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Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study

Published:October 10, 2018DOI:https://doi.org/10.1016/j.msard.2018.10.006

      Highlights

      • Cladribine (2-chloro-2′-deoxyadenosine) is an adenosine deaminase-resistant purine nucleoside analog with preferential lymphocyte reducing properties acting through the mode of pulsed immune reconstitution.
      • We focused on the effect of cladribine on oligoclonal bands (OCB) expression in the CSF in relapsing-remitting MS (RRMS) patients observed over 10 years.
      • Isoelectric focusing revealed that 55% of patients did not have OCB in CSF after cladribine treatment as compared to baseline testing when 100% of patients were positive for OCB.
      • At the last follow-up (Year 10), OCB-negative patients had lower disability compared to OCB-positive patients.
      • Cladribine-induced immune reconstitution leads to long lasting suppression of intrathecal humoral response, which might be an additional mechanism that enhances the therapeutic effect on disease progression in RRMS patients.

      Abstract

      Background

      There has been long-term interest in cladribine as a drug for the treatment of MS. The current study focused on the effect of cladribine on oligoclonal bands (OCB) expression in the CSF in relapsing-remitting MS (RRMS) patients observed over 10 years.

      Methods

      29 treatment-naive subjects with RRMS were prospectively enrolled and received induction therapy with subcutaneous parenteral cladribine (at a cumulative dose of 1.8 mg/kg; divided into 6 courses every 5 weeks given for 4–6 days, depending on patients’ body weight). Selected patients received maintenance doses in the follow-up period.

      Results

      Isoelectric focusing revealed that 55% of patients did not have OCB in CSF after cladribine treatment as compared to baseline testing when 100% of patients were positive for OCB. There were no significant differences in Expanded Disability Status Scale scores at baseline and at the end of treatment cycle between OCB-positive vs. OCB-negative subgroups. At the last follow-up, OCB-negative patients had lower disability compared to OCB-positive patients (p = 0.03).

      Conclusion

      Cladribine-induced immune reconstitution leads to long lasting suppression of intrathecal humoral response, which might be an additional mechanism that enhances the therapeutic effect on disease progression in RRMS patients.

