Cladribine tablets' potential in multiple sclerosis treatment.
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system occurring in genetically susceptible individuals (Frohman, Racke, & Raine, 2006). The inflammatory phase typically results in demyelination, one of the pathophysiologic hallmarks of MS (Frohman et al.). Inflammation and subsequent demyelination may correlate with clinical symptoms such as relapses, functional loss, and disability (Peterson & Fujinami, 2007). Remyelination often follows and may explain remissions in patients with relapsing forms of MS (Bruck, Kuhlmann, & Stadelmann, 2003). A temporal sequence of MS phases has been suggested; according to this theory, the initial inflammatory phase is followed by a neurodegenerative phase (Frohman et al.). But more recent information suggests the inflammatory and neurodegenerative phases may be independent processes or may occur simultaneously, or that neurodegeneration may provoke an inflammatory response (Charil & Filippi, 2007; Lassmann, Bruck, & Lucchinetti, 2007). Incomplete remyelination may be associated with progression to axonal damage, which can result in permanent disability (Lisak, 2007).
Our understanding of the immunopathophysiology of MS still is evolving. Many immune cells and secreted mediators are thought to be operative in the development of MS. These include several subsets of T and B lymphocytes; plasma-cell and B-cell antibodies; macrophages and microglia, which can serve as antigen-presenting cells to trigger the autoimmune response; excitotoxins; reactive oxygen species; proinflammatory cytokines; and various other inflammatory mediators (Frohman et al., 2006; Kleinschnitz, Meuth, Kieseier, & Wiendl, 2007; Peterson & Fujinami, 2007). Although T lymphocytes, especially the CD4+ subtype, have long been recognized as being involved in both the experimental model for MS (experimental autoimmune encephalitis) and MS, the critical roles of CD8+ T lymphocytes and B cells recently were recognized. Consequently, T lymphocytes, including CD4+, CD8+, and B lymphocytes, now are recognized as among the most important immune mediators involved in MS immunopathophysiology (Frohman et al.; Kleinschnitz et al.; Peterson & Fujinami).
A number of therapies presently are available for MS (Fontoura, Steinman, & Miller, 2006; Kleinschnitz et al., 2007). These include the immunomodulatory medications interferon beta and glatiramer acetate for the treatment of relapsing forms of MS; the monoclonal antibody natalizumab, which is available through a risk-management program for patients with relapsing forms of MS; and mitoxantrone for secondary progressive MS or worsening relapsing MS (Fontoura et al.; Kleinschnitz et al.). In addition, several new agents with different mechanisms of action targeting different aspects of the inflammatory process are in the late stages of development (Fontoura et al.; Kleinschnitz et al.).
Current unmet needs in MS treatment include the lack of available agents that provide greater efficacy without presenting serious safety concerns and the need for more convenient forms of administration (Boissy & Fox, 2007; Kleinschnitz et al., 2007; Leist & Vermersch, 2007). All current MS therapies involve parenteral delivery: either subcutaneous or intramuscular injections of interferon beta and glatiramer acetate, or intravenous infusions of natalizumab and mitoxantrone. Agents delivered subcutaneously or intramuscularly usually are administered by patient self-injection. Studies have shown that many patients have difficulty with injections, however, which leads to problems with adherence--a measure of how well a patient conforms to a treatment regimen over time (Cox & Stone, 2006; Mohr, Boudewyn, Likosky, Levine, & Goodkin, 2001). According to a recent large multicenter retrospective trial in patients treated with various formulations of interferon beta or glatiramer acetate, nonadherence to MS therapy frequently involves injection issues such as injection fatigue or injection-site reactions (Treadaway et al., 2005; Fig 1). Subcutaneous interferon can cause injection-site erythema, discomfort, and, rarely, necrosis. Glatiramer acetate can cause injection site erythema, discomfort, and lipoatrophy. An oral MS therapy can be of great benefit to patients in terms of convenience, quality of life, and improved adherence. Cladribine, which targets both T and B lymphocytes (Sipe, 2005), has the potential to be the first oral therapy for relapsing forms of MS.
