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Switching from fingolimod to alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis: Α case series
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Switching from fingolimod to alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis: A case series Konstantinos Notas , Efrosini Papadaki , Anastasios Orologas , Maria Moschou , Vasilios K. Kimiskidis Professor PII: DOI: Reference:
S2211-0348(19)30838-7 https://doi.org/10.1016/j.msard.2019.101517 MSARD 101517
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
8 July 2019 2 November 2019 10 November 2019
Please cite this article as: Konstantinos Notas , Efrosini Papadaki , Anastasios Orologas , Maria Moschou , Vasilios K. Kimiskidis Professor , Switching from fingolimod to alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis: A case series, Multiple Sclerosis and Related Disorders (2019), doi: https://doi.org/10.1016/j.msard.2019.101517
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Highlights Alemtuzumab appears to be effective in highly active MS cases who fail fingolimod Alemtuzumab may be beneficial for the treatment of disease flare-up post fingolimod One patient developed persistent lymphocytosis after alemtuzumab administration
Switching from fingolimod to alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis: Α case series
Konstantinos Notasa, Efrosini Papadakib, Anastasios Orologasc, Maria Moschoua, Vasilios K. Kimiskidisa* a
Laboratory of Clinical Neurophysiology, Aristotle University of Thessaloniki, AHEPA University Hospital, Stilponos Kyriakidi 1, 54636, Thessaloniki, Greece. b
Department of Radiology, School of Medicine, University of Crete, Heraklion, 70013, Crete, Greece c
Multiple Sclerosis Center, Saint Luke’s Hospital, Panorama, 55236, Thessaloniki, Greece
*Corresponding author: Professor Vasilios K. Kimiskidis, Laboratory of Clinical Neurophysiology, Aristotle University of Thessaloniki, AHEPA University Hospital, Stilponos Kyriakidi 1, 54636, Thessaloniki, Greece. Email address: [email protected]
Abstract: Background: The management of “aggressive” and “highly-active” relapsing-remitting multiple sclerosis remains problematic. Although a number of highly efficacious agents are currently available, the optimal timing of their use and the balancing between efficacy and immediate and long-term consequences are still a matter of conjecture. Methods: We describe the clinical, radiological and immunological profile of three multiple sclerosis patients with persistent clinical and radiological disease activity under fingolimod treatment. After fingolimod cessation patients demonstrated severe disease exacerbation and were successfully treated with alemtuzumab. Results: All patients experienced significant improvement after the administration of alemtuzumab and achieved no evidence of disease activity status that persisted after a median of 19 months of follow-up (range: 17-25 months). Confirmed disability improvement was achieved in all cases. Quantitative MRI data demonstrated a reduction of the T2 lesion load in 2 out of 3 patients and complete abrogation of inflammatory activity in all patients after the administration of alemtuzumab. Α patient presented a previously unreported, persistent lymphocytosis after alemtuzumab administration, that was not associated with infectious, lymphoproliferative or autoimmune diseases and had no apparent clinical implications. Conclusions: Alemtuzumab appears to be an effective and safe short-term therapeutic option both as a rescue therapy for the disease flare-up associated with fingolimod withdrawal, as well as for the reversal of the deteriorating course observed in patients who fail treatment with fingolimod.
Keywords highly-active multiple sclerosis; alemtuzumab; fingolimod
Manuscript 1. Introduction The natural course of multiple sclerosis (MS) is characterized by significant heterogeneity, depending on the underlying pathophysiology. Relapsing-remitting is the most frequent disease subtype (RRMS) which occasionally takes the form of “aggressive” and “highly-active” RRMS. These ill-defined terms typically refer to a disease course with persistent relapses, rapid accumulation of disability, and severe inflammatory activity in magnetic resonance imaging (MRI) (Fernandez, 2017). The management of these entities remains problematic. Although a number of highly efficacious agents are currently available, the optimal timing of their use and the balancing between efficacy and immediate and long-term consequences are still a matter of conjecture. The present report contributes to the relevant literature by describing the clinical, radiological and immunological profile of 3 cases of highly active RRMS, characterized by severe disease reactivation after fingolimod cessation, that were successfully treated with alemtuzumab. Informed consent for inclusion in this study was obtained from the patients. Volumetric measurements were performed using the Image J Software (Image J κ1.45, NIH, USA). 