Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis

Handle URI:
http://hdl.handle.net/10754/561916
Title:
Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis
Authors:
Hill-Cawthorne, Grant A. ( 0000-0002-3828-5473 ) ; Button, Tom; Tuohy, Orla C.; Jones, Joanne L.; May, Karen; Somerfield, Jennifer; Green, Alison J E; Giovannoni, Gavin; Compston, Alastair D.; Fahey, Michael T.; Coles, Alasdair J.
Abstract:
Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods: The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.
KAUST Department:
Pathogen Genomics Laboratory; Bioscience Program
Publisher:
BMJ
Journal:
Journal of Neurology, Neurosurgery & Psychiatry
Issue Date:
5-Nov-2011
DOI:
10.1136/jnnp-2011-300826
PubMed ID:
22056965
Type:
Article
ISSN:
00223050
Sponsors:
During the course of this work, AJC was supported by an MRC Clinical Training Fellowship, Wellcome Intermediate Fellowship and now by the Biomedical Research Centre, Cambridge, NIHR. JLJ is also supported by the Biomedical Research Centre, Cambridge, NIHR. The original studies were supported by a grant from MuSTER.
Appears in Collections:
Articles; Bioscience Program

Full metadata record

DC FieldValue Language
dc.contributor.authorHill-Cawthorne, Grant A.en
dc.contributor.authorButton, Tomen
dc.contributor.authorTuohy, Orla C.en
dc.contributor.authorJones, Joanne L.en
dc.contributor.authorMay, Karenen
dc.contributor.authorSomerfield, Jenniferen
dc.contributor.authorGreen, Alison J Een
dc.contributor.authorGiovannoni, Gavinen
dc.contributor.authorCompston, Alastair D.en
dc.contributor.authorFahey, Michael T.en
dc.contributor.authorColes, Alasdair J.en
dc.date.accessioned2015-08-03T09:34:03Zen
dc.date.available2015-08-03T09:34:03Zen
dc.date.issued2011-11-05en
dc.identifier.issn00223050en
dc.identifier.pmid22056965en
dc.identifier.doi10.1136/jnnp-2011-300826en
dc.identifier.urihttp://hdl.handle.net/10754/561916en
dc.description.abstractBackground: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods: The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.en
dc.description.sponsorshipDuring the course of this work, AJC was supported by an MRC Clinical Training Fellowship, Wellcome Intermediate Fellowship and now by the Biomedical Research Centre, Cambridge, NIHR. JLJ is also supported by the Biomedical Research Centre, Cambridge, NIHR. The original studies were supported by a grant from MuSTER.en
dc.publisherBMJen
dc.titleLong term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosisen
dc.typeArticleen
dc.contributor.departmentPathogen Genomics Laboratoryen
dc.contributor.departmentBioscience Programen
dc.identifier.journalJournal of Neurology, Neurosurgery & Psychiatryen
dc.contributor.institutionDepartment of Neurology, University of Cambridge, Cambridge, United Kingdomen
dc.contributor.institutionDepartment of Medicine, University of Auckland, Auckland, New Zealanden
dc.contributor.institutionNational CJD Surveillance Unit, University of Edinburgh, Edinburgh, United Kingdomen
dc.contributor.institutionInstitute of Neurology, University College London, London, United Kingdomen
dc.contributor.institutionCentre for Neuroscience and Trauma, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdomen
dc.contributor.institutionCentre for Applied Medical Statistics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdomen
dc.contributor.institutionDivision of Mathematics, Informatics and Statistics, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Clayton South, VIC, Australiaen
kaust.authorHill-Cawthorne, Grant A.en

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