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Pharmacology of Cladribine
Cladribine is an analog of the purine nucleoside adenosine, one of the building blocks of nucleic acids, which is incorporated into the DNA of cells (Sipe, 2005). Cladribine, a preferential lymphocytedepleting therapy, is a prodrug designed to exploit the specific enzymatic degradation of deoxynucleotides in lymphocytes (Sipe). Phosphorylation by cellular enzymes is necessary to activate cladribine (Sipe). Lymphocytes have high levels of the enzyme deoxycytidine kinase, which phosphorylates and activates cladribine. In contrast, lymphocytes have relatively low levels of the enzyme deoxynucleotidase, which degrades and inactivates phosphorylated cladribine and keeps it from accumulating in cells. Because cladribine is resistant to another inactivating cellular enzyme, adenosine deaminase, it accumulates mostly in lymphocytes and results in preferential lymphocyte depletion (Sipe). Many cells other than lymphocytes have sufficient levels of deoxynucleotidase to keep cladribine from accumulating and exerting toxic effects (Sipe). Among the most important immune mediators involved in MS immunopathophysiology, cladribine accumulates preferentially in lymphocytes, ultimately interfering with cell metabolism or DNA repair processes, causing programmed lymphocyte depletion (Sipe). Typically, lymphocyte levels gradually recover over time (Rice, Filippi, & Comi, 2000; Sipe). Other immune cells (e.g., neutrophils) usually are spared from the effects of cladribine when it is administered at doses previously established for MS treatment (Rice et al.; Sipe).
History of Cladribine in Disease States Other Than MS
Clinical trials have demonstrated the efficacy and safety of parenteral formulations of cladribine in various hematologic malignancies (Beutler, 1992). These malignancies include hairy-cell leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, cutaneous T-cell lymphoma, and non-Hodgkin's lymphoma (Beutler). The parenteral form of cladribine has been approved by the U.S. Food and Drug Administration (FDA) for hairy-cell leukemia (Beutler). Cladribine also has been studied in other autoimmune diseases including psoriatic arthritis, Sjogren's syndrome, rheumatoid arthritis, and inflammatory bowel disease (Beutler et al., 1996; Schirmer, Mur, Pfeiffer, Thaler, & Konwalinka, 1997; Sipe, 2005). In a study assessing the safety of subcutaneous cladribine 0.05 mg/kg weekly over a period of 8 weeks in 5 patients with refractory rheumatoid arthritis, cladribine was found to lower the levels of T and B cells, whereas levels of natural killer cells remained stable; lymphocyte depletion was the only side effect noted during treatment (Schirmer et al.). In previous clinical trials of cladribine for various hematologic malignancies and autoimmune diseases, lower doses of parenteral cladribine have been associated with less toxicity (Sipe). These studies helped guide the clinical development program for cladribine use in MS (Sipe).
History of Cladribine Treatment in MS
As the result of extensive study of cladribine in hematologic and nonhematologic malignancies, the dose ranges, toxicity, and pharmacokinetics in humans were well characterized before parenteral forms of cladribine were studied in patients with MS. Both phase II and phase III studies of parenteral cladribine in MS have demonstrated significant effects on MRI outcome measurements. Clinical outcomes were not as significant, but due to the highly positive MRI outcomes, it has been suggested that cladribine may be more effective in an earlier inflammatory, demyelinating phase of MS (Beutler & Koziol, 2000; Beutler et al., 1999; Sipe, 2005). See Table 1 for a summary of phase II and phase III studies of parenteral cladribine in MS. A complete review and discussion of the history of phase I, II, and III clinical trials in MS has been compiled (Sipe).
Safety of Cladribine in MS
As noted, cladribine has preferential effects for lymphocytes, and, to a lesser extent, monocytes (Sipe, 2005). The safety profile of cladribine is dose-dependent; this drug generally is well tolerated, with few adverse events at lower doses. Higher doses may result in rare idiosyncratic bone marrow suppression, leading to thrombocytopenia, leukopenia, and anemia (Beutler et al., 1994). This adverse event usually is observed in patients exposed to other myelosuppressive drugs (Beutler et al., 1994). In early MS clinical trials with parenteral formulations, opportunistic infections were infrequent (Sipe). Mild segmental herpes zoster occurred in several patients (Sipe). Hepatitis B occurred in 1 patient, resulting in fatal fulminant autoimmune hepatic necrosis; however, there was no evidence this condition was related to cladribine use (Beutler et al., 1996). No cases of progressive multifocal leukoencephalopathy were seen in any of the MS patients treated with cladribine.