2. Case reports 2.1 Patient 1 Patient 1 is a 32-year-old female with an 11-year history of RRMS. After her diagnosis, patient refused to receive any treatment for four years. After a relapse, she was treated with glatiramer acetate for just one year, which was replaced by fingolimod due to a new severe relapse [Expanded Disability Status Scale (EDSS):3]. The patient remained free of any disease activity for more than six years (EDSS:2.5), but eventually presented a disabling relapse (EDSS:4), accompanied by significant MRI inflammatory activity (Table 1), (Supplementary Table), (Figure 1A). Taking into consideration the patient’s reproductive plan, an escalation to alemtuzumab was decided. Two months after fingolimod withdrawal, the patient developed a multifocal severe relapse (EDSS:6), and her brain MRI demonstrated numerous new focal and coalescent demyelinating lesions, some of them with ring or nodular enhancement, indicative of active disease (Figure 1B). The patient’s lymphocyte counts were normal, so alemtuzumab was initiated, along with a steroid tapering cycle. In the next months, her disability improved remarkably (at month two post-infusion EDSS was 4, and ten months later EDSS was 2.5). At month nine post-infusion, a new brain MRI scan revealed substantial improvement with decrease of T2 lesions load (Table 1) and no evidence of disease activity (Figure 1C). The patient’s absolute lymphocyte counts (ALC) after alemtuzumab administration normalized rapidly (<3 months) (baseline ALC: 2491 cells/mm³, ALC at month 3: 1800 cells/mm³), but thereafter reversed to a previously unreported, persistent lymphocytosis, not associated with infectious, lymphoproliferative or autoimmune diseases (peak ALC at month 9: 6100 cells/mm³). Immunophenotype of the peripheral blood lymphocytes 12 months after alemtuzumab administration
demonstrated excessive proliferation of CD8+ T cells [ALC: 3380 cells/mm³, CD19+: 394,41 cells/mm³ (11,7%), CD4+: 756.88 cells/mm³ (22,4%), CD8+:1778,9 cells/mm³ (52,6%)]. After the second cycle of alemtuzumab administration, the patient’s lymphocyte counts demonstrated the same kinetics of recovery, with a different subpopulation pattern (Supplementary figure). 2.2 Patient 2 Patient 2 is a 41-year-old male with a 3-year history of MS. After his first relapse, the patient developed spastic paraparesis due to a spinal cord lesion, with incomplete recovery, despite high dose steroid treatment (EDSS:3.5). Anti-aquaporin-4 and antimyelin oligodendrocyte glycoprotein antibody tests were negative and he did not fulfil the criteria for a seronegative neuromyelitis optica spectrum disorder. The patient was initially treated with interferon beta 1a. After five months, treatment escalated to fingolimod due to a new relapse (EDSS:4). Two years later, the patient’s disability deteriorated further (EDSS:5) and a new spinal cord lesion was detected in the MRI in the absence of active brain lesions (Supplementary Table). The patient was positive for anti-John Cunningham Virus (JCV) antibodies. Due to rapid accumulation of disability, a switch to alemtuzumab was decided. Three months after fingolimod discontinuation, the patient was clinically stable and his lymphocyte counts were normal. Remarkably, brain MRI demonstrated numerous new ring and nodular enhancing demyelinating lesions, indicating inflammatory activity. Alemtuzumab was administered, with satisfactory clinical response (no further relapses, reduction in disability (EDSS:4)) and tolerance. A follow-up brain MRI 11 months after the first cycle showed improvement of T2 lesion load and absence of gadolinium enhancing (Gd+) lesions (Table 1). An uneventful second alemtuzumab cycle was recently administered. 2.3 Patient 3 Patient 3 is a 25-year-old female with a 9-year history of RRMS. The patient was on interferon beta 1b treatment for two years, before initiating to fingolimod due to persistent disease activity. After four stable years under fingolimod treatment (EDSS:1,5), the patient presented with three clinical relapses in one year, accompanied by intense radiological activity (Table 1) (EDSS:2,5). The patient was positive for anti-JCV antibodies, with a high index (2,7). A switch to alemtuzumab was planned; however, the patient developed prolonged lymphopenia for 24 weeks after fingolimod discontinuation. During this period, she suffered consecutive relapses every six weeks and was treated with three steroid cycles, followed by intravenous immunoglobulin (EDSS:3,5). Alemtuzumab was then initiated and the patient has been free of any disease activity afterward (EDSS:2). Six months after the second course of alemtuzumab, brain MRI revealed improvement of the T2 lesion load and lack of Gd+ lesions (Table 1), (Supplementary Table). 3. Discussion The present small-scale case series confirms and extends previously reported real world data from German and Italian cohorts suggesting that alemtuzumab is a promising therapeutic option in patients with highly-active RRMS on fingolimod (Frau et al., 2019; Huhn et al., 2018) All three patients reported herein, fulfilled the criteria of highly-active MS, as evidenced by persistent clinical and radiological disease activity under treatment and further exacerbation after withdrawal of fingolimod. Strictly speaking, one patient
(Patient 1) suffered from a rebound phenomenon and the other two from severe disease reactivation (Frau et al., 2018). Discontinuation of fingolimod in active RRMS patients may trigger disease reactivation, that may be related to the aggressive course of a highly active disease or occur subsequent to a massive exit of lymphocytes, possibly including Th17 T cells, to the periphery (Cavone et al., 2015). The exact incidence of this phenomenon is not clear. Hatcher et al. detailed the concept of a possible rebound after fingolimod cessation, describing severe clinical and inflammatory activity, that exceeded baseline activity, in 5 out of 46 patients (10,9%) (Hatcher et al., 2016). On the contrary, a post-hoc analysis, albeit with certain limitations, of the core Phase III fingolimod trials failed to recognize any pattern of unusually high disease activity after fingolimod withdrawal (Vermersch et al., 2017). Recently, Frau et al. described a cohort of 100 patients and concluded that the risk of a rebound phenomenon and severe reactivation is lower than previously thought (5% and 10% respectively) (Frau et al., 2018). Despite this aggressive clinical course, all patients rapidly experienced significant improvement after the administration of alemtuzumab and achieved No