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Current Neuropharmacology

Author(s): Sebastiano Arena, Clara Grazia Chisari, Simona Toscano, Sebastiano Bucello, Luigi Maria Grimaldi, Paolo Ragonese, Sabrina Realmuto, Salvatore Cottone, Davide Maimone, Chiara Finocchiaro, Paola Reitano and Francesco Patti*

DOI: 10.2174/1570159X21666230322140711

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Real-World Effectiveness of Cladribine for Patients with Multiple Sclerosis: A Sicilian Multicentric Experience (Rewind Study)

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Abstract

Background: Cladribine tablets are a highly effective option for the treatment of relapsingremitting multiple sclerosis (RRMS).

Objective: The study aims to evaluate the effectiveness of cladribine in a real-world setting.

Methods: This prospective real-world study consecutively screened all RRMS patients from seven different MS centers in Sicily (Italy) who completed the 2-year treatment course of cladribine tablets in the period between 11th March 2019 and 31st October 2021. Data about Expanded Disability Status Scale (EDSS), relapses, previous treatments, adverse events (AEs) and magnetic resonance imaging (MRI) were collected. Patients who were previously treated with other DMTs were further stratified into moderately active treatment (MAT) and highly active treatment (HAT) patients.

Results: A total of 217 patients (70% women, with a mean age of 38.4 ± 11.3 years) were enrolled. Fifty patients (23.0%) were naïve to treatment and 167 (77%) switched from other disease modifying therapies. After the second year of treatment, about 80% were EDSS progression free, 88% remained relapse-free at T24, and 48% of patients were MRI activity-free. Kaplan Meier analyses showed significant differences between MT and HAT in terms of time to first clinical relapse (HR: 2.43, IC 1.02- 5.76; p = 0.04), time to the first new T1-gadolinium enhancing lesion (HR: 3.43, IC 1.35-8.70; p = 0.009) and time to MRI worsening (HR: 2.42, IC 1.15-5.09; p = 0.02).

Conclusion: This study confirmed that cladribine is an effective treatment for MS, particularly in naïve patients and those who have switched from MATs.

Keywords: Multiple sclerosis, disease modifying therapies, switching therapies, cladribine, moderately active treatment, highly active treatment.