      Keywords

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      References

        • Annunziata P.
        • Giorgio A.
        • De Santi L.
        • Zipoli V.
        • Portaccio E.
        • Amato M.P.
        • et al.
        Absence of cerebrospinal fluid oligoclonal bands is associated with delayed disability progression in relapsing-remitting MS patients treated with interferon-beta.
        J. Neurol. Sci. 2006; 244: 97-102
        • Beutler E.
        • Sipe J.C.
        • Romine J.S.
        • Koziol J.A.
        • McMillan R.
        • Zyroff J.
        The treatment of chronic progressive multiple sclerosis with cladribine.
        Proc. Natl. Acad. Sci. U.S.A. 1996; 93: 1716-1720
        • Braendstrup P.
        • Langkilde A.R.
        • Schreiber K.
        • Ravnborg M.
        • Sellebjerg F.
        • Vindeløv L.
        • et al.
        Progression and CSF inflammation after eradication of oligoclonal bands in an MS patient treated with allogeneic hematopoietic cell transplantation for follicular lymphoma.
        Case. Rep. Neurol. 2012; 4: 101-106
        • Freedman M.S.
        • Thompson E.J.
        • Deisenhammer F.
        • Giovannoni G.
        • Grimsley G.
        • Keir G.
        • et al.
        Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement.
        Arch. Neurol. 2005; 62: 865-870
        • Giovannoni G.
        • Comi G.
        • Cook S.
        • Rammohan K.
        • Rieckmann P.
        • Soelberg Sørensen P.
        • et al.
        A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.
        N. Engl. J. Med. 2010; 362: 416-426
        • Giovannoni G.
        • Cook S.
        • Rammohan K.
        • Rieckmann P.
        • Sørensen P.S.
        • Vermersch P.
        • et al.
        Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.
        Lancet Neurol. 2011; 10: 329-337
        • Giovannoni G.
        Cladribine to treat relapsing forms of multiple sclerosis.
        Neurotherapeutics. 2017; 14: 874-887
        • Górski A.
        • Grieb P.
        • Makula J.
        • Stepień-Sopniewska B.
        • Mrowiec T.
        • Nowaczyk M.
        2-Chloro-2-deoxyadenosine–a novel immunosuppressive agent.
        Transplantation. 1993; 56: 1253-1257
        • Grieb P.
        • Stelmasiak Z.
        • Solski J.
        • Nowicki J.
        • Jakubowska B.
        • Ryba M.
        Effect of repeated treatments with cladribine (2-chlorodeoxyadenosine) on blood counts in multiple sclerosis patients.
        Arch. Immunol. Ther. Exp. (Warsz). 1995; 43: 323-327
        • Grieb P.
        • Ryba M.
        • Stelmasiak Z.
        • Nowicki J.
        • Solski J.
        • Jakubowska B.
        Cladribine treatment of multiple sclerosis.
        Lancet. 1994; 344: 537-538
        • Lefvert A.K.
        • Link H.
        IgG production within the central nervous system: a critical review of proposed formulae.
        Ann. Neurol. 1985; 17: 13-20
        • Liliemark J.
        • Albertioni F.
        • Hassan M.
        • Juliusson G.
        On the bioavailability of oral and subcutaneous 2-chloro-2′-deoxyadenosine in humans: alternative routes of administration.
        J Clin. Oncol. 1992; 10: 1514-1518
        • Link H.
        • Huang Y.M.
        Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness.
        J. Neuroimmunol. 2006; 180: 17-28
        • Mancuso R.
        • Franciotta D.
        • Rovaris M.
        • Caputo D.
        • Sala A.
        • Hernis A.
        • et al.
        Effects of natalizumab on oligoclonal bands in the cerebrospinal fluid of multiple sclerosis patients: a longitudinal study.
        Mult. Scler. 2014; 20: 1900-1903
        • McDonald W.I.
        • Compston A.
        • Edan G.
        • Goodkin D.
        • Hartung H.P.
        • Lublin F.D.
        • et al.
        Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis.
        Ann. Neurol. 2001; 50: 121-127
        • Mitosek-Szewczyk K.
        • Tabarkiewicz J.
        • Wilczynska B.
        • Lobejko K.
        • Berbecki J.
        • Nastaj M.
        • et al.
        Impact of cladribine therapy on changes in circulating dendritic cell subsets, T cells and B cells in patients with multiple sclerosis.
        J. Neurol. Sci. 2013; 332: 35-40
        • Petzold A.
        Intrathecal oligoclonal IgG synthesis in multiple sclerosis.
        J. Neuroimmunol. 2013; 262: 1-10
        • Sipe J.C.
        • Romine J.S.
        • Koziol J.A.
        • McMillan R.
        • Zyroff J.
        • Beutler E.
        Cladribine in treatment of chronic progressive multiple sclerosis.
        Lancet. 1994; 344: 9-13
        • Stelmasiak Z.
        • Solski J.
        • Nowicki J.
        • Jakubowska B.
        • Ryba M.
        • Grieb P.
        Effect of parenteral cladribine on relapse rates in patients with relapsing forms of multiple sclerosis: results of a 2-year, double-blind, placebo-controlled, crossover study.
        Mult. Scler. 2009; 15: 767-770
        • Stelmasiak Z.
        • Solski J.
        • Nowicki J.
        • Jakubowska B.
        • Ryba M.
        • Grieb P.
        A pilot trial of cladribine (2-chlorodeoxyadenosine) in remitting-elapsing multiple sclerosis.
        Med. Sci. Monit. 1998; 4: 4-8
        • von Glehn F.
        • Farias A.S.
        • de Oliveira A.C.
        • Damasceno A.
        • Longhini A.L.
        • Oliveira E.C.
        • et al.
        Disappearance of cerebrospinal fluid oligoclonal bands after natalizumab treatment of multiple sclerosis patients.
        Mult. Scler. 2012; 18: 1038-1041
        • Wiendl H.
        Cladribine - an old newcomer for pulsed immune reconstitution in MS.
        Nat. Rev. Neurol. 2017; 13: 573-574
        • Zeman A.Z.
        • Kidd D.
        • McLean B.N.
        • Kelly M.A.
        • Francis D.A.
        • Miller D.H.
        • et al.
        A study of oligoclonal band negative multiple sclerosis.
        J. Neurol. Neurosurg. Psychiatry. 1996; 60: 27-30