Evidence of Disease Activity (NEDA) status that persists after a median of 19 months of follow-up (range: 17-25 months). A previous study by Alcala et al in 28 RRMS patients who failed treatment with fingolimod, demonstrated that alemtuzumab induced NEDA in 82%, and conferred Confirmed Disability Improvement (CDI) in 35.7% of the patients. Comparable positive results were also observed with the use of anti-CD20 therapies, such as rituximab (Alcala et al., 2019). On the other hand, Schmidt and Schulten described a transient disease aggravation in 2 ocrelizumab treated patients, that presented rebound phenomenon after fingolimod cessation (Schmidt and Schulten, 2019). In our cohort, CDI was achieved in all cases in reference to both their worst neurological status, just before the administration of alemtuzumab, but also just before the withdrawal of fingolimod (Table 1). This observation indicates that alemtuzumab is an effective therapeutic option both as a rescue therapy for the disease flare-up associated with fingolimod withdrawal as well as for the reversal of the deteriorating course observed in patients who fail treatment with fingolimod. Interestingly enough, alemtuzumab proved to be effective even in a patient (Patient 2) that might be considered a case of primary progressive MS with relapses. These favourable clinical effects were corroborated by quantitative MRI data demonstrating a reduction of the T2 lesion load in 2 out of 3 patients and complete abrogation of inflammatory activity in all patients after the administration of alemtuzumab. These findings are in line with previous studies demonstrating a decrease in the number of new T2 lesions and a reduction of T1 Gd+ lesions under alemtuzumab (Frau et al., 2019; Huhn et al., 2018). It is worth noting that two of our patients developed tumefactive lesions after fingolimod withdrawal, which responded dramatically, from a clinical and radiological point of view, after the administration of alemtuzumab. A previous study described a beneficial effect of alemtuzumab in two cases that developed tumefactive lesions after fingolimod withdrawal, although no MRI data were provided (Sanchez et al., 2018).
On the other hand, there are reports of persistent or increased disease activity in alemtuzumab-treated patients following fingolimod withdrawal. An observational study by Willis et al. identified 9 out of 36 such cases, raising the hypothesis that the unexpected disease activity is stimulated by isolated lymphocytes, which remain hidden inside the lymph nodes, eluding from the usual depletion caused by alemtuzumab, due to a short (median six weeks) washout period (Willis et al., 2017). It should be noted, however, that refractory disease activity on alemtuzumab did not correlate with the baseline lymphocyte counts or the washout interval both in German and Italian cohorts (median washout periods 19 and 7 weeks, respectively) (Frau et al., 2019; Huhn et al., 2018). When shifting from fingolimod to alemtuzumab, it is reasonable to wait for a sufficient time interval, until lymphocyte counts recover. The optimal wash out period remains a matter of debate, due to limited published data, and should be individualized. According to the aforementioned studies, a short washout period (6-7 weeks) is preferable and has the advantage of minimizing the risk of disease reactivation after fingolimod withdrawal. Still, if a patient develops prolonged moderate to severe lymphopenia after fingolimod cessation, restraining the administration of alemtuzumab, certain strategies should be adopted, particularly if severe disease reactivation occurs during the wash-out period. These include steroid pulse therapies, plasma exchange or, theoretically, short-term administration of other agents that prevent immune cell trafficking. Assessment of Th17 T cells might be useful in predicting a possible disease flair-up (Cavone et al., 2015; Haas et al., 2017). The decision to administer alemtuzumab must be carefully reached, in the light of recent reports of rare but serious adverse effects and the warnings issued by the European Medicines Agency and United States Food and Drugs Administration (EMA/583516/2019, 2019, October 31; U.S. Food and Drug Administration, 2018, November 29). In our patients, alemtuzumab was not associated with any unexpected safety issues. On the other hand, the persistent lymphocytosis observed in Patient 1, although unassociated with clinical worsening or any complications, warrants further investigation as to its possible pathogenetic mechanisms and clinical implications (Supplementary figure). In conclusion, alemtuzumab appears to be an effective and safe short-term therapeutic option in highly active RRMS patients who fail fingolimod treatment, including cases with tumefactive MS. Prospective larger studies are warranted to verify these results and unveil any additional long-term safety issues.
Acknowledgements None
Conflict of interest K.N received travel grants and/or speaking honoraria and consultation fees from Sanofi-Genzyme, Novartis, Genesis Pharma, Teva Pharmaceuticals, Mylan, Roche and Merck; received research grants from Genesis Pharma. E.P declared no relative to this work conflict of interest. A.O. received travel grants and/or speaking honoraria and consultation fees from Merck, Bayer Schering, Sanofi-Genzyme, Teva Pharmaceuticals, Novartis, Genesis Pharma, Mylan, Roche; received research grant support from Merck, Sanofi-Genzyme, Teva Pharmaceuticals, Novartis, Genesis Pharma. M.M. received travel grants from Sanofi-Genzyme, Novartis, Mylan and Merck and research grants from Sanofi-Genzyme. V.K.K. within the past 24 months received honoraria as a member of an advisory board or panel from Specifar-Teva Pharmaceuticals, Sanofi-Genzyme, UCB, Genesis Pharma and Merck.