Graphical Abstract

[1]
Chisari, C.G.; Toscano, S.; D’Amico, E.; Lo Fermo, S.; Zanghì, A.; Arena, S.; Zappia, M.; Patti, F. An update on the safety of treating relapsing-remitting multiple sclerosis. Expert Opin. Drug Saf., 2019, 18(10), 925-948.
[http://dx.doi.org/10.1080/14740338.2019.1658741] [PMID: 31429602]
[2]
Simonsen, C.S.; Flemmen, H.Ø.; Broch, L.; Brunborg, C.; Berg-Hansen, P.; Moen, S.M.; Celius, E.G. Early high efficacy treatment in multiple sclerosis is the best predictor of future disease activity over 1 and 2 years in a norwegian population-based registry. Front. Neurol., 2021, 12, 693017.
[http://dx.doi.org/10.3389/fneur.2021.693017] [PMID: 34220694]
[3]
Wiendl, H.; Gold, R.; Berger, T.; Derfuss, T.; Linker, R.; Mäurer, M.; Aktas, O.; Baum, K.; Berghoff, M.; Bittner, S.; Chan, A.; Czaplinski, A.; Deisenhammer, F.; Di Pauli, F.; Du Pasquier, R.; Enzinger, C.; Fertl, E.; Gass, A.; Gehring, K.; Gobbi, C.; Goebels, N.; Guger, M.; Haghikia, A.; Hartung, H.P.; Heidenreich, F.; Hoffmann, O.; Kallmann, B.; Kleinschnitz, C.; Klotz, L.; Leussink, V.I.; Leutmezer, F.; Limmroth, V.; Lünemann, J.D.; Lutterotti, A.; Meuth, S.G.; Meyding-Lamadé, U.; Platten, M.; Rieckmann, P.; Schmidt, S.; Tumani, H.; Weber, F.; Weber, M.S.; Zettl, U.K.; Ziemssen, T.; Zipp, F. Multiple Sclerosis Therapy Consensus Group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper). Ther. Adv. Neurol. Disord., 2021, 14, 17562864211039648.
[http://dx.doi.org/10.1177/17562864211039648] [PMID: 34422112]
[4]
Comi, G. Induction vs. escalating therapy in multiple sclerosis: practical implications. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2008, 29(Suppl 2), S253-5.
[5]
Shimizu, Y.; Ikeguchi, R.; Kitagawa, K. When and how disease-modifying drugs for multiple sclerosis should be changed in daily practice. Clin. Exp. Neuroimmunol., 2017, 8(1), 71-80.
[http://dx.doi.org/10.1111/cen3.12380]
[6]
AlSharoqi, I.A.; Aljumah, M.; Bohlega, S.; Boz, C.; Daif, A.; El-Koussa, S.; Inshasi, J.; Kurtuncu, M.; Müller, T.; Retief, C.; Sahraian, M.A.; Shaygannejad, V.; Slassi, I.; Taha, K.; Zakaria, M.; Sørensen, P.S. Immune reconstitution therapy or continuous immunosuppression for the management of active relapsing-remitting multiple sclerosis patients? A narrative review. Neurol. Ther., 2020, 9(1), 55-66.
[http://dx.doi.org/10.1007/s40120-020-00187-3] [PMID: 32297127]
[7]
Chisari, C.G.; Sgarlata, E.; Arena, S.; Toscano, S.; Luca, M.; Patti, F. Rituximab for the treatment of multiple sclerosis: a review. J. Neurol., 2022, 269(1), 159-183.
[http://dx.doi.org/10.1007/s00415-020-10362-z] [PMID: 33416999]
[8]
Sorensen, P.S.; Sellebjerg, F. Pulsed immune reconstitution therapy in multiple sclerosis. Ther. Adv. Neurol. Disord., 2019, 12.
[http://dx.doi.org/10.1177/1756286419836913] [PMID: 30944586]
[9]
AlJumah, M.; Alkhawajah, M.M.; Qureshi, S.; Al-Thubaiti, I.; Ayoub, O.; Bohlega, S.A.; Bushnag, A.; Cupler, E.; Daif, A.; El Boghdady, A.; Hassan, A.; Al Malik, Y.; Saeedi, J.; Al-Shamrany, F.; Shosha, E.; Rieckmann, P. Cladribine tablets and relapsing–remitting multiple sclerosis: A pragmatic, narrative review of what physicians need to know. Neurol. Ther., 2020, 9(1), 11-23.
[http://dx.doi.org/10.1007/s40120-020-00177-5] [PMID: 32056129]
[10]
Steinberg, S.C.; Faris, R.J.; Chang, C.F.; Chan, A.; Tankersley, M.A. Impact of adherence to interferons in the treatment of multiple sclerosis: a non-experimental, retrospective, cohort study. Clin. Drug Investig., 2010, 30(2), 89-100.
[http://dx.doi.org/10.2165/11533330-000000000-00000] [PMID: 20067327]
[11]
