Cladribine: Mode of action and implications for treatment of multiple sclerosis

Clinical Neuropharmacology

Volumn 34, Issue 1, 2011, Pages 28-35

  Leist, Thomas P ^a   Weissert, Robert ^b,c  

^a THOMAS JEFFERSON UNIVERSITY   (United States)

^b MERCK SERONO S A   (Switzerland)

^c GENEVA UNIVERSITY HOSPITALS   (Switzerland)

Author keywords

cladribine tablets; mechanism of action; multiple sclerosis; purine nucleoside analog

Indexed keywords

BETA INTERFERON; CLADRIBINE; PLACEBO;

CELL DEATH; CEREBROSPINAL FLUID; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG PENETRATION; DRUG STRUCTURE; HUMAN; MAXIMUM PLASMA CONCENTRATION; MULTIPLE SCLEROSIS; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION; NEUROIMAGING; OUTCOME ASSESSMENT; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TABLET FORMULATION;

ADMINISTRATION, ORAL; CLADRIBINE; CLINICAL TRIALS AS TOPIC; HUMANS; IMMUNOSUPPRESSIVE AGENTS; LYMPHOCYTES; MULTIPLE SCLEROSIS; MULTIPLE SCLEROSIS, RELAPSING-REMITTING; TREATMENT OUTCOME;

EID: 79551579477     PISSN: 03625664     EISSN: None     Source Type: Journal    
DOI: 10.1097/WNF.0b013e318204cd90     Document Type: Review

References (75)