Study funding This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
References: Alcala, C., Gascon, F., Perez-Miralles, F., Dominguez, J.A., Gil-Perotin, S., Casanova, B., 2019. Treatment with alemtuzumab or rituximab after fingolimod withdrawal in relapsing-remitting multiple sclerosis is effective and safe. Journal of neurology 266(3), 726-734. doi: 10.1007/s00415-019-09195-2 Cavone, L., Felici, R., Lapucci, A., Buonvicino, D., Pratesi, S., Muzzi, M., Hakiki, B., Maggi, L., Peruzzi, B., Caporale, R., Annunziato, F., Amato, M.P., Chiarugi, A., 2015. Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound. Brain, behavior, and immunity 50, 78-86. doi: 10.1016/j.bbi.2015.06.019 EMA/583516/2019, 2019, October 31. Lemtrada for multiple sclerosis: measures to minimise risk of serious side effects. https://www.ema.europa.eu/en/documents/referral/lemtrada-article-20-procedurelemtrada-multiple-sclerosis-measures-minimise-risk-serious-side_en.pdf. Fernandez, O., 2017. Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS? Multiple sclerosis and related disorders 17, 75-83. doi: 10.1016/j.msard.2017.07.003 Frau, J., Sacca, F., Signori, A., Baroncini, D., Fenu, G., Annovazzi, P., Capobianco, M., Signoriello, E., Laroni, A., La Gioia, S., Sartori, A., Maniscalco, G.T., Bonavita, S., Clerico, M., Russo, C.V., Gallo, A., Lapucci, C., Carotenuto, A., Sormani, M.P., Cocco, E., 2019. Outcomes after fingolimod to alemtuzumab treatment shift in relapsing-remitting MS patients: a multicentre cohort study. Journal of neurology. doi: 10.1007/s00415-019-09424-8 Frau, J., Sormani, M.P., Signori, A., Realmuto, S., Baroncini, D., Annovazzi, P., Signoriello, E., Maniscalco, G.T., La Gioia, S., Cordioli, C., Frigeni, B., Rasia, S., Fenu, G., Grasso, R., Sartori, A., Lanzillo, R., 2018. Clinical activity after fingolimod cessation: disease reactivation or rebound? 25(10), 1270-1275. doi: 10.1111/ene.13694 Haas, J., Schneider, K., Schwarz, A., Korporal-Kuhnke, M., Faller, S., von Glehn, F., Jarius, S., Wildemann, B., 2017. Th17 cells: A prognostic marker for MS rebound after natalizumab cessation? Multiple sclerosis (Houndmills, Basingstoke, England) 23(1), 114-118. doi: 10.1177/1352458516640609 Hatcher, S.E., Waubant, E., Nourbakhsh, B., Crabtree-Hartman, E., Graves, J.S., 2016. Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment. JAMA neurology 73(7), 790-794. doi: 10.1001/jamaneurol.2016.0826 Huhn, K., Bayas, A., Doerck, S., Frank, B., Gerbershagen, K., Hellwig, K., Kallmann, B., Kleinschnitz, C., Kleiter, I., Lee, D.H., Limmroth, V., Maurer, M., Meuth, S., Rieckmann, P., Ruck, T., Gold, R., Linker, R.A., 2018. Alemtuzumab as rescue therapy in a cohort of 50 relapsing-remitting MS patients with breakthrough disease on fingolimod: a multi-center observational study. Journal of neurology 265(7), 15211527. doi: 10.1007/s00415-018-8871-2 Sanchez, P., Meca-Lallana, V., Vivancos, J., 2018. Tumefactive multiple sclerosis lesions associated with fingolimod treatment: Report of 5 cases. Multiple sclerosis and related disorders 25, 95-98. doi: 10.1016/j.msard.2018.07.001
Schmidt, S., Schulten, T., 2019. Severe rebound after cessation of fingolimod treated with ocrelizumab with coincidental transient aggravation: report of two cases. Therapeutic advances in neurological disorders 12, 1756286419846818. doi: 10.1177/1756286419846818 U.S. Food and Drug Administration, 2018, November 29. FDA warns about rare but serious risks of stroke and blood vessel wall tears with multiple sclerosis drug Lemtrada (alemtuzumab). https://www.fda.gov/drugs/drug-safety-and-availability/fdawarns-about-rare-serious-risks-stroke-and-blood-vessel-wall-tears-multiple-sclerosisdrug. Vermersch, P., Radue, E.W., Putzki, N., Ritter, S., Merschhemke, M., Freedman, M.S., 2017. A comparison of multiple sclerosis disease activity after discontinuation of fingolimod and placebo. Multiple sclerosis journal - experimental, translational and clinical 3(3), 2055217317730096. doi: 10.1177/2055217317730096 Willis, M., Pearson, O., Illes, Z., Sejbaek, T., Nielsen, C., Duddy, M., Petheram, K., van Munster, C., Killestein, J., Malmestrom, C., Tallantyre, E., Robertson, N., 2017. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurology(R) neuroimmunology & neuroinflammation 4(2), e320. doi: 10.1212/NXI.0000000000000320
Table 1 Comparison of relapse rates and MRI characteristics in three RRMS patients that switched from fingolimod to alemtuzumab treatment, due to refractory disease activity. Pt 1
Pt 2
Pt 3
Relapses under Fingolimod (last 12 months)
1
1
3
Wash out interval (weeks)
8
10
24
Relapses during wash out period
1
0
4
Relapses post Alemtuzumab
0
0
0
T2 lesion load under Fingolimod (mm3 )
34121
4463
18890
T2 lesion load during wash out period (mm3 )
70952
8071
n/a
T2 lesion load post Alemtuzumab (mm3 )
27199
6629
15748
Number/T1 load (mm3) of gadolinium enhancing lesions under Fingolimod
4/331
0
9/829
