Risks associated with Wash-Out Duration when switching from Fingolimod to cell-depleting agents
SYNOPSIS AND RESULTS
Decisions regarding the duration of washout periods between disease-modifying therapies (DMTs) in multiple sclerosis (MS) patients need to take both the risk of disease reactivation and safety issues regarding overlapping immunological mechanisms of action into account. Fingolimod is an oral DMT, approved for the treatment of highly active relapsing-remitting (RR) MS. It induces sequestration of B and T lymphocytes in secondary lymphoid organs, with decrease of absolute lymphocyte counts (ALC) to 20%– 30% of baseline values between days 3 and 7 of treatment initiation. After FTY discontinuation ALC progressively increase and return within the normal range for approximately half the patients by six weeks and to approximately 80% of pre-treatment values by 12 weeks. Following the publication of case-series and case-reports on the lack of response to alemtuzumab, rituximab and ocrelizumab following FTY withdrawal, it has been hypothesized that their efficacy may be incomplete if commenced before ALC has recovered, possibly because sequestered lymphocytes are protected from cell-depleting agents. Studies on larger cohorts, however, have found both alemtuzumab and rituximab to be an effective option after FTY withdrawal, and that disease activity during alemtuzumab did not correlate with the baseline ALC or with the washout interval. Seeing the kinetics of lymphocyte reconstitution, it is plausible to think that the risk of incomplete lymphocyte recovery is greater in the first 6-8 weeks following FTY discontinuation. This potential risk, however, has to be balanced with the risk of return of disease activity/persisting disease activity or even of a rebound syndrome, starting from 4 weeks after ceasing FTY. Given the growing complexity of treatment choices it is important to gather information on drug- sequencing and on the most appropriate washout duration between drugs. Aim of this study was, therefore, to assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent (aletumzumab, cladribine or anti-CD20 agents – ocrelizumab and rituximab) in relation to the duration of washout, using data from the Italian MS Register.
Data start
Data end
2020-01-16
2020-06-15
PARTICIPATING CENTERS
Pietro Iaffaldano, Tommaso Guerra, Damiano Paolicelli and Maria Trojano, Centro SM, Dipartimento di Scienze Mediche di Base, Neuroscienze ed Organi di Senso Università di Bari, Bari Matilde Inglese, Maria Cellerino, Dipartimento di Neuroscienze, Riabilitazione Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Ospedale Policlinico San Martino-IRCCS, Genova Antonio Bertolotto, Marco Capobianco, Centro Regionale di riferimento per la SM, Unità Neurologica, Ospedale Universitario San Luigi, Orbassano, TO Vincenzo Brescia Morra, Centro SM - AOU Policlinico Federico II, Napoli Mauro Zaffaroni, Centro Sclerosi Multipla, Ospedale Gallarate, ASST della Valle Olona, Gallarate, (VA) Massimiliano Mirabella, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome and Università Cattolica del Sacro Cuore, Rome Giacomo Lus, Centro SM, II Clinica Neurologica, Università della Campania "L. Vanvitelli", Napoli Francesco Patti Centro Sclerosi Multipla, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania Paola Cavalla, Centro SM, Dipartimento di Neuroscienze, Università degli Studi di Torino, Torino
-Dr. Valentina Camera, neurologist in training at the Center for Demyelinating Diseases; valentina.camera@gmail.
