Predictors of lymphocyte count recovery after dimethyl fumarate-induced lymphopenia in people with multiple sclerosis.

Dimethyl Fumarate / adverse effects Humans Immunosuppressive Agents / adverse effects Lymphocyte Count Lymphopenia / chemically induced Multiple Sclerosis Multiple Sclerosis, Relapsing-Remitting / drug therapy
Dimethyl fumarate Lymphopenia Multiple sclerosis Real-world study

Journal

Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161

Informations de publication

Date de publication:
Jun 2021
Historique:
received: 17 11 2020
accepted: 15 01 2021
revised: 13 01 2021
pubmed: 27 1 2021
medline: 22 6 2021
entrez: 26 1 2021
Statut: ppublish

Résumé

Dimethyl fumarate (DMF) is an oral drug approved for Relapsing Multiple Sclerosis (RMS) patients. Grade III lymphopenia is reported in 5-10% DMF-treated patients. Data on lymphocyte count (ALC) recovery after DMF withdrawal following prolonged lymphopenia are still scarce. To characterize ALC recovery and to identify predictors of slower recovery after DMF interruption. Multicenter data from RMS patients who started DMF and developed lymphopenia during treatment were collected. In patients with grade II-III lymphopenia, ALCs were evaluated from DMF withdrawal until reaching lymphocyte counts > 800/mm Among 1034 patients who started DMF, we found 198 (19.1%) patients with lymphopenia and 65 patients (6.3%) who discontinued DMF due to persistent grade II-III lymphopenia. Complete data were available for 51 patients. All patients recovered to ALC > 800 cells/mm ALC recovery after DMF withdrawal is usually rapid, nevertheless it may require longer time in patients with lower ALC count at DMF interruption, longer disease duration and previous exposure to MS treatments, potentially leading to delayed initiation of a new therapy.

Sections du résumé

BACKGROUND BACKGROUND
Dimethyl fumarate (DMF) is an oral drug approved for Relapsing Multiple Sclerosis (RMS) patients. Grade III lymphopenia is reported in 5-10% DMF-treated patients. Data on lymphocyte count (ALC) recovery after DMF withdrawal following prolonged lymphopenia are still scarce.
OBJECTIVES OBJECTIVE
To characterize ALC recovery and to identify predictors of slower recovery after DMF interruption.
METHODS METHODS
Multicenter data from RMS patients who started DMF and developed lymphopenia during treatment were collected. In patients with grade II-III lymphopenia, ALCs were evaluated from DMF withdrawal until reaching lymphocyte counts > 800/mm
RESULTS RESULTS
Among 1034 patients who started DMF, we found 198 (19.1%) patients with lymphopenia and 65 patients (6.3%) who discontinued DMF due to persistent grade II-III lymphopenia. Complete data were available for 51 patients. All patients recovered to ALC > 800 cells/mm
CONCLUSION CONCLUSIONS
ALC recovery after DMF withdrawal is usually rapid, nevertheless it may require longer time in patients with lower ALC count at DMF interruption, longer disease duration and previous exposure to MS treatments, potentially leading to delayed initiation of a new therapy.

Identifiants

DOI: 10.1007/s00415-021-10412-0 PMID: 33496861 PMC: PMC8179888
pubmed: 33496861
doi: 10.1007/s00415-021-10412-0
pii: 10.1007/s00415-021-10412-0
pmc: PMC8179888
doi:

Substances chimiques

Immunosuppressive Agents 0
Dimethyl Fumarate FO2303MNI2

Types de publication

Journal Article Multicenter Study

Langues

eng

Sous-ensembles de citation

IM

Pagination

2238-2245

Références

Fox EJ, Buckle GJ, Singer B, Singh V, Boster A (2019) Lymphopenia and DMTs for relapsing forms of MS: considerations for the treating neurologist. Neurol Clin Pract 9(1):53–63. https://doi.org/10.1212/cpj.0000000000000567
doi: 10.1212/cpj.0000000000000567 pubmed: 30859008 pmcid: 6382377
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. https://www.ctepcancergov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_85x11pdf . Accessed 15 Oct 2020
Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367(12):1098–1107. https://doi.org/10.1056/NEJMoa1114287
doi: 10.1056/NEJMoa1114287 pubmed: 22992073
Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367(12):1087–1097. https://doi.org/10.1056/NEJMoa1206328
doi: 10.1056/NEJMoa1206328 pubmed: 22992072
Fox RJ, Chan A, Gold R, Phillips JT, Selmaj K, Chang I, Novas M, Rana J, Marantz JL (2016) Characterizing absolute lymphocyte count profiles in dimethyl fumarate-treated patients with MS: Patient management considerations. Neurol Clin Pract 6(3):220–229. https://doi.org/10.1212/cpj.0000000000000238
doi: 10.1212/cpj.0000000000000238 pubmed: 27347439 pmcid: 4909524
Mills EA, Ogrodnik MA, Plave A, Mao-Draayer Y (2018) Emerging understanding of the mechanism of action for dimethyl fumarate in the treatment of multiple sclerosis. Front Neurol 9:5. https://doi.org/10.3389/fneur.2018.00005
doi: 10.3389/fneur.2018.00005 pubmed: 29410647 pmcid: 5787128
Rosenkranz T, Novas M, Terborg C (2015) PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med 372(15):1476–1478. https://doi.org/10.1056/NEJMc1415408
doi: 10.1056/NEJMc1415408 pubmed: 25853765
Berger JR (2017) Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord 12:59–63. https://doi.org/10.1016/j.msard.2017.01.006
doi: 10.1016/j.msard.2017.01.006 pubmed: 28283109
Gieselbach RJ, Muller-Hansma AH, Wijburg MT, de Bruin-Weller MS, van Oosten BW, Nieuwkamp DJ, Coenjaerts FE, Wattjes MP, Murk JL (2017) Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases. J Neurol 264(6):1155–1164. https://doi.org/10.1007/s00415-017-8509-9
doi: 10.1007/s00415-017-8509-9 pubmed: 28536921
Mirabella M, Prosperini L, Lucchini M, Boffa L, Borriello G, Buscarinu MC, Centonze D, Cortese A, De Fino C, De Giglio L, Elia G, Fantozzi R, Ferraro E, Francia A, Galgani S, Gasperini C, Haggiag S, Landi D, Marfia GA, Millefiorini E, Monteleone F, Nociti V, Salvetti M, Sgarlata E, Pozzilli C (2018) Safety and efficacy of dimethyl fumarate in multiple sclerosis: an Italian, multicenter, real-world study. CNS Drugs 32(10):963–970. https://doi.org/10.1007/s40263-018-0543-3
doi: 10.1007/s40263-018-0543-3 pubmed: 30022464
Smoot K, Spinelli KJ, Stuchiner T, Lucas L, Chen C, Grote L, Baraban E, Kresa-Reahl K, Cohan S (2017) Three-year clinical outcomes of relapsing multiple sclerosis patients treated with dimethyl fumarate in a United States community health center. Multiple sclerosis (Houndmills, Basingstoke, England). https://doi.org/10.1177/1352458517709956
doi: 10.1177/1352458517709956
Baharnoori M, Gonzalez CT, Chua A, Diaz-Cruz C, Healy BC, Stankiewicz J, Weiner HL, Chitnis T (2018) Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count. Mult Scler Relat Disord 20:51–57. https://doi.org/10.1016/j.msard.2017.12.003
doi: 10.1016/j.msard.2017.12.003 pubmed: 29304497
Morales FS, Koralnik IJ, Gautam S, Samaan S, Sloane JA (2020) Risk factors for lymphopenia in patients with relapsing-remitting multiple sclerosis treated with dimethyl fumarate. J Neurol 267(1):125–131. https://doi.org/10.1007/s00415-019-09557-w
doi: 10.1007/s00415-019-09557-w pubmed: 31583427
Anon. Tecfidera, INN-dimethyl fumarate - WC500162069.pdf. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/WC500162069.pdf . Accessed 10 Jan 2021
https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/tecfidera-dimethyl-fumarate-information .