Number/T1 load (mm3) of gadolinium enhancing lesions during wash out period Number/T1 load (mm3) of gadolinium enhancing lesions post Alemtuzumab
23/12956 7/930 0/0
0/0
n/a 0/0
MRI: magnetic resonance imaging; RRMS: relapsing remitting multiple sclerosis; Pt: patient; n/a: not available; mm: millimetre
Figures
Figure 1. Brain MRI of patient 1 in A) Fluid attenuation inversion recovery (FLAIR) (TR/TE/TI = 9502/144/2350msec) and post-gadolinium T1 Multi Echo Multiplanar (MEMP) (TR/TE = 660/12msec), B) FLAIR (TR/TE/TI = 8002/143.2/2000 msec) and post-gadolinium T1 three dimension fast spoiled gradient echo (TR/TE = 12.4/5.1 msec) and C) FLAIR (TR/TE/TI=8002/142.8/2000 msec) and post-gadolinium T1 MEMP (TR/TE= 480/10 msec) sequences. Typical ovoid, coalescent, hyperintense on FLAIR, demyelinating lesions, under fingolimod treatment, some of them with gadolinium enhancement (upper row=A). Two months after the discontinuation of fingolimod (middle row=B), there is remarkable deterioration of the findings, with increase of the number and size of the lesions, increase in the number of the enhancing lesions and presence of a large tumefactive subcortical lesion, with peripheral enhancement at the right frontal lobe. Nine months after the administration of alemtuzumab, there is significant decrease in the number of the lesions and no evidence of gadolinium enhancement (lower row=C).
Switching from fingolimod to alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis: A case series Konstantinos Notas , Efrosini Papadaki , Anastasios Orologas , Maria Moschou , Vasilios K. Kimiskidis Professor PII: DOI: Reference:
S2211-0348(19)30838-7 https://doi.org/10.1016/j.msard.2019.101517 MSARD 101517
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
8 July 2019 2 November 2019 10 November 2019
Please cite this article as: Konstantinos Notas , Efrosini Papadaki , Anastasios Orologas , Maria Moschou , Vasilios K. Kimiskidis Professor , Switching from fingolimod to alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis: A case series, Multiple Sclerosis and Related Disorders (2019), doi: https://doi.org/10.1016/j.msard.2019.101517
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
Highlights Alemtuzumab appears to be effective in highly active MS cases who fail fingolimod Alemtuzumab may be beneficial for the treatment of disease flare-up post fingolimod One patient developed persistent lymphocytosis after alemtuzumab administration
Switching from fingolimod to alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis: Α case series
Konstantinos Notasa, Efrosini Papadakib, Anastasios Orologasc, Maria Moschoua, Vasilios K. Kimiskidisa* a
Laboratory of Clinical Neurophysiology, Aristotle University of Thessaloniki, AHEPA University Hospital, Stilponos Kyriakidi 1, 54636, Thessaloniki, Greece. b
Department of Radiology, School of Medicine, University of Crete, Heraklion, 70013, Crete, Greece c
Multiple Sclerosis Center, Saint Luke’s Hospital, Panorama, 55236, Thessaloniki, Greece
*Corresponding author: Professor Vasilios K. Kimiskidis, Laboratory of Clinical Neurophysiology, Aristotle University of Thessaloniki, AHEPA University Hospital, Stilponos Kyriakidi 1, 54636, Thessaloniki, Greece. Email address: [email protected]
Abstract: Background: The management of “aggressive” and “highly-active” relapsing-remitting multiple sclerosis remains problematic. Although a number of highly efficacious agents are currently available, the optimal timing of their use and the balancing between efficacy and immediate and long-term consequences are still a matter of conjecture. Methods: We describe the clinical, radiological and immunological profile of three multiple sclerosis patients with persistent clinical and radiological disease activity under fingolimod treatment. After fingolimod cessation patients demonstrated severe disease exacerbation and were successfully treated with alemtuzumab. Results: All patients experienced significant improvement after the administration of alemtuzumab and achieved no evidence of disease activity status that persisted after a median of 19 months of follow-up (range: 17-25 months). Confirmed disability improvement was achieved in all cases. Quantitative MRI data demonstrated a reduction of the T2 lesion load in 2 out of 3 patients and complete abrogation of inflammatory activity in all patients after the administration of alemtuzumab. Α patient presented a previously unreported, persistent lymphocytosis after alemtuzumab administration, that was not associated with infectious, lymphoproliferative or autoimmune diseases and had no apparent clinical implications. Conclusions: Alemtuzumab appears to be an effective and safe short-term therapeutic option both as a rescue therapy for the disease flare-up associated with fingolimod withdrawal, as well as for the reversal of the deteriorating course observed in patients who fail treatment with fingolimod.