Collaborators: -Dr. Pietro Iaffaldano, neurologist at the Center for Demyelinating Diseases of the Azienda Ospedaliera Policlinico of Bari; pietro.iaffaldano@uniba.it -Prof. Maria Trojano, neurologist, Head of the Center for Demyelinating Diseases of the Azienda Ospedaliera Policlinico of Bari; mtrojano@neurol.uniba.it
OUTCOME
Introduction and aims Decisions regarding the duration of washout periods between disease-modifying therapies (DMTs) in multiple sclerosis (MS) patients need to take both the risk of disease reactivation and safety issues regarding overlapping immunological mechanisms of action into account. Fingolimod is an oral DMT, approved for the treatment of highly active relapsing-remitting (RR) MS. It induces sequestration of B and T lymphocytes in secondary lymphoid organs, with decrease of absolute lymphocyte counts (ALC) to 20%– 30% of baseline values between days 3 and 7 of treatment initiation. After FTY discontinuation ALC progressively increase and return within the normal range for approximately half the patients by six weeks and to approximately 80% of pre-treatment values by 12 weeks. Following the publication of case-series and case-reports on the lack of response to alemtuzumab, rituximab and ocrelizumab following FTY withdrawal, it has been hypothesized that their efficacy may be incomplete if commenced before ALC has recovered, possibly because sequestered lymphocytes are protected from cell-depleting agents. Studies on larger cohorts, however, have found both alemtuzumab and rituximab to be an effective option after FTY withdrawal, and that disease activity during alemtuzumab did not correlate with the baseline ALC or with the washout interval. Seeing the kinetics of lymphocyte reconstitution, it is plausible to think that the risk of incomplete lymphocyte recovery is greater in the first 6-8 weeks following FTY discontinuation. This potential risk, however, has to be balanced with the risk of return of disease activity/persisting disease activity or even of a rebound syndrome, starting from 4 weeks after ceasing FTY. Given the growing complexity of treatment choices it is important to gather information on drug- sequencing and on the most appropriate washout duration between drugs. Aim of this study was, therefore, to assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent (aletumzumab, cladribine or anti-CD20 agents – ocrelizumab and rituximab) in relation to the duration of washout, using data from the Italian MS Register.
Results Out of 61625 patient records available at the time of data extraction (on November 14th 2019), a total of 329 patients were included in the analysis (226F, 103M; mean age 41±10 years). Ninety patients relapsed during the washout period and 72 during the subsequent cell-depleting therapy. During the cell-depleting treatment, the incidence rate ratio (IRR) for a relapse was significantly greater in patients with a washout-period of 12-17 (IRR (95%CI): 2.4 (1,1-5,5); p=0.037) and >/=18 weeks (6.0 (2.8-12.7); p<0.001) compared to the reference period (<6 weeks). The multivariable Cox analysis showed that the time to a relapse (hazard ratio – HR) was significantly influenced by the occurrence of relapses during FTY treatment [HR (95%CI): 1.4 (1.2-1.7); p<0.001]. Moreover, washout durations of 6-11, 12-17 and >/=18 weeks were associated with a higher risk of a relapse in comparison to washout durations shorter than 6 weeks [HR: 3.7 (1.1-12.7), p=0.041; 5.7 (1.6-20.6), p=0.008; 15.9 (4.6-54.6), p<0.001, respectively].
Conclusions Results of the present study underline the risk of disease reactivation, which increases with the duration of washout when switching from FTY to lymphocyte-depleting agents. Real-life studies on large populations and on MS registries such as this one can provide useful data to guide clinicians on strategies for treatment switches.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents. Poster (P0913), MSVirtual2020 ECTRIMS, Multiple Sclerosis Journal 2020; 26: (S3) 552–659
Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents. Comunicazione orale, Congresso Società Italiana di Neurologia virtuale 2020, Neurol Sci (2020) 41 (Suppl 1):S1–S347
PUBLICATIONS
Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents. Poster (P0913), MSVirtual2020 ECTRIMS, Multiple Sclerosis Journal 2020; 26: (S3) 552–659.
Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents. Comunicazione orale, Congresso Società Italiana di Neurologia virtuale 2020, Neurol Sci (2020) 41 (Suppl 1):S1–S347.
Ferraro D, Iaffaldano P, Guerra T, Inglese M, Capobianco M, Brescia Morra V, Zaffaroni M, Mirabella M, Lus G, Patti F, Cavalla P, Cellerino M, Malucchi S, Pisano E, Vitetta F, Paolicelli D, Sola P, Trojano M. Italian MS Register.Risk of multiple sclerosis relapses when switching from fingolimod to cell-depleting agents: the role of washout duration. J Neurol. 2022 Mar;269(3):1463-1469. doi: 10.1007/s00415-021-10708-1. Online ahead of print.PMID: 34292396
Fondazione Italiana Sclerosi Multipla – FISM – Ente del Terzo Settore/ETS e, in forma abbreviata, FISM ETS. Iscrizione al RUNTS Rep. N° 89695 - Fondazione con Riconoscimento di Personalità Giuridica - C.F. 95051730109
Risks associated with Wash-Out Duration when switching from Fingolimod to cell-depleting agents
Decisions regarding the duration of washout periods between disease-modifying therapies (DMTs) in multiple sclerosis (MS) patients need to take both the risk of disease reactivation and safety issues regarding overlapping immunological mechanisms of action into account.