Current Ongoing Clinical Trials with Cladribine Tablets for Relapsing Forms of MS
A 10-mg tablet of oral cladribine has been developed specifically for use in patients with relapsing forms of MS. The bioavailability of oral cladribine is 37%-51% of the bioavailability of parenteral doses (Sipe, 2005). The number of tablets administered is standardized based on weight (mg/kg) in 10-kg increments.
The results from the MS studies involving parenteral cladribine that were reviewed for this article were the basis for the selection of the dosage range for the two current trials with cladribine tablets (Fig 2).
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There are two phase III trials of cladribine tablets in relapsing-remitting MS currently in progress. The first, entitled CLARITY (CLAdRibine tablets In Treating MS orallY), is a 2-year phase III multicenter, randomized, double-blind, placebo-controlled trial involving 1,327 patients with relapsing forms of MS enrolled at 157 clinical sites worldwide. The administration of cladribine tablets is by short course. One treatment course with cladribine tablets is defined as once-daily therapy for 4-5 consecutive days during a 28-day period. CLARITY involves two cladribine tablet dosage arms. One course consists of two courses for the first and second year; the other arm consists of four courses for the first year and two courses for the second year (Fig 3). The primary efficacy end point is the relapse rate at 96 weeks; secondary end points are listed in Figure 4. The FDA has granted fast-track status to cladribine tablets, and final results of the CLARITY study are expected in 2009.
The second clinical trial, ONWARD (oral cladribine added ON to rebif new formulation in patients With Active Relapsing Disease), is a 2-year phase II multicenter, randomized, double-blind, placebo-controlled study of the safety and efficacy of cladribine tablets using the same dosing schedule as used in CLARITY plus subcutaneous interferon beta-la in patients with relapsing forms of MS. The primary end point is the safety of this therapeutic combination at 2 years. The study was launched in January 2007 in the United States and Spain.
The CLARITY Extension Study, which is designed to study the efficacy and safety of cladribine tablets in subjects with relapsing forms of MS for an additional 24 months, is under development.
The Nursing Role
MS treatment is challenging for both patients and healthcare professionals. Nurses play a critical role in helping patients better understand the MS disease process and the ways early treatment can affect relapse and disability outcomes. Nurses educate patients regarding treatment options, assist them with treatment initiation, and help them maintain long-term treatment adherence. Nurses are patient advocates, helping to secure insurance coverage for disease-modifying treatments. In addition, nurses teach patients how to correctly administer MS treatments and manage side effects. Through collaborative therapeutic relationships, nurses support patients to help them maintain the motivation to adhere to treatments.
Helping patients maintain long-term adherence to MS therapies can be challenging. One way nurses help enhance patient adherence is to foster self-efficacy, which is defined as a person's belief in their ability to exert some measure of control over their life (Bandura, 1994). In the realm of health care, self-efficacy can be defined as patients' belief in their ability to exert control over their disease. A recent study found that patients who scored higher on the MS Self-Efficacy (MSSE) control and function subscales had higher rates of adherence to immunomodulatory therapy (Fraser, Hadjimichael, & Vollmer, 2003).
Issues Specific to Cladribine Tablets
Cladribine is a preferential lymphocyte-depleting therapy. Its efficacy in MS is based on its ability to reduce the number of circulating autoreactive lymphocytes believed to be involved in the pathophysiology of MS. Consequently, all patients must meet certain hematologic criteria to receive cladribine therapy. Based on past clinical experience, pretreatment blood count criteria for patients with MS who have been identified as appropriate candidates for cladribine have been developed (Sipe, 2005; Fig 5). Hematologic monitoring must continue throughout the course of cladribine therapy. Nurses will play a critical role in monitoring patients for hematologic and other potential adverse events in consultation with hematology and neurological specialists.
Because cladribine tablets result in sustained lymphocyte depletion, traditional daily dosing is not necessary. Rather, a short-course, annual schedule is used. Although this dosing regimen may improve adherence, there is a risk that patients may lose track of the dosing schedule. Nurses must help patients maintain their dosing schedule through phone or e-mail contact. Regular contact also will help nurses assess new MS symptoms, remind patients about their safety blood tests, and inquire about medication side effects.