Keywords highly-active multiple sclerosis; alemtuzumab; fingolimod
Manuscript 1. Introduction The natural course of multiple sclerosis (MS) is characterized by significant heterogeneity, depending on the underlying pathophysiology. Relapsing-remitting is the most frequent disease subtype (RRMS) which occasionally takes the form of “aggressive” and “highly-active” RRMS. These ill-defined terms typically refer to a disease course with persistent relapses, rapid accumulation of disability, and severe inflammatory activity in magnetic resonance imaging (MRI) (Fernandez, 2017). The management of these entities remains problematic. Although a number of highly efficacious agents are currently available, the optimal timing of their use and the balancing between efficacy and immediate and long-term consequences are still a matter of conjecture. The present report contributes to the relevant literature by describing the clinical, radiological and immunological profile of 3 cases of highly active RRMS, characterized by severe disease reactivation after fingolimod cessation, that were successfully treated with alemtuzumab. Informed consent for inclusion in this study was obtained from the patients. Volumetric measurements were performed using the Image J Software (Image J κ1.45, NIH, USA). 2. Case reports 2.1 Patient 1 Patient 1 is a 32-year-old female with an 11-year history of RRMS. After her diagnosis, patient refused to receive any treatment for four years. After a relapse, she was treated with glatiramer acetate for just one year, which was replaced by fingolimod due to a new severe relapse [Expanded Disability Status Scale (EDSS):3]. The patient remained free of any disease activity for more than six years (EDSS:2.5), but eventually presented a disabling relapse (EDSS:4), accompanied by significant MRI inflammatory activity (Table 1), (Supplementary Table), (Figure 1A). Taking into consideration the patient’s reproductive plan, an escalation to alemtuzumab was decided. Two months after fingolimod withdrawal, the patient developed a multifocal severe relapse (EDSS:6), and her brain MRI demonstrated numerous new focal and coalescent demyelinating lesions, some of them with ring or nodular enhancement, indicative of active disease (Figure 1B). The patient’s lymphocyte counts were normal, so alemtuzumab was initiated, along with a steroid tapering cycle. In the next months, her disability improved remarkably (at month two post-infusion EDSS was 4, and ten months later EDSS was 2.5). At month nine post-infusion, a new brain MRI scan revealed substantial improvement with decrease of T2 lesions load (Table 1) and no evidence of disease activity (Figure 1C). The patient’s absolute lymphocyte counts (ALC) after alemtuzumab administration normalized rapidly (<3 months) (baseline ALC: 2491 cells/mm³, ALC at month 3: 1800 cells/mm³), but thereafter reversed to a previously unreported, persistent lymphocytosis, not associated with infectious, lymphoproliferative or autoimmune diseases (peak ALC at month 9: 6100 cells/mm³). Immunophenotype of the peripheral blood lymphocytes 12 months after alemtuzumab administration
demonstrated excessive proliferation of CD8+ T cells [ALC: 3380 cells/mm³, CD19+: 394,41 cells/mm³ (11,7%), CD4+: 756.88 cells/mm³ (22,4%), CD8+:1778,9 cells/mm³ (52,6%)]. After the second cycle of alemtuzumab administration, the patient’s lymphocyte counts demonstrated the same kinetics of recovery, with a different subpopulation pattern (Supplementary figure). 2.2 Patient 2 Patient 2 is a 41-year-old male with a 3-year history of MS. After his first relapse, the patient developed spastic paraparesis due to a spinal cord lesion, with incomplete recovery, despite high dose steroid treatment (EDSS:3.5). Anti-aquaporin-4 and antimyelin oligodendrocyte glycoprotein antibody tests were negative and he did not fulfil the criteria for a seronegative neuromyelitis optica spectrum disorder. The patient was initially treated with interferon beta 1a. After five months, treatment escalated to fingolimod due to a new relapse (EDSS:4). Two years later, the patient’s disability deteriorated further (EDSS:5) and a new spinal cord lesion was detected in the MRI in the absence of active brain lesions (Supplementary Table). The patient was positive for anti-John Cunningham Virus (JCV) antibodies. Due to rapid accumulation of disability, a switch to alemtuzumab was decided. Three months after fingolimod discontinuation, the patient was clinically stable and his lymphocyte counts were normal. Remarkably, brain MRI demonstrated numerous new ring and nodular enhancing demyelinating lesions, indicating inflammatory activity. Alemtuzumab was administered, with satisfactory clinical response (no further relapses, reduction in disability (EDSS:4)) and tolerance. A follow-up brain MRI 11 months after the first cycle showed improvement of T2 lesion load and absence of gadolinium enhancing (Gd+) lesions (Table 1). An uneventful second alemtuzumab cycle was recently administered. 