Fingolimod is an oral DMT, approved for the treatment of highly active relapsing-remitting (RR) MS. It induces sequestration of B and T lymphocytes in secondary lymphoid organs, with decrease of absolute lymphocyte counts (ALC) to 20%– 30% of baseline values between days 3 and 7 of treatment initiation. After FTY discontinuation ALC progressively increase and return within the normal range for approximately half the patients by six weeks and to approximately 80% of pre-treatment values by 12 weeks.
Following the publication of case-series and case-reports on the lack of response to alemtuzumab, rituximab and ocrelizumab following FTY withdrawal, it has been hypothesized that their efficacy may be incomplete if commenced before ALC has recovered, possibly because sequestered lymphocytes are protected from cell-depleting agents. Studies on larger cohorts, however, have found both alemtuzumab and rituximab to be an effective option after FTY withdrawal, and that disease activity during alemtuzumab did not correlate with the baseline ALC or with the washout interval.
Seeing the kinetics of lymphocyte reconstitution, it is plausible to think that the risk of incomplete lymphocyte recovery is greater in the first 6-8 weeks following FTY discontinuation. This potential risk, however, has to be balanced with the risk of return of disease activity/persisting disease activity or even of a rebound syndrome, starting from 4 weeks after ceasing FTY.
Given the growing complexity of treatment choices it is important to gather information on drug- sequencing and on the most appropriate washout duration between drugs.
Aim of this study was, therefore, to assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent (aletumzumab, cladribine or anti-CD20 agents – ocrelizumab and rituximab) in relation to the duration of washout, using data from the Italian MS Register.
Pietro Iaffaldano, Tommaso Guerra, Damiano Paolicelli and Maria Trojano, Centro SM, Dipartimento di Scienze Mediche di Base, Neuroscienze ed Organi di Senso Università di Bari, Bari
Matilde Inglese, Maria Cellerino, Dipartimento di Neuroscienze, Riabilitazione Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Ospedale Policlinico San Martino-IRCCS, Genova
Antonio Bertolotto, Marco Capobianco, Centro Regionale di riferimento per la SM, Unità Neurologica, Ospedale Universitario San Luigi, Orbassano, TO
Vincenzo Brescia Morra, Centro SM - AOU Policlinico Federico II, Napoli
Mauro Zaffaroni, Centro Sclerosi Multipla, Ospedale Gallarate, ASST della Valle Olona, Gallarate, (VA)
Massimiliano Mirabella, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome and Università Cattolica del Sacro Cuore, Rome
Giacomo Lus, Centro SM, II Clinica Neurologica, Università della Campania "L. Vanvitelli", Napoli
Francesco Patti Centro Sclerosi Multipla, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania
Paola Cavalla, Centro SM, Dipartimento di Neuroscienze, Università degli Studi di Torino, Torino
-Dr. Valentina Camera, neurologist in training at the Center for Demyelinating Diseases; valentina.camera@gmail.
Collaborators:
-Dr. Pietro Iaffaldano, neurologist at the Center for Demyelinating Diseases of the Azienda Ospedaliera Policlinico of Bari; pietro.iaffaldano@uniba.it
-Prof. Maria Trojano, neurologist, Head of the Center for Demyelinating Diseases of the Azienda Ospedaliera Policlinico of Bari; mtrojano@neurol.uniba.it
Introduction and aims
Decisions regarding the duration of washout periods between disease-modifying therapies (DMTs) in multiple sclerosis (MS) patients need to take both the risk of disease reactivation and safety issues regarding overlapping immunological mechanisms of action into account.