De Meo, E.; Portaccio, E.; Giorgio, A.; Ruano, L.; Goretti, B.; Niccolai, C.; Patti, F.; Chisari, C.G.; Gallo, P.; Grossi, P.; Ghezzi, A.; Roscio, M.; Mattioli, F.; Stampatori, C.; Simone, M.; Viterbo, R.G.; Bonacchi, R.; Rocca, M.A.; De Stefano, N.; Filippi, M.; Amato, M.P. Identifying the distinct cognitive phenotypes in multiple sclerosis. JAMA Neurol., 2021, 78(4), 414-425.
[http://dx.doi.org/10.1001/jamaneurol.2020.4920] [PMID: 33393981]
[12]
Pakpoor, J.; Disanto, G.; Altmann, D.R.; Pavitt, S.; Turner, B.P.; Marta, M.; Juliusson, G.; Baker, D.; Chataway, J.; Schmierer, K. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol. Neuroimmunol. Neuroinflamm., 2015, 2(6), e158.
[http://dx.doi.org/10.1212/NXI.0000000000000158] [PMID: 26468472]
[13]
Fissolo, N.; Calvo-Barreiro, L.; Eixarch, H.; Boschert, U.; Espejo, C.; Montalban, X.; Comabella, M. Immunomodulatory effects associated with cladribine treatment. Cells, 2021, 10(12), 3488.
[http://dx.doi.org/10.3390/cells10123488] [PMID: 34943995]
[14]
Laugel, B.; Borlat, F.; Galibert, L.; Vicari, A.; Weissert, R.; Chvatchko, Y.; Bruniquel, D. Cladribine inhibits cytokine secretion by T cells independently of deoxycytidine kinase activity. J. Neuroimmunol., 2011, 240-241, 52-57.
[http://dx.doi.org/10.1016/j.jneuroim.2011.09.010] [PMID: 22035961]
[15]
Giovannoni, G.; Comi, G.; Cook, S.; Rammohan, K.; Rieckmann, P.; Sørensen, P.S.; Vermersch, P.; Chang, P.; Hamlett, A.; Musch, B.; Greenberg, S.J.; Group, C.S. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med., 2010, 362(5), 416-426.
[http://dx.doi.org/10.1056/NEJMoa0902533] [PMID: 20089960]
[16]
Giovannoni, G.; Soelberg Sorensen, P.; Cook, S.; Rammohan, K.; Rieckmann, P.; Comi, G.; Dangond, F.; Adeniji, A.K.; Vermersch, P. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study. Mult. Scler., 2018, 24(12), 1594-1604.
[http://dx.doi.org/10.1177/1352458517727603] [PMID: 28870107]
[17]
Giovannoni, G.; Soelberg Sorensen, P.; Cook, S.; Rammohan, K.W.; Rieckmann, P.; Comi, G.; Dangond, F.; Hicking, C.; Vermersch, P. Efficacy of Cladribine Tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study. Mult. Scler., 2019, 25(6), 819-827.
[http://dx.doi.org/10.1177/1352458518771875] [PMID: 29716436]
[18]
Petracca, M.; Ruggieri, S.; Barbuti, E.; Ianniello, A.; Fantozzi, R.; Maniscalco, G.T.; Andreone, V.; Landi, D.; Marfia, G.A.; Di Gregorio, M.; Iodice, R.; Sinisi, L.; Maida, E.; Missione, R.; Coppola, C.; Bonavita, S.; Borriello, G.; Centonze, D.; Lus, G.; Pozzilli, C.; Signoriello, E. Predictors of cladribine effectiveness and safety in multiple sclerosis: a real-world, multicenter, 2-year follow-up study. Neurol. Ther., 2022, 11(3), 1193-1208.
[http://dx.doi.org/10.1007/s40120-022-00364-6] [PMID: 35653061]
[19]
Moser, T.; Ziemssen, T.; Sellner, J. Real-world evidence for cladribine tablets in multiple sclerosis: further insights into efficacy and safety. Wien. Med. Wochenschr., 2022, 172(15-16), 365-372.
[http://dx.doi.org/10.1007/s10354-022-00931-4] [PMID: 35451662]
[20]
Pfeuffer, S.; Rolfes, L.; Hackert, J.; Kleinschnitz, K.; Ruck, T.; Wiendl, H.; Klotz, L.; Kleinschnitz, C.; Meuth, S.G.; Pul, R. Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres. Mult. Scler., 2021, 13524585211012227.
[http://dx.doi.org/10.1177/13524585211012227] [PMID: 33975489]
[21]
Bose, G.; Rush, C.; Atkins, H.L.; Freedman, M.S. A real-world single-centre analysis of alemtuzumab and cladribine for multiple sclerosis. Mult. Scler. Relat. Disord., 2021, 52, 102945.
[http://dx.doi.org/10.1016/j.msard.2021.102945] [PMID: 33901969]
[22]
Leist, T.P.; Comi, G.; Cree, B.A.C.; Coyle, P.K.; Freedman, M.S.; Hartung, H.P.; Vermersch, P.; Casset-Semanaz, F.; Scaramozza, M. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol., 2014, 13(3), 257-267.
[http://dx.doi.org/10.1016/S1474-4422(14)70005-5] [PMID: 24502830]
[23]