1. Tremlett HL, Oger J. Interrupted therapy: stopping and switching of the beta-inter feronsprescribed for MS. Neurology 2003;61(4):551-554.
2. Mohr DC, Boudewyn AC, Likosky W, et al. Injectable medication for the treatment of multiple sclerosis: the influence of self-efficacy expectations and injection anxiety on adherence and ability to self-inject. Ann Behav Med 2001;23(2):125-132.
3. Cohen BA, Rieckmann P. Emerging oral therapies for multiple sclerosis. Int J Clin Pract 2007;61(11):1922-1930.
4. World Health Organization. World Health Organization. Adherence to long-term therapies: evidence for action. Available at: http://apps.who.int/ medicinedocs/pdf/s4883e/s4883e.pdf Last accessed 19 November 2009.
5. Leist TP, Vermersch P. The potential role for cladribine in the treatment of multiple sclerosis: clinical experience and development of an oral tablet formulation. Curr Med Res Opin 2007;23(11):2667-2676.
6. Spurgeon S, Yu M, Phillips JD, et al. Cladribine: not just another purine analogue? Expert Opin Investig Drugs 2009;18(8):1169-1181.
7. Dimopoulos MA, Kantarjian H, Estey E, et al. Treatment of Waldenstrom macroglobulinemia with 2-chlorodeoxyadenosine. Ann Intern Med 1993;118(3):195-198.
8. Robak T, Blonski JZ, Kasznicki M, et al. Cladribine with or without prednisone in the treatment of previously treated and untreated B-cell chronic lymphocytic leukaemia\updated results of the multicentre study of 378 patients. Br J Haematol 2000;108(2):357-368.
9. Rummel MJ, Chow KU, Jager E, et al. Treatment ofmantle-cell lymphomas with intermittent two-hour infusion of cladribine as first-line therapy or in first relapse. Ann Oncol 1999;10(1):115-117.
10. Robak T. Purine nucleoside analogues in the treatment of myeloid leukemias. LeukLymphoma 2003;44(3):391-409.
11. Kong LR, Samuelson E, Rosen ST, et al. 2-Chlorodeoxyadenosine in cutaneous T-cell lymphoproliferative disorders. Leuk Lymphoma 1997;26(1-2):89-97.
12. Blum KA, Johnson JL, Niedzwiecki D, et al. Prolonged follow-up after initial therapy with 2-chlorodeoxyadenosine in patients with indolent non-Hodgkin lymphoma: results of Cancer and Leukemia Group B Study 9153. Cancer 2006;107(12):2817-2825.
13. Valencak J, Trautinger F, Fiebiger WCC, et al. Complete remission of chronic plaque psoriasis and gastric marginal zone B-cell lymphoma of MALT type after treatment with 2-chlorodeoxyadenosine. Ann Hematol 2002;8(11):662-665.
14. Schirmer M, Mur E, Pfeiffer KP, et al. The safety profile of low-dose cladribine in refractory rheumatoid arthritis. A pilot trial. Scand J Rheumatol 1997;26(5):376-379.
15. Davis JC Jr, Austin H III, Boumpas D, et al. A pilot study of 2-chloro-2'-deoxyadenosine in the treatment of systemic lupus erythematosus-associated glomerulonephritis. Arthritis Rheum 1998;41(2):335-343.
16. Duchini A, Younossi ZM, Saven A, et al. An open-label pilot trial of cladribine (2-chlorodeoxyadenosine) in patients with primary sclerosing cholangitis. J Clin Gastroenterol 2000;31(4):292-296.
17. Romine JS, Sipe JC, Koziol JA, et al. A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Phys 1999;111(1):35-44.
18. Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 2000;54(5):1145-1155.
19. Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994;344(8914):9-13.
20. Beutler E, Sipe JC, Romine JS, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci US A 1996;93(4):1716-1720.
21. Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial oforal cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362(5):416-426.
22. Giovannoni G, Comi G, Rammohan K, et al. Disease-free status achieved with cladribine tablets in the 96-week, phase III, double-blind, placebo-controlled CLARITY study in patients with relapsing-remitting multiple sclerosis (RRMS) (Annual Congress of European Committee for Treatment and Research in Multiple Sclerosis [ECTRIMS], Dusseldorf, Germany, 9-12 September 2009). [Poster P471]. Poster presented at ECTRIMS 2009.
23. Viglietta V, Greenberg S, Mikol D, et al. Clinical development plan for cladribine tablets, an oral immunomodulator, for the treatment of multiple sclerosis (Annual Congress of European Committee for Treatment and Research in Multiple Sclerosis [ECTRIMS], Dusseldorf, Germany, 9-12 September 2009). [Poster P439]. Poster presented at ECTRIMS 2009.