Mehta D, Miller C, Arnold DL, Bame E, Bar-Or A, Gold R, Hanna J, Kappos L, Liu S, Matta A, Phillips JT, Robertson D, von Hehn CA, Campbell J, Spach K, Yang L, Fox RJ (2019) Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice. Neurology 92(15):e1724–e1738. https://doi.org/10.1212/wnl.0000000000007262
doi: 10.1212/wnl.0000000000007262 pubmed: 30918100 pmcid: 6511089
Briner M, Bagnoud M, Miclea A, Friedli C, Diem L, Chan A, Hoepner R, Salmen A (2019) Time course of lymphocyte repopulation after dimethyl fumarate-induced grade 3 lymphopenia: contribution of patient age. Ther Adv NeurolDisord 12:1756286419843450. https://doi.org/10.1177/1756286419843450
doi: 10.1177/1756286419843450
Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302. https://doi.org/10.1002/ana.22366
doi: 10.1002/ana.22366 pubmed: 21387374 pmcid: 3084507
Buckle G, Bandari D, Greenstein J, Gudesblatt M, Khatri B, Kita M, Repovic P, Riser E, Weinstock-Guttman B, Thrower B, Loring S, Riester K, Everage N, Prada C, Koulinska I, Mann M (2020) Effect of dimethyl fumarate on lymphocyte subsets in patients with relapsing multiple sclerosis. Mult Scler J Exp Transl Clin 6(2):2055217320918619. https://doi.org/10.1177/2055217320918619
doi: 10.1177/2055217320918619 pubmed: 32440353 pmcid: 7227148
Longbrake EE, Ramsbottom MJ, Cantoni C, Ghezzi L, Cross AH, Piccio L (2016) Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients. Mult Scler (Houndmills, Basingstoke, England) 22(8):1061–1070. https://doi.org/10.1177/1352458515608961
doi: 10.1177/1352458515608961
Longbrake EE, Cantoni C, Chahin S, Cignarella F, Cross AH, Piccio L (2017) Dimethyl fumarate induces changes in B- and T-lymphocyte function independent of the effects on absolute lymphocyte count. Mult Scler (Houndmills, Basingstoke, England). https://doi.org/10.1177/1352458517707069
doi: 10.1177/1352458517707069
Chaves C, Ganguly R, Ceresia C, Camac A (2017) Lymphocyte subtypes in relapsing-remitting multiple sclerosis patients treated with dimethyl fumarate. Mult Scler J Exp Transl Clin 3(2):2055217317702933. https://doi.org/10.1177/2055217317702933
doi: 10.1177/2055217317702933 pubmed: 28607757 pmcid: 5408504
Gold R, Arnold DL, Bar-Or A, Fox RJ, Kappos L, Chen C, Parks B, Miller C (2020) Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years’ follow-up of DEFINE, CONFIRM, and ENDORSE. Ther Adv Neurol Disord 13:1756286420915005. https://doi.org/10.1177/1756286420915005
doi: 10.1177/1756286420915005 pubmed: 32426039 pmcid: 7222239
Lanzillo R, Moccia M, Palladino R, Signoriello E, Carotenuto A, Maniscalco GT, Saccà F, Bonavita S, Russo CV, Iodice R, Petruzzo M, Sinisi L, De Angelis M, Lavorgna L, De Rosa A, Romano F, Orlando V, Ronga B, Florio C, Lus G, Brescia Morra V (2020) Clinical predictors of Dimethyl Fumarate response in multiple sclerosis: a real life multicentre study. Mult Scler Relat Disord 38:101871. https://doi.org/10.1016/j.msard.2019.101871
doi: 10.1016/j.msard.2019.101871 pubmed: 31786463
Mallucci G, Annovazzi P, Miante S, Torri-Clerici V, Matta M, La Gioia S, Cavarretta R, Mantero V, Costantini G, D’Ambrosio V, Zaffaroni M, Ghezzi A, Perini P, Rossi S, Bertolotto A, Rottoli MR, Rovaris M, Balgera R, Cavalla P, Montomoli C, Bergamaschi R (2018) Two-year real-life efficacy, tolerability and safety of dimethyl fumarate in an Italian multicentre study. J Neurol 265(8):1850–1859. https://doi.org/10.1007/s00415-018-8916-6
doi: 10.1007/s00415-018-8916-6 pubmed: 29948245
Sabin J, Urtiaga S, Pilo B, Thuissard I, Galan V, Sainz de la Maza S, Costa-Frossard L, Gómez-Moreno M, Díaz-Díaz J, Oreja-Guevara C, Martínez-Ginés ML, Lozano A, Borrega L, Ayuso L, Castro A, Sanchez P, Meca-Lallana V, Muñoz C, Casanova I, López de Silanes C, Martín H, Rodriguez-García E, Moreno I, García-Merino JA, Aladro Y (2020) Tolerability and safety of dimethyl fumarate in relapsing multiple sclerosis: a prospective observational multicenter study in a real-life Spanish population. J Neurol. https://doi.org/10.1007/s00415-020-09848-7
doi: 10.1007/s00415-020-09848-7 pubmed: 32350647