Thompson, A.J.; Banwell, B.L.; Barkhof, F.; Carroll, W.M.; Coetzee, T.; Comi, G.; Correale, J.; Fazekas, F.; Filippi, M.; Freedman, M.S.; Fujihara, K.; Galetta, S.L.; Hartung, H.P.; Kappos, L.; Lublin, F.D.; Marrie, R.A.; Miller, A.E.; Miller, D.H.; Montalban, X.; Mowry, E.M.; Sorensen, P.S.; Tintoré, M.; Traboulsee, A.L.; Trojano, M.; Uitdehaag, B.M.J.; Vukusic, S.; Waubant, E.; Weinshenker, B.G.; Reingold, S.C.; Cohen, J.A. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol., 2018, 17(2), 162-173.
[http://dx.doi.org/10.1016/S1474-4422(17)30470-2] [PMID: 29275977]
[24]
StataCorp. Stata Statistical Software: Release 17; StataCorp LLC: College Station, TX, 2021.
[25]
Calabresi, P.A.; Radue, E.W.; Goodin, D.; Jeffery, D.; Rammohan, K.W.; Reder, A.T.; Vollmer, T.; Agius, M.A.; Kappos, L.; Stites, T.; Li, B.; Cappiello, L.; von Rosenstiel, P.; Lublin, F.D. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol., 2014, 13(6), 545-556.
[http://dx.doi.org/10.1016/S1474-4422(14)70049-3] [PMID: 24685276]
[26]
G. G., A. Aydemir, E. Verdun Di Cantogno, on behalf of the CLASSIC-MS Steering Committee;, Primary Results from 8-11 Years of Follow-up in the CLASSIC-MS study show long-term efficacy for patients who received cladribine tablets in ORACLE MS. ACTRIMS Forum 2022 2022, Session VP1-VP1. Virtual Poster Session P107..
[27]
Helmut Butzkueven, T.S. MSBase study group, real-world comparative effectiveness and persistence of cladribine tablets and other oral disease-modifying treatments for multiple sclerosis from GLIMPSE: Results from the MSBase registry. American Academy of Neurology- 2nd-7th April 2022 poster session, 2022, pp. P12- 4.003.
[28]
Freedman, M.S.; Coyle, P.K.; Comi, G.L; Scarberry, S.; Damian, D.; Hyvert, Y.; Dangond, F.; Galazka, A.; Jack, D.; Lebson, L.A; Leist, T.P Early MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study. Mult. Scler. J. Exp. Transl. Clin., 2021, 7(1), 2055217321990852.
[http://dx.doi.org/10.1177/2055217321990852] [PMID: 33717501]
[29]
Giovannoni, G.; Cook, S.; Rammohan, K.; Rieckmann, P.; Sørensen, P.S.; Vermersch, P.; Hamlett, A.; Viglietta, V.; Greenberg, S. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol., 2011, 10(4), 329-337.
[http://dx.doi.org/10.1016/S1474-4422(11)70023-0] [PMID: 21397565]
[30]
Comi, G.; Cook, S.; Rammohan, K.; Soelberg, S.P.; Vermersch, P.; Adeniji, A.K.; Dangond, F.; Giovannoni, G. Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY extension study. Ther. Adv. Neurol. Disord., 2018, 11, 1756285617753365.
[http://dx.doi.org/10.1177/1756285617753365] [PMID: 29399054]
[31]
de Stefano, N.; Barkhof, F.; Montalban, X.; Achiron, A.; Derfuss, T.; Chan, A.; Hodgkinson, S.; Prat, A.; Leocani, L.; Schmierer, K.; Sellebjerg, F.; Vermersch, P.; Wiendl, H.; Keller, B.; Mwape, C.; Roy, S. Early reduction of MRI activity during 6 months of treatment with cladribine tablets for highly active relapsing multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm., 2022, 9(4), e1187.
[http://dx.doi.org/10.1212/NXI.0000000000001187] [PMID: 35701185]
[32]
Signori, A.; Ponzano, M.; Alexandri, N.; Giovannoni, G.; Sormani, M.P. Prevalence of disability improvement in relapsing-remitting multiple sclerosis patients treated with cladribine tablets. Eur. J. Neurol., 2022, 29(7), 2144-2147.
[http://dx.doi.org/10.1111/ene.15316] [PMID: 35258154]
[33]
Samjoo, I.A.; Worthington, E.; Drudge, C.; Zhao, M.; Cameron, C.; Häring, D.A.; Stoneman, D.; Klotz, L.; Adlard, N. Efficacy classification of modern therapies in multiple sclerosis. J. Comp. Eff. Res., 2021, 10(6), 495-507.
[http://dx.doi.org/10.2217/cer-2020-0267] [PMID: 33620251]
[34]