2.3 Patient 3 Patient 3 is a 25-year-old female with a 9-year history of RRMS. The patient was on interferon beta 1b treatment for two years, before initiating to fingolimod due to persistent disease activity. After four stable years under fingolimod treatment (EDSS:1,5), the patient presented with three clinical relapses in one year, accompanied by intense radiological activity (Table 1) (EDSS:2,5). The patient was positive for anti-JCV antibodies, with a high index (2,7). A switch to alemtuzumab was planned; however, the patient developed prolonged lymphopenia for 24 weeks after fingolimod discontinuation. During this period, she suffered consecutive relapses every six weeks and was treated with three steroid cycles, followed by intravenous immunoglobulin (EDSS:3,5). Alemtuzumab was then initiated and the patient has been free of any disease activity afterward (EDSS:2). Six months after the second course of alemtuzumab, brain MRI revealed improvement of the T2 lesion load and lack of Gd+ lesions (Table 1), (Supplementary Table). 3. Discussion The present small-scale case series confirms and extends previously reported real world data from German and Italian cohorts suggesting that alemtuzumab is a promising therapeutic option in patients with highly-active RRMS on fingolimod (Frau et al., 2019; Huhn et al., 2018) All three patients reported herein, fulfilled the criteria of highly-active MS, as evidenced by persistent clinical and radiological disease activity under treatment and further exacerbation after withdrawal of fingolimod. Strictly speaking, one patient
(Patient 1) suffered from a rebound phenomenon and the other two from severe disease reactivation (Frau et al., 2018). Discontinuation of fingolimod in active RRMS patients may trigger disease reactivation, that may be related to the aggressive course of a highly active disease or occur subsequent to a massive exit of lymphocytes, possibly including Th17 T cells, to the periphery (Cavone et al., 2015). The exact incidence of this phenomenon is not clear. Hatcher et al. detailed the concept of a possible rebound after fingolimod cessation, describing severe clinical and inflammatory activity, that exceeded baseline activity, in 5 out of 46 patients (10,9%) (Hatcher et al., 2016). On the contrary, a post-hoc analysis, albeit with certain limitations, of the core Phase III fingolimod trials failed to recognize any pattern of unusually high disease activity after fingolimod withdrawal (Vermersch et al., 2017). Recently, Frau et al. described a cohort of 100 patients and concluded that the risk of a rebound phenomenon and severe reactivation is lower than previously thought (5% and 10% respectively) (Frau et al., 2018). Despite this aggressive clinical course, all patients rapidly experienced significant improvement after the administration of alemtuzumab and achieved No Evidence of Disease Activity (NEDA) status that persists after a median of 19 months of follow-up (range: 17-25 months). A previous study by Alcala et al in 28 RRMS patients who failed treatment with fingolimod, demonstrated that alemtuzumab induced NEDA in 82%, and conferred Confirmed Disability Improvement (CDI) in 35.7% of the patients. Comparable positive results were also observed with the use of anti-CD20 therapies, such as rituximab (Alcala et al., 2019). On the other hand, Schmidt and Schulten described a transient disease aggravation in 2 ocrelizumab treated patients, that presented rebound phenomenon after fingolimod cessation (Schmidt and Schulten, 2019). In our cohort, CDI was achieved in all cases in reference to both their worst neurological status, just before the administration of alemtuzumab, but also just before the withdrawal of fingolimod (Table 1). This observation indicates that alemtuzumab is an effective therapeutic option both as a rescue therapy for the disease flare-up associated with fingolimod withdrawal as well as for the reversal of the deteriorating course observed in patients who fail treatment with fingolimod. Interestingly enough, alemtuzumab proved to be effective even in a patient (Patient 2) that might be considered a case of primary progressive MS with relapses. These favourable clinical effects were corroborated by quantitative MRI data demonstrating a reduction of the T2 lesion load in 2 out of 3 patients and complete abrogation of inflammatory activity in all patients after the administration of alemtuzumab. These findings are in line with previous studies demonstrating a decrease in the number of new T2 lesions and a reduction of T1 Gd+ lesions under alemtuzumab (Frau et al., 2019; Huhn et al., 2018). It is worth noting that two of our patients developed tumefactive lesions after fingolimod withdrawal, which responded dramatically, from a clinical and radiological point of view, after the administration of alemtuzumab. A previous study described a beneficial effect of alemtuzumab in two cases that developed tumefactive lesions after fingolimod withdrawal, although no MRI data were provided (Sanchez et al., 2018).
