who had a high MR activity present at month 6. Mild relapses occurred during the following month, with complete recovery after steroid treatment Table 2 Clinical and radiological evolution of the series after NTZ withdrawal Case no. Reason for withdrawal Time follow up (m) Cumulated relapses m 6 Cumulated relapses end of follow-up (months after withdrawal) GEL at 3 m GEL at 6 m EDSS m 6 Return to NTZ 1 Protocol 12 Yes Yes (6) Yes 2 Anaphylaxis 6 Yes Yes (4) No (SAE) 3 Protocol 12 No Yes (8) Yes 4 Systemic infection 18 No Yes (8) No (VJC-DNA?) 5 Protocol 9 No No Yes 6 Protocol 6 No No No (stabilized) 7 Protocol 8 Yes Yes (6) Yes 8 Protocol 10 No No No (stabilized) 9 Protocol 12 No Yes (9) Yes 10 Protocol 12 No Yes (7) Yes 11 Protocol 9 No Yes (7) Yes 12 Protocol 11 No Yes (7) Yes 13 Protocol 7 No No No (stabilized) 14 Protocol 6 No No Yes 15 Protocol 12 No No No (stabilized) 16 Protocol 8 No No No (stabilized) 17 Treatment failure a 11 No No No (progression) 18 Protocol 12 No No No (stabilized) Mean range (%) 10.5 (6 18) 3/18 (16%) 9/18 (50%) (0 18) 3.3 ( ) 9/18 (50%) Case n case number, y years, m months, GEL gadolinium-enhancing lesions a In this case, NTZ was withdrawn because a sustained increase in the EDSS 6 months before NTZ withdrawn was present, and she continued to progress after NTZ withdrawal

6 of PML (20 months of follow-up). In this patient, NTZ therapy has not been re-established in spite of the appearance of new relapses. In a new lumbar puncture performed 20 months later, no JVC was detected. Discussion Alternative treatment with pulsed methylprednisolone followed by glatiramer acetate after NTZ withdrawal was safe and well tolerated. There were no cases of IRIS in our series. Clinical relapses at 6 months occurred in 16.6% of patients, and MS reactivation occurred in more than half of the patients, with radiological activity in 55.5% of cases by month 6 while clinical activity was more frequent after month 6. All patients that experienced further relapses after month 6 had inflammatory activity present in the sixth month MRI. Our series included highly inflammatory MS patients (at least one relapse and inflammatory activity on MRI in spite of immunomodulatory or immunosuppressant treatment). The reduction of the annual relapse rate of 83.8% was similar to previously reported reduction of 80% in aggressive MS [16]. Several NTZ withdrawal experiences have been reported. First, the interruption of NTZ in the safety-extension studies of AFFIRM, SENTINEL, and GLANCE studies was reported in two studies [11, 17]. In a subset of 23 patients followed prospectively, cessation of NTZ was not followed by clinical, radiological, or immunological rebound [11]. But when retrospective analysis included 946 of 949 patients treated with NTZ in the extension phase, disease activity was shown to rapidly return after discontinuation, and treatment with other disease-modifying therapies did not influence the rebound, although diseasemodifying therapy had been used in the majority of cases [17]. The return of inflammatory activity seems to be related to the pre-ntz level of activity [18, 19], which could explain the absence of rebound in the subset of 23 patients initially reported. In other work, a subgroup of 10 patients with active disease discontinued NTZ without alternative treatment [5]. Cumulatively, a combination of clinical relapse and new and/or enhanced lesions on MRI had occurred in 5 of 10 patients by month 3, and 7 of 10 patients by month 6. They also report the occurrence of one case of IRIS. Relapse onset seems to occur in a median time of 3 months after discontinuation [13]. Additional communications with similar results have been recently reported by several groups [20 22]. Two groups have reported the preliminary experiences with immunomodulatory treatment after NTZ interruption [18 23]. No relapses have been observed after a mean of 2.5 months in 7 patients treated with glatiramer acetate (5 patients) or interferon beta (2 patients) [18]. In the other study, glatiramer acetate was used as an alternative treatment to prevent inflammatrory activity rebound, but at sixth month MRI 9 of 22 patients (49.9%) developed gadolinium enhahcing lesions. Relapses occur mainly after 6 months, unlike in the studies in which NTZ was interrupted without alternative treatment, and there were no IRIS. This could be due at least in part to the alternative treatment. The