Fingolimod is an oral DMT, approved for the treatment of highly active relapsing-remitting (RR) MS. It induces sequestration of B and T lymphocytes in secondary lymphoid organs, with decrease of absolute lymphocyte counts (ALC) to 20%– 30% of baseline values between days 3 and 7 of treatment initiation. After FTY discontinuation ALC progressively increase and return within the normal range for approximately half the patients by six weeks and to approximately 80% of pre-treatment values by 12 weeks.
Following the publication of case-series and case-reports on the lack of response to alemtuzumab, rituximab and ocrelizumab following FTY withdrawal, it has been hypothesized that their efficacy may be incomplete if commenced before ALC has recovered, possibly because sequestered lymphocytes are protected from cell-depleting agents. Studies on larger cohorts, however, have found both alemtuzumab and rituximab to be an effective option after FTY withdrawal, and that disease activity during alemtuzumab did not correlate with the baseline ALC or with the washout interval.
Seeing the kinetics of lymphocyte reconstitution, it is plausible to think that the risk of incomplete lymphocyte recovery is greater in the first 6-8 weeks following FTY discontinuation. This potential risk, however, has to be balanced with the risk of return of disease activity/persisting disease activity or even of a rebound syndrome, starting from 4 weeks after ceasing FTY.
Given the growing complexity of treatment choices it is important to gather information on drug- sequencing and on the most appropriate washout duration between drugs.
Aim of this study was, therefore, to assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent (aletumzumab, cladribine or anti-CD20 agents – ocrelizumab and rituximab) in relation to the duration of washout, using data from the Italian MS Register.
Results
Out of 61625 patient records available at the time of data extraction (on November 14th 2019), a total of 329 patients were included in the analysis (226F, 103M; mean age 41±10 years).
Ninety patients relapsed during the washout period and 72 during the subsequent cell-depleting therapy. During the cell-depleting treatment, the incidence rate ratio (IRR) for a relapse was significantly greater in patients with a washout-period of 12-17 (IRR (95%CI): 2.4 (1,1-5,5); p=0.037) and >/=18 weeks (6.0 (2.8-12.7); p<0.001) compared to the reference period (<6 weeks).
The multivariable Cox analysis showed that the time to a relapse (hazard ratio – HR) was significantly influenced by the occurrence of relapses during FTY treatment [HR (95%CI): 1.4 (1.2-1.7); p<0.001]. Moreover, washout durations of 6-11, 12-17 and >/=18 weeks were associated with a higher risk of a relapse in comparison to washout durations shorter than 6 weeks [HR: 3.7 (1.1-12.7), p=0.041; 5.7 (1.6-20.6), p=0.008; 15.9 (4.6-54.6), p<0.001, respectively].
Conclusions
Results of the present study underline the risk of disease reactivation, which increases with the duration of washout when switching from FTY to lymphocyte-depleting agents.
Real-life studies on large populations and on MS registries such as this one can provide useful data to guide clinicians on strategies for treatment switches.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations
Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents. Poster (P0913), MSVirtual2020 ECTRIMS, Multiple Sclerosis Journal 2020; 26: (S3) 552–659
Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents. Comunicazione orale, Congresso Società Italiana di Neurologia virtuale 2020, Neurol Sci (2020) 41 (Suppl 1):S1–S347
Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents. Poster (P0913), MSVirtual2020 ECTRIMS, Multiple Sclerosis Journal 2020; 26: (S3) 552–659.
Risks associated with wash-out duration when switching from fingolimod to cell-depleting agents. Comunicazione orale, Congresso Società Italiana di Neurologia virtuale 2020, Neurol Sci (2020) 41 (Suppl 1):S1–S347.
Ferraro D, Iaffaldano P, Guerra T, Inglese M, Capobianco M, Brescia Morra V, Zaffaroni M, Mirabella M, Lus G, Patti F, Cavalla P, Cellerino M, Malucchi S, Pisano E, Vitetta F, Paolicelli D, Sola P, Trojano M. Italian MS Register.Risk of multiple sclerosis relapses when switching from fingolimod to cell-depleting agents: the role of washout duration. J Neurol. 2022 Mar;269(3):1463-1469. doi: 10.1007/s00415-021-10708-1. Online ahead of print.PMID: 34292396