24. Chofflon M. Mechanisms of action for treatments in multiple sclerosis: does a heterogeneous disease demand a multi-targeted therapeutic approach? BioDrugs 2005;19(5):299-308.
25. Hemmer B, Cepok S, Zhou D, et al. Multiple sclerosis\a coordinated immune attack across the blood brain barrier. Curr Neurovasc Res 2004;1(2):141-150.
26. Chitnis T. The role of CD4 T cells in the pathogenesis of multiple sclerosis. Int Rev Neurobiol 2007;7943-7972.
27. Bitsch A, Schuchardt J, Bunkowski S, et al. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 2000;123(Pt 6):1174-1183.
28. Babbe H, Roers A, Waisman A, et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. JExp Med 2000;192(3):393-404.
29. McDole J, Johnson AJ, Pirko I. The role of CD8+ T-cells in lesion formation and axonal dysfunction in multiple sclerosis. Neurol Res 2006;28(3):256-261.
30. Bennett JL, Stuve O. Update on inflammation, neurodegeneration, and immunoregulation in multiple sclerosis: therapeutic implications. Clin Neuropharmacol 2009;32(3):121-132.
31. Kuhlmann T, Lingfeld G, Bitsch A, et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases overtime. Brain 2002;125(Pt 10):2202-2212.
32. Medana I, Martinic MA, Wekerle H, et al. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am J Pathol 2001;159(3):809-815.
33. Cepok S, Jacobsen M, Schock S, et al. Patterns ofcerebrospinal fluid pathology correlate with disease progression in multiple sclerosis. Brain 2001;124(Pt 11):2169-2176.
34. Opdenakker G, Nelissen I, Van DJ. Functional roles and therapeutic targeting of gelatinase B and chemokines in multiple sclerosis. Lancet Neurol 2003;2(12):747-756.
35. Szczucinski A, Losy J. Chemokines and chemokine receptors in multiple sclerosis. Potential targets for new therapies. BMJ 2007;115(3):137-146.
36. Kivisakk P, Mahad DJ, Callahan MK, et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci USA 2003;100(14):8389-8394.
37. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992;340(8825):952-956.
38. Sipe JC Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother 2005;5(6):721-727.
39. Smal C, Vertommen D, Bertrand L, et al. Identification of in vivo phosphorylation sites on human deoxycytidine kinase. Role of Ser-74 in the control of enzyme activity. J Biol Chem 2006;281(8):4887-4893.
40. Kawasaki H, Carrera CJ, Piro LD, et al. Relationship of deoxycytidine kinase and cytoplasmic 5'-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine. Blood 1993;81(3):597-601.
41. Saven A, Piro LD. 2-Chlorodeoxyadenosine: a newer purine analog active in the treatment of indolent lymphoid malignancies. Ann Intern Med 1994;120(9):784-791.
42. Spasokoukotskaja T, Arner ES, Brosjo O, et al. Expression of deoxycytidine kinase andphosphorylation of 2-chlorodeoxyadenosine in human normal and tumour cells and tissues. Eur J Cancer 1995;31A(2):202-208. Available at: http://biogps.gnf org. Accessed August, 2008.
43. Salvat C, Curchod M-L, Guedj E, et al. Cellular expression profiling of genes involved in the cladribine metabolic pathway: insights into mechanism of action in multiple sclerosis (Annual Congress of European Committee for Treatment and Research in Multiple Sclerosis [ECTRIMS], Dusseldorf, Germany, 9-12, September 2009). [Poster P280]. Poster presented at ECTRIMS 2009.
44. Hartman WR, Hentosh P. The antileukemia drug 2-chloro-2'-deoxyadenosine: an intrinsic transcriptional antagonist. Mol Pharmacol 2004;65(1):227-234.
45. Griffig J, Koob R, Blakley RL. Mechanisms of inhibition of DNA synthesis by 2-chlorodeoxyadenosine in human lymphoblastic cells. Cancer Lett 1989;49(24 Pt 1):6923-6928.
46. Galmarini CM, Voorzanger N, Falette N, et al. Influence ofp53 and p21(WAF1) expression on sensitivity of cancer cells to cladribine. Biochem Pharmacol 2003;65(1):121-129.
47. Lotfi K, Juliusson G, Albertioni F Pharmacological basis for cladribine resistance. Leuk Lymphoma 2003;44(10):1705-1712.
48. Lindemalm S, Liliemark J, Juliusson G, et al. Cytotoxicity and pharmacokinetics of cladribine metabolite, 2-chloroadenine in patients with leukemia. Cancer Lett 2004;210(2):171-177.
49. +/CD38 hematopoietic progenitor cells: selective effects of doxorubicin and 2-CdA with protection of immature cells. Leuk Lymphoma 2002;43(2):377-384.
