Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis

Grant A. Hill-Cawthorne, Tom Button, Orla Tuohy, Joanne L. Jones, Karen May, Jennifer Somerfield, Alison Green, Gavin Giovannoni, D. Alastair S. Compston, Michael T. Fahey, Alasdair J. Coles

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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.

Original languageEnglish
Pages (from-to)298-304
Number of pages7
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume83
Issue number3
DOIs
Publication statusPublished - Mar 2012
Externally publishedYes

Cite this

Hill-Cawthorne, G. A., Button, T., Tuohy, O., Jones, J. L., May, K., Somerfield, J., ... Coles, A. J. (2012). Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry, 83(3), 298-304. https://doi.org/10.1136/jnnp-2011-300826
Hill-Cawthorne, Grant A. ; Button, Tom ; Tuohy, Orla ; Jones, Joanne L. ; May, Karen ; Somerfield, Jennifer ; Green, Alison ; Giovannoni, Gavin ; Compston, D. Alastair S. ; Fahey, Michael T. ; Coles, Alasdair J. / Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. In: Journal of Neurology, Neurosurgery and Psychiatry. 2012 ; Vol. 83, No. 3. pp. 298-304.
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title = "Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis",
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.",
author = "Hill-Cawthorne, {Grant A.} and Tom Button and Orla Tuohy and Jones, {Joanne L.} and Karen May and Jennifer Somerfield and Alison Green and Gavin Giovannoni and Compston, {D. Alastair S.} and Fahey, {Michael T.} and Coles, {Alasdair J.}",
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Hill-Cawthorne, GA, Button, T, Tuohy, O, Jones, JL, May, K, Somerfield, J, Green, A, Giovannoni, G, Compston, DAS, Fahey, MT & Coles, AJ 2012, 'Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis', Journal of Neurology, Neurosurgery and Psychiatry, vol. 83, no. 3, pp. 298-304. https://doi.org/10.1136/jnnp-2011-300826

Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. / Hill-Cawthorne, Grant A.; Button, Tom; Tuohy, Orla; Jones, Joanne L.; May, Karen; Somerfield, Jennifer; Green, Alison; Giovannoni, Gavin; Compston, D. Alastair S.; Fahey, Michael T.; Coles, Alasdair J.

In: Journal of Neurology, Neurosurgery and Psychiatry, Vol. 83, No. 3, 03.2012, p. 298-304.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis

AU - Hill-Cawthorne, Grant A.

AU - Button, Tom

AU - Tuohy, Orla

AU - Jones, Joanne L.

AU - May, Karen

AU - Somerfield, Jennifer

AU - Green, Alison

AU - Giovannoni, Gavin

AU - Compston, D. Alastair S.

AU - Fahey, Michael T.

AU - Coles, Alasdair J.

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

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U2 - 10.1136/jnnp-2011-300826

DO - 10.1136/jnnp-2011-300826

M3 - Article

AN - SCOPUS:84857055778

VL - 83

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JO - Journal of Neurology, Neurosurgery and Psychiatry

JF - Journal of Neurology, Neurosurgery and Psychiatry

SN - 0022-3050

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