On the other hand, there are reports of persistent or increased disease activity in alemtuzumab-treated patients following fingolimod withdrawal. An observational study by Willis et al. identified 9 out of 36 such cases, raising the hypothesis that the unexpected disease activity is stimulated by isolated lymphocytes, which remain hidden inside the lymph nodes, eluding from the usual depletion caused by alemtuzumab, due to a short (median six weeks) washout period (Willis et al., 2017). It should be noted, however, that refractory disease activity on alemtuzumab did not correlate with the baseline lymphocyte counts or the washout interval both in German and Italian cohorts (median washout periods 19 and 7 weeks, respectively) (Frau et al., 2019; Huhn et al., 2018). When shifting from fingolimod to alemtuzumab, it is reasonable to wait for a sufficient time interval, until lymphocyte counts recover. The optimal wash out period remains a matter of debate, due to limited published data, and should be individualized. According to the aforementioned studies, a short washout period (6-7 weeks) is preferable and has the advantage of minimizing the risk of disease reactivation after fingolimod withdrawal. Still, if a patient develops prolonged moderate to severe lymphopenia after fingolimod cessation, restraining the administration of alemtuzumab, certain strategies should be adopted, particularly if severe disease reactivation occurs during the wash-out period. These include steroid pulse therapies, plasma exchange or, theoretically, short-term administration of other agents that prevent immune cell trafficking. Assessment of Th17 T cells might be useful in predicting a possible disease flair-up (Cavone et al., 2015; Haas et al., 2017). The decision to administer alemtuzumab must be carefully reached, in the light of recent reports of rare but serious adverse effects and the warnings issued by the European Medicines Agency and United States Food and Drugs Administration (EMA/583516/2019, 2019, October 31; U.S. Food and Drug Administration, 2018, November 29). In our patients, alemtuzumab was not associated with any unexpected safety issues. On the other hand, the persistent lymphocytosis observed in Patient 1, although unassociated with clinical worsening or any complications, warrants further investigation as to its possible pathogenetic mechanisms and clinical implications (Supplementary figure). In conclusion, alemtuzumab appears to be an effective and safe short-term therapeutic option in highly active RRMS patients who fail fingolimod treatment, including cases with tumefactive MS. Prospective larger studies are warranted to verify these results and unveil any additional long-term safety issues.
Acknowledgements None
Conflict of interest K.N received travel grants and/or speaking honoraria and consultation fees from Sanofi-Genzyme, Novartis, Genesis Pharma, Teva Pharmaceuticals, Mylan, Roche and Merck; received research grants from Genesis Pharma. E.P declared no relative to this work conflict of interest. A.O. received travel grants and/or speaking honoraria and consultation fees from Merck, Bayer Schering, Sanofi-Genzyme, Teva Pharmaceuticals, Novartis, Genesis Pharma, Mylan, Roche; received research grant support from Merck, Sanofi-Genzyme, Teva Pharmaceuticals, Novartis, Genesis Pharma. M.M. received travel grants from Sanofi-Genzyme, Novartis, Mylan and Merck and research grants from Sanofi-Genzyme. V.K.K. within the past 24 months received honoraria as a member of an advisory board or panel from Specifar-Teva Pharmaceuticals, Sanofi-Genzyme, UCB, Genesis Pharma and Merck.
Study funding This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Table 1 Comparison of relapse rates and MRI characteristics in three RRMS patients that switched from fingolimod to alemtuzumab treatment, due to refractory disease activity. Pt 1
Pt 2
Pt 3
Relapses under Fingolimod (last 12 months)
1
1
3
Wash out interval (weeks)
8
10
24
Relapses during wash out period
1
0
4
Relapses post Alemtuzumab
0
0
0
T2 lesion load under Fingolimod (mm3 )
34121
4463
18890
T2 lesion load during wash out period (mm3 )
70952
8071
n/a
T2 lesion load post Alemtuzumab (mm3 )
27199
6629
15748
Number/T1 load (mm3) of gadolinium enhancing lesions under Fingolimod
4/331
0
9/829
Number/T1 load (mm3) of gadolinium enhancing lesions during wash out period Number/T1 load (mm3) of gadolinium enhancing lesions post Alemtuzumab
23/12956 7/930 0/0
0/0
n/a 0/0
MRI: magnetic resonance imaging; RRMS: relapsing remitting multiple sclerosis; Pt: patient; n/a: not available; mm: millimetre
Figures
Figure 1. Brain MRI of patient 1 in A) Fluid attenuation inversion recovery (FLAIR) (TR/TE/TI = 9502/144/2350msec) and post-gadolinium T1 Multi Echo Multiplanar (MEMP) (TR/TE = 660/12msec), B) FLAIR (TR/TE/TI = 8002/143.2/2000 msec) and post-gadolinium T1 three dimension fast spoiled gradient echo (TR/TE = 12.4/5.1 msec) and C) FLAIR (TR/TE/TI=8002/142.8/2000 msec) and post-gadolinium T1 MEMP (TR/TE= 480/10 msec) sequences. Typical ovoid, coalescent, hyperintense on FLAIR, demyelinating lesions, under fingolimod treatment, some of them with gadolinium enhancement (upper row=A). Two months after the discontinuation of fingolimod (middle row=B), there is remarkable deterioration of the findings, with increase of the number and size of the lesions, increase in the number of the enhancing lesions and presence of a large tumefactive subcortical lesion, with peripheral enhancement at the right frontal lobe. Nine months after the administration of alemtuzumab, there is significant decrease in the number of the lesions and no evidence of gadolinium enhancement (lower row=C).