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Improved efficacy, safety, and routes of administration are the major unmet needs for MS therapy. Cladribine may become the first therapy to address the need for oral MS treatment. This agent provides preferential lymphocyte depletion that is achieved with an intermittent dosing regimen. This new short-course, annual oral regimen may help improve adherence and provide greater freedom for patients with MS. Parenteral formulations of cladribine have a clinical history of safety in other disease states, as well as in relapsing and progressive forms of MS. A phase III trial with cladribine tablets in patients with relapsing forms of MS now is underway, with results expected in 2009. Nurses will play a central role in the safe and effective use of this new agent for patients with relapsing forms of MS.
The authors would like to thank Carole Post, PhD MS, for support in the development of this manuscript. Jack C. Sipe, MD, is a consultant for Merck Serono.
Bandura, A. (1994). Self-efficacy. In V. S. Ramachaudran (Ed.), Encyclopedia of human behavior (Vol. 4, pp. 71-81). New York: Academic Press.
Beutler, E. (1992). Cladribine (2-chlorodeoxyadenosine). Lancet, 340(8825), 952-956.
Beutler, E., & Koziol, J. A. (2000). The cladribine trial in secondary progressive multiple sclerosis. A reanalysis. Neuroepidemiology, 19(2), 109-112.
Beutler, E., Koziol, J. A., McMillan, R., Sipe, J. C., Romine, J. S., & Carrera, C. J. (1994). Marrow suppression produced by repeated doses of cladribine. Acta Haematologica, 91(1), 10-15.
Beutler, E., Sipe, J. C., Romine, J. S., Koziol, J. A., McMillan, R., & Zyroff, J. (1999). The treatment of chronic progressive multiple sclerosis with cladribine. Proceedings of the National Academy of Sciences of the United States of America, 93, 1716-1720.
Beutler, E., Sipe, J., Romine, J., McMillan, R., Zyroff, J., & Koziol, J. (1996). Treatment of multiple sclerosis and other autoimmune diseases with cladribine. Seminars in Hematology, 22(1; Suppl. 1), 45-52.
Boissy, A., & Fox, R. J. (2007). Current treatment options in multiple sclerosis. Current Treatment Options in Neurology, 9(3), 176-186.
Bruck, W., Kuhlmann, T., & Stadelmann, C. (2003). Remyelination in multiple sclerosis. Journal of the Neurological Sciences, 206(2), 181-185.
Charil, A., & Filippi, M. (2007). Inflammatory demyelination and neurodegeneration in early multiple sclerosis. Journal of Neurological Sciences, 259, 7-14.
Cox, D., & Stone, J. (2006). Managing self-injection difficulties in patients with relapsing-remitting multiple sclerosis. Journal of Neuroscience Nursing, 38(3), 167-171.
Fontoura, P., Steinman, L., & Miller, A. (2006). Emerging therapeutic targets in multiple sclerosis. Current Opinion in Neurology, 19(3), 260-266.
Fraser, C., Hadjimichael, O., & Vollmer, T. (2003). Predictors of adherence to glatiramer acetate therapy in individuals with self-reported progressive forms of multiple sclerosis. Journal of Neuroscience Nursing, 35(3), 163-170.
Frohman, E. M., Racke, M. K., & Raine, C. (2006). Multiple sclerosis-The plaque and its pathogenesis. New England Journal of Medicine, 354(9), 942-955.
Kleinschnitz, C., Meuth, S. G., Kieseier, B. C., & Wiendl, H. (2007). Immunotherapeutic approaches in MS: Update on pathophysiology and emerging agents or strategies 2006. Endocrine, Metabolic and Immune Disorders Drug Targets, 7(1), 35-63.
Lassmann, H., Bruck, W., & Lucchinetti, C. F. (2007). The immunopathology of multiple sclerosis: An overview. Brain Pathology, 17(2), 210-218.
Leist T. P., & Vermersch, P. (2007). The potential role for cladribine in the treatment of multiple sclerosis: Clinical experience and development of an oral tablet formulation. Current Medical Research and Opinion, 23(11), 2667-2776.
