Circulating lymphocyte levels and relationship with infection status in patients with relapsing–remitting multiple sclerosis treated with daclizumab beta

Abstract

Background:

Reversible lymphocyte count reductions have occurred following daclizumab beta treatment for relapsing–remitting multiple sclerosis.

Objective:

To analyse total and differential lymphocyte levels and relationship with infection status.

Methods:

In DECIDE, blood samples were collected at 12-week intervals from daclizumab beta- (n = 919) or intramuscular interferon beta-1a–treated (n = 922) patients. Infections/serious infections were assessed proximate to grade 2/3 lymphopenia or low CD4⁺/CD8⁺ T-cell counts. Total safety population (TSP) data were additionally analysed from the entire clinical development programme (n = 2236).

Results:

Over 96 weeks in DECIDE, mean absolute lymphocyte count (ALC), CD4⁺ and CD8⁺ T-cell counts decreased <10% (7.1% vs 1.6%, 9.7% vs 2.0%, 9.3% vs 5.9%: daclizumab beta vs interferon beta-1a, respectively); shifts to ALC below lower limit of normal occurred in 13% versus 15%, respectively. Grade 3 lymphopenia was uncommon (TSP: <1%) and transient. Lymphocyte changes generally occurred within 24 weeks after treatment initiation and were reversible within 12 weeks of discontinuation. In DECIDE, mean CD4⁺/CD8⁺ T-cell counts were similar regardless of infection status. TSP data were consistent with DECIDE.

Conclusion:

When observed, ALC and CD4⁺/CD8⁺ T-cell count decreases in daclizumab beta–treated patients were generally mild-to-modest, reversible upon treatment discontinuation and not associated with increased risk of infections, including opportunistic infections.

Keywords

Relapsing–remitting multiple sclerosis disease-modifying therapies immunology

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References

European Medicines Agency. Zinbryta summary of product characteristics, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003862/WC500210598.pdf (accessed 30 August 2017).

ZINBRYTA (package insert), https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761029s007lbl.pdf (accessed 30 August 2017).

Kappos

Cohan

Arnold

et al . Interim report on the safety and efficacy of long-term daclizumab treatment for up to 5 years (EXTEND trial). In: Presented at the 32nd congress of the European Committee for treatment and research in multiple sclerosis, London, 14–17 September 2016.

Gold

Radue

Giovannoni

et al . Safety and efficacy of daclizumab in relapsing-remitting multiple sclerosis: 3-year results from the SELECTED open-label extension study. BMC Neurol 2016; 16: 117.

Gold

Giovannoni

Selmaj

et al .; SELECT Study Investigators. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): A randomised, double-blind, placebo-controlled trial. Lancet 2013; 381: 2167–2175.

Kappos

Wiendl

Selmaj

et al . Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2015; 373: 1418–1428.

Giovannoni

Gold

Selmaj

et al .; SELECTION Study Investigators. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): A multicentre, randomised, double-blind extension trial. Lancet Neurol 2014; 13: 472–481.

Fam

Mokliatchouk

Mehta

et al . Reversible effects of daclizumab HYP on lymphocyte counts in RRMS patients: Data from the SELECT Trilogy studies. Neurology 2016; 86(16 suppl.): P5.281.

Giovannoni

Kappos

Gold

et al . Safety and tolerability profile of daclizumab in patients with relapsing-remitting multiple sclerosis: An integrated analysis of clinical studies. Mult Scler Relat Disord 2016; 9: 36–46.

10.

Delgado-Alvarado

Sedano

González-Quintanilla

et al . Progressive multifocal leukoencephalopathy and idiopathic CD4 lymphocytopenia. J Neurol Sci 2013; 327: 75–79.

11.

Molloy

Calabrese

LH.

Progressive multifocal leukoencephalopathy: A national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum 2009; 60: 3761–3765.

12.

Molloy

Calabrese

LH.

Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: Evolving role of biologic therapies. Arthritis Rheum 2012; 64: 3043–3051.

13.

Gheuens

Bord

Kesari

et al . Role of CD4⁺ and CD8⁺ T-cell responses against JC virus in the outcome of patients with progressive multifocal leukoencephalopathy (PML) and PML with immune reconstitution inflammatory syndrome. J Virol 2011; 85: 7256–7263.

14.

Johnson

Shames

Keezer

et al . Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin Immunol 2010; 137: 15–20.

15.

Francis

Kappos

O’Connor

et al . Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler 2014; 20: 471–480.

16.

European Medicines Agency. Gilenya summary of product characteristics, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf (accessed 25 January 2017).

17.

TECFIDERA (package insert), https://www.tecfidera.com/content/dam/commercial/multiple-sclerosis/tecfidera/pat/en_us/pdf/full-prescribing-info.pdf (accessed 28 November 2016).

18.

Fox

Chan

Gold

et al . Characterizing absolute lymphocyte count profiles in dimethyl fumarate–treated patients with MS: Patient management considerations. Neurol Clin Pract 2016; 6: 220–229.

19.

Williamson

Berger

JR.

Infection risk in patients on multiple sclerosis therapeutics. CNS Drugs 2015; 29: 229–244.

20.

Gold

Arnold

Bar-Or

et al . Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study. Mult Scler 2017; 23: 253–265.

21.

Rali

Veer

Gupta

et al . Opportunistic pulmonary infections in immunocompromised hosts. Crit Care Nurs Q 2016; 39: 161–175.

22.

Bryant

Baddley

JW.

Opportunistic infections in biological therapy, risk and prevention. Rheum Dis Clin North Am 2017; 43: 27–41.

23.

US Department of Health and Human Services, National Institutes of Health and National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (accessed 25 January 2017).

24.

Winkelmann

Loebermann

Reisinger

et al . Disease-modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol 2016; 12: 217–233.

25.

Dubey

Cano

Stuve

Update on monitoring and adverse effects of approved second-generation disease-modifying therapies in relapsing forms of multiple sclerosis. Curr Opin Neurol 2016; 29: 278–285.

26.

Coles

Twyman

Arnold

et al .; CARE-MS II Investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet 2012; 380: 1829–1839.

27.

Gold

Kappos

Arnold

et al .; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367: 1098–1107.

28.

Calabresi

Radue

Goodin

et al . 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: 545–556.

29.

Polman

O’Connor

Havrdova

et al .; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899–910.

30.

Vermersch

Czlonkowska

Grimaldi

et al .; TENERE Trial Group. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: A randomised, controlled phase 3 trial. Mult Scler 2014; 20: 705–716.

31.

Criswell

Couch

Greenberg

et al . The lymphocyte response to influenza in humans. Am Rev Respir Dis 1979; 120: 700–704.

32.

Kamphuis

Junt

Waibler

et al . Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia. Blood 2006; 108: 3253–3261.

33.

Lin

Winokur

Blake

et al . Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis. Ann Clin Transl Neurol 2015; 2: 445–455.

34.

Wiendl

Gross

CC.

Modulation of IL-2Rα with daclizumab for treatment of multiple sclerosis. Nat Rev Neurol 2013; 9: 394–404.

35.

Berger

Houff

Opportunistic infections and other risks with newer multiple sclerosis therapies. Ann Neurol 2009; 65: 367–377.

36.

Grigoriadis

Linnebank

Alexandri

et al . Considerations on long-term immuno-intervention in the treatment of multiple sclerosis: An expert opinion. Expert Opin Pharmacother 2016; 17: 2085–2095.

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