Sangalli, F.; Moiola, L.; Ferrè, L.; Radaelli, M.; Barcella, V.; Rodegher, M.; Colombo, B.; Boneschi, F.M.; Martinelli, V.; Comi, G. Long-term management of natalizumab discontinuation in a large monocentric cohort of multiple sclerosis patients. Mult. Scler. Relat. Disord., 2014, 3(4), 520-526.
[http://dx.doi.org/10.1016/j.msard.2014.04.003] [PMID: 25877065]
[35]
Coss-Rovirosa, F.; Salado-Burbano, J.; Casallas-Vanegas, A.; Caire-Herrera, L.E.; Gómez-Figueroa, E.; Flores-Rivera, J. Severe fingolimod rebound syndrome after switching to cladribine treatment. Mult. Scler. Relat. Disord., 2020, 40, 101938.
[http://dx.doi.org/10.1016/j.msard.2020.101938] [PMID: 31982666]
[36]
Cellerino, M.; Bonavita, S.; Ferrero, M.; Inglese, M.; Boffa, G. Severe disease activity in MS patients treated with cladribine after fingolimod withdrawal. J. Neurol. Sci., 2020, 418, 117156.
[http://dx.doi.org/10.1016/j.jns.2020.117156] [PMID: 33010653]
[37]
Radlberger, R.F.; Sakic, I.; Moser, T.; Pilz, G.; Harrer, A.; Wipfler, P. Immune phenotyping study revealing caveats regarding a switch from fingolimod to cladribine. Mult. Scler. Relat. Disord., 2021, 48, 102727.
[http://dx.doi.org/10.1016/j.msard.2020.102727] [PMID: 33418308]
[38]
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. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurology(R). Neuroimmunology & Neuroinflammatio., 2017, 4(2), e320.
[39]
Möhn, N.; Skripuletz, T.; Sühs, K.W.; Menck, S.; Voß, E.; Stangel, M. Therapy with cladribine is efficient and safe in patients previously treated with natalizumab. Ther. Adv. Neurol. Disord., 2019, 12, 1756286419887596.
[http://dx.doi.org/10.1177/1756286419887596] [PMID: 31832100]
[40]
Agency, E.M. Mavenclad - summary of EPAR., 2017, 2019
[41]
Rockland, M.E.S. Mavenclad [package insert]., Inc., 2019.
[42]
Scientifico, C. T. Medicinale Mavenclad (cladribina). Valutazione dell'innovatività. 2018.
[43]
Polman, C.H.; O’Connor, P.W.; Havrdova, E.; Hutchinson, M.; Kappos, L.; Miller, D.H.; Phillips, J.T.; Lublin, F.D.; Giovannoni, G.; Wajgt, A.; Toal, M.; Lynn, F.; Panzara, M.A.; Sandrock, A.W.; Investigators, A. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med., 2006, 354(9), 899-910.
[http://dx.doi.org/10.1056/NEJMoa044397] [PMID: 16510744]
[44]
Cook, S.; Leist, T.; Comi, G.; Montalban, X.; Giovannoni, G.; Nolting, A.; Hicking, C.; Galazka, A.; Sylvester, E. Safety of cladribine tablets in the treatment of patients with multiple sclerosis: An integrated analysis. Mult. Scler. Relat. Disord., 2019, 29, 157-167.
[http://dx.doi.org/10.1016/j.msard.2018.11.021] [PMID: 30885374]
[45]
Freedman, M.S.; Leist, T.P.; Comi, G.; Cree, B.A.C.; Coyle, P.K.; Hartung, H.P.; Vermersch, P.; Damian, D.; Dangond, F. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult. Scler. J. Exp. Transl. Clin., 2017, 3(4), 2055217317732802.
[http://dx.doi.org/10.1177/2055217317732802] [PMID: 29051829]
[46]
Montalban, X.; Leist, T. P.; Cohen, B. A.; Moses, H.; Campbell, J.; Hicking, C.; Dangond, F. Cladribine tablets added to IFN-beta in active relapsing MS: The ONWARD study. Neurology(R) neuroimmunology & neuroinflammation, 2018, 5(5), e477.
[47]
Cook, S.; Vermersch, P.; Comi, G.; Giovannoni, G.; Rammohan, K.; Rieckmann, P.; Sørensen, P.S.; Hamlett, A.; Miret, M.; Weiner, J.; Viglietta, V.; Musch, B.; Greenberg, S.J.; Group, C.S. Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study. Mult. Scler., 2011, 17(5), 578-593.
[http://dx.doi.org/10.1177/1352458510391344] [PMID: 21228029]
[48]
Disanto, G.; Moccia, M.; Sacco, R.; Spiezia, A.L.; Carotenuto, A.; Brescia Morra, V.; Gobbi, C.; Zecca, C. Monitoring of safety and effectiveness of cladribine in multiple sclerosis patients over 50 years. Mult. Scler. Relat. Disord., 2022, 58, 103490.
[http://dx.doi.org/10.1016/j.msard.2022.103490] [PMID: 35007823]