presence of a control group would have helped to establish the effectiveness of alternative treatment. Finally, it should be stressed that after 6 months 50% of patients treated with this protocol returned to the previous inflammatory activity, mostly patients with active MRI at month 6, while patients without activity in the MRI at 6 months remained stable, in a manner that was similarly observed in the two studies in which withdrawal of NTZ was follow by immunmodulatory therapy [17 23], the only difference with the aforementioned studies and our protocol is the use of pulsed methylprednisolone that can help to prevent the development of IRIS. In conclusion, NTZ withdrawal is follow by a return to the previous inflammatory activity despite the use of inmunomodulatory alternative treatment, but adding a regimen of pulsed methylprednisolone can reduce the presentation of IRIS and improve the control in the rebound of the inflammatory activity. Acknowledgments This work has been performed with the financial support from the following national projects (FIS PI and FIS PS09/00551 from the Carlos III Institute from Spain). The authors also thank nurses of the MS units (Matilde Escutia and Ana Bernal). Conflict of interest References None. 1. Polman CH, O Connor PW, Havrdova E et al (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354: Rudick RA, Stuart WH, Calabresi PA et al (2006) Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354: Safety report from Biogen Idec, data on file. October Miravalle A, Jensen R, Kinkel RP et al (2010) Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol. [Epub ahead of print] 5. Killestein J, Vennegoor A, Strijbis EM et al (2010) Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol 68: Lenhard T, Biller A, Mueller W, Metz I, Schönberger J, Wildemann B (2010) Immune reconstitution inflammatory syndrome after withdrawal of natalizumab? Neurology 75(9): Vellinga MM, Castelijns JA, Barkhof F, Uitdehaag BM, Polman CH (2008) Postwithdrawal rebound increase in T2 lesional

7 activity in natalizumab-treated MS patients. Neurology 70: Hartung HP (2009) New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol 8: Miller DH, Khan OA, Sheremata WA et al (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348: Dalton CM, Miszkiel KA, Barker GJ et al (2004) Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis. J Neurol 251: Stüve O, Cravens PD, Frohman EM et al (2009) Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 72: Giannuli E, Marousi S, Karkanis I, Graigos A, Kotsi V (2010) Natalizumab discontinuation after long-term administration: our own experience. Mult Scler 16:S West TW, Cree BA (2010) Natalizumab dosage suspension: are we helping or hurting? Ann Neurol 68: Tan K, Roda R, Ostrow L, McArthur J, Nath A (2009) PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 72: Shelburne SA, Montes M, Hamill RJ (2006) Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 57: Hutchinson M, Kappos L, Calabresi PA et al (2009) The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL. J Neurol 256: O Connor PW, Goodman AD, Kappos L et al (2009) Return of disease activity after cessation of natalizumab therapy in patients with multiple sclerosis. Mult Scler 15:S Sangalli F, Moiola L, Radaelli M, Barcella V, Martinelli V, Comi G (2010) Starting immunomodulatand shortly after natalizumab discontinuation: initial impressions. Mult Scler 16:S Kebrat A, Le Page E, Leray E et al (2010) Assessment of disease activity within 6 months after natalizumab discontinuation: and observational study of 28 consecutive relapsing-remitting multiple sclerosis patients. Mult Scler 16:S Pesci I, Magnani S, Carini D et al (2010) Stopping natalizumab therapy: experience of follow-up in a MS center, FIdrenza, Italy. Mult Scler 16:S Baugmartner A, Stich O, Rauer S (2010) Clinical and radiological diseases reactivation after cessation of long-term therapy with natalizumab. Mult Scler 16:S Cocco E, Lorefice L, Frau J et al (2010) Natalizumab discontnuiation in multiple sclerosis: experience of a single center. Mult Scler 16:S Rossi S, Ristori G, Studer V et al (2010) An open-label, nonrandomized, prospective, multicenter study to evaluate the safety and tolerability of glatiramer acetate 20 mg sc once daily in patients with severe relapsing-remitting multiple sclerosis that have discontinued natalizumab after 12 to 18 months therapy. Preliminary results. Mult Scler 16:S133