50. Holowiecki J, Grosicki S, Sadus-Wojciechowska M, et al. Addition of cladribine to induction/consolidation regimen does not impair peripheral blood stem cell mobilization and bone marrow harvest for autotransplantation in acute myeloid leukemia patients. Transplant Proc 2005;37(10):4482-4487.
51. Leupin N, Schuller JC, Solenthaler M, et al. Efficacy of rituximab and cladribine in patients with chronic lymphocytic leukemia and feasibility of stem cell mobilization: a prospective multicenter phase II trial (protocol SAKK 34/02). Leuk Lymphoma 2010;51(4):613-619.
52. Manoussakis MN, Papadopoulos GK, Drosos AA, et al. Soluble interleukin 2 receptor molecules in the serum of patients with autoimmune diseases. Clin ImmunolImmunopathol 1989;50(3):321-332.
53. Janiec K, Wajgt A, Kondera-Anasz Z. Effect of immunosuppressive cladribine treatment on serum leucocytes system in two-year clinical trial in patients with chronic progressive multiple sclerosis. Med Sci Monit 2001;7(1):93-98.
54. Bartosik-Psujek H, Belniak E, Mitosek-Szewczyk K, et al. Interleukin-8 and RANTES levels in patients with relapsing-remitting multiple sclerosis (RR-MS) treated with cladribine. BMJ 2004;109(6):390-392.
55. Liliemark J. The clinical pharmacokinetics of cladribine. Clin Pharmacokinet 1997;32(2):120-131.
56. Mitosek-Szewczyk K, Stelmasiak Z, Bartosik-Psujek H, et al. Impact of cladribine on soluble adhesion molecules in multiple sclerosis. Acta Neurol Scand 2010;122(6):409-413.
57. Kopadze T, Dobert M, Leussink VI, et al. Cladribine impedes in vitro migration of mononuclear cells: a possible implication for treating multiple sclerosis. Eur J Neurol 2009;16(3):409-412.
58. Sospedra M, Martin R. Immunology of multiple sclerosis. Ann Rev Immunol 2005;23:683-747.
59. Sipe JC Cladribine tablets: a potential new short-course annual treatment for relapsing multiple sclerosis. Expert Rev Neurother 2010. 10(3) 365-375.
60. Albertioni F, Juliusson G, Liliemark J. On the bioavailability of 2-chloro-2'-deoxyadenosine (CdA). The influence of food and omeprazole. Eur J Clin Pharmacol 1993;44(6):579-582.
61. Lucchinetti CF, Bruck W, Lassmann H. Evidence for pathogenic heterogeneity in multiple sclerosis. Ann Neurol 2004;56(2):308.
62. Lucchinetti CF, Bruck W, Rodriguez M, et al. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol 1996;6(3):259-274.
63. Fontoura P, Steinman L, Miller A. Emerging therapeutic targets in multiple sclerosis. Curr Opin Neurol 2006;19(3):260-266.
64. Miron VE, Schubart A, Antel JP Central nervous system-directed effects ofFTY720 (fingolimod). J Neurol Sci 2008;274(1-2):13-17.
65. Tallantyre E, Evangelou N, Constantinescu CS. Spotlight on teriflunomide. IntMS J2008;15(2):62-68.
66. Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008;371(9630):2085-2092.
67. Lee DH, Linker RA, Gold R. Spotlight on fumarates. Int MS J 2008;15(1):12-18.
68. Kappos L, Gold R, Miller DH, et al. Efficacy and safety oforal fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008;372(9648):1463-1472.
69. Albertioni F, Herngren L, Juliusson G, et al. Protein binding of 2-chloro 2'-deoxyadenosine (cladribine) in healthy subjects and in patients with leukaemia. Eur J Clin Pharmacol 1994;46(6):563-564.
70. Bertolotto A, Gilli F, Sala A, et al. Persistent neutralizing antibodies abolish the interferon beta bioavailability in MS patients. Neurology 2003;60(4):634-639.
71. Salama HH, Hong J, Zang YC, et al. Blocking effects of serum reactive antibodies induced by glatiramer acetate treatment in multiple sclerosis. Brain 2003;126(Pt 12):2638-2647.
72. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354(9):899-910.
73. Hartung HP, Aktas O, Kieseier B, et al. Development oforal cladribine for the treatment of multiple sclerosis. J Neurol 2009;257(2):163-170.
74. Cook S, Vermersch P, Comi C, et al. Safety of cladribine tablets in relapsing-remitting multiple sclerosis (RRMS): results from the CLARITY study, a 96-week, phase III, double-blind, placebo-controlled trial (European Neurological Society [ENS], Milan, Italy, 20-24 June 2009) [Poster P360]. Poster presented at ENS 2009.
75. Orlowski RZ. Successful pregnancy after cladribine therapy for hairy cell leukemia. Leuk Lymphoma 2004;45(1):187-188.