Auteurs

Matteo Lucchini (M)

Multiple Sclerosis Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy. lucchinimatteo87@gmail.com.
Università Cattolica del Sacro Cuore, Rome, Italy. lucchinimatteo87@gmail.com.
ORCID: 0000-0002-0447-2297

Luca Prosperini (L)

S. Camillo Forlanini Hospital, Rome, Italy.

Maria Chiara Buscarinu (MC)

Center for Experimental Neurological Therapies, NESMOS, S. Andrea Hospital, Rome, Italy.

Diego Centonze (D)

Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
IRCCS Neuromed, Pozzilli, Isernia, Italy.

Antonella Conte (A)

IRCCS Neuromed, Pozzilli, Isernia, Italy.
Department of Human Neurosciences, Sapienza University, Rome, Italy.

Antonio Cortese (A)

Department of Human Neurosciences, Sapienza University, Rome, Italy.
San Filippo Neri Hospital, Rome, Italy.

Giorgia Elia (G)

Multiple Sclerosis Center, Ospedale S. Andrea, Rome, Italy.

Roberta Fantozzi (R)

IRCCS Neuromed, Pozzilli, Isernia, Italy.

Elisabetta Ferraro (E)

San Filippo Neri Hospital, Rome, Italy.

Claudio Gasperini (C)

S. Camillo Forlanini Hospital, Rome, Italy.

Antonio Ianniello (A)

Multiple Sclerosis Center, Ospedale S. Andrea, Rome, Italy.

Doriana Landi (D)

Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
Multiple Sclerosis Clinical and Research Unit, Fondazione Policlinico di Tor Vergata, Rome, Italy.

Girolama Alessandra Marfia (GA)

Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
IRCCS Neuromed, Pozzilli, Isernia, Italy.
Multiple Sclerosis Clinical and Research Unit, Fondazione Policlinico di Tor Vergata, Rome, Italy.

Viviana Nociti (V)

Multiple Sclerosis Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy.
Università Cattolica del Sacro Cuore, Rome, Italy.

Carlo Pozzilli (C)

Multiple Sclerosis Center, Ospedale S. Andrea, Rome, Italy.
Department of Neurology and Psychiatry, Sapienza University, Rome, Italy.

Marco Salvetti (M)

Center for Experimental Neurological Therapies, NESMOS, S. Andrea Hospital, Rome, Italy.
IRCCS Neuromed, Pozzilli, Isernia, Italy.

Carla Tortorella (C)

S. Camillo Forlanini Hospital, Rome, Italy.

Massimiliano Mirabella (M)

Multiple Sclerosis Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy.
Università Cattolica del Sacro Cuore, Rome, Italy.
ORCID: 0000-0002-7783-114X

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Classifications MeSH

questionsmedicales.fr › Composés chimiques organiques › Acides carboxyliques › Acides acycliques › Diacides carboxyliques › Fumarates › Fumarate de diméthyle › Predictors of lymphocyte count recovery after...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Predictors of lymphocyte count recovery after...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Facteurs immunologiques › Immunosuppresseurs › Predictors of lymphocyte count recovery after...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiogiques du sang › Hémogramme › Numération des leucocytes › Numération des lymphocytes › Predictors of lymphocyte count recovery after...
questionsmedicales.fr › Maladies du système immunitaire › Déficits immunitaires › Lymphopénie › Predictors of lymphocyte count recovery after...
questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Maladies auto-immunes du système nerveux › Maladies démyélinisantes auto-immunes du SNC › Sclérose en plaques › Predictors of lymphocyte count recovery after...
questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Maladies auto-immunes du système nerveux › Maladies démyélinisantes auto-immunes du SNC › Sclérose en plaques › Sclérose en plaques récurrente-rémittente › Predictors of lymphocyte count recovery after...