Lisak, R. P. (2007). Neurodegeneration in multiple sclerosis: Defining the problem. Neurology, 68(22; Suppl. 3), S5-S12.
Mohr, D. C., Boudewyn, A. C., Likosky, W., Levine, E., & Goodkin, W. E. (2001). Injectable medication for the treatment of multiple sclerosis: The influence of self-efficacy expectations and injection anxiety on adherence and ability to self-inject. Annals of Behavioral Medicine, 23(2), 125-132.
Peterson, L. K., &. Fujinami, R. S. (2007). Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. Journal of Neuroimmunology, 184(1-2), 37-44.
Rice, G. P. A., Filippi, M., & Comi, G. (2000). Cladribine and progressive MS: Clinical and MRI outcomes of a multicenter controlled trial. Neurology, 54, 1145-1155.
Romine, J. S., Sipe, J. C., Koziol, J. A., Zyroff, J., & Beutler, E. (1999). A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proceedings of the Association of American Physicians, 111(1), 35-44.
Schirmer, M., Mur, E., Pfeiffer, K. P., Thaler, J., & Konwalinka, G. (1997). The safety profile of low-dose cladribine in refractory rheumatoid arthritis: A pilot trial. Scandinavian Journal of Rheumatology, 26(5), 376-379.
Sipe, J. C. (2005). Cladribine for multiple sclerosis: Review and current status. Expert Review of Neurotherapeutics, 5(6), 721-727.
Treadaway, K., Hawker, K., Racke, M., Brannon, K., Morrison, A., Remington, G., et al. (2005, June). Factors that influence adherence to disease-modifying therapy in multiple sclerosis. Poster session presented at the 19th annual meeting of the Consortium of Multiple Sclerosis Centers, Orlando, FL.
Questions or comments about this article may be directed to Kathleen Costello, MS CRNP MSCN, KCostello@som.umaryland.edu. She is a nurse practitioner and MS program director at Maryland Center for Multiple Sclerosis Treatment and Research at the University of Maryland, Baltimore.
Jack C. Sipe, MD, is a senior consultant in neurology at the Scripps Clinic and associate professor of neurology in the Department of Molecular and Experimental Medicine at the Scripps Research Institute, La Jolla, CA.
Table 1. Summary of Phase II and Phase III Multiple Sclerosis Trials with Parenteral Cladribine Patient Cladribine Trial Design Population Cumulative Dose Phase II, 48 with CPMS Year 1: randomized, (43 in year 2) 2.8 mg/kg IV placebo-controlled, Year 2: double-blind, (crossover phase): crossover study 1.4 mg/kg IV (Beutler et al., 1999 Phase II, 52 with RRMS 2.1 mg/kg SC randomized, placebo-controlled, double-blind study (Romine, Sipe, Koziol, Zyroff, & Beutler, 1999) Phase III, 159 with 2.1 mg/kg sc (n = 52) randomized, SPMS/PPMS or placebo-controlled, double-blind study 0.7 mg/kg sc (n = 54) (Rice et al., 2000) Trial Design Primary Efficacy Results Phase II, Year 1: randomized, * Mean paired difference (placebo minus placebo-controlled, matched cladribine) double-blind, --EDSS score: 1.3 (95% CI 0.6-2.0) crossover study --SNRS score: -12.5 (95% CI -16.7---8.2) (Beutler et al., * Placebo group had more patients with EDSS 1999 scores [greater than or equal to] 1 point, indicating disease progression (p < .02) Year 2: * Patients initially treated with cladribine (2.8 mg/kg cumulative dose) continued to show improvement in both EDSS (p = .0026) and SNRS (p [less than or equal to] .001) scores * Less robust effects seen in first-year placebo patients crossed over to cladribine Phase II, Relapse rate, 7-12 months: randomized, * Cladribine group: 0.77/year placebo-controlled, (95% CI 0.37-1.41) double-blind study * Placebo: 1.67/year (95% CI 1.02-2.57) (Romine, Sipe, Relapse rate, 7-18 months: Koziol, Zyroff, & * Cladribine group: 0.66/year (95% Beutler, 1999) CI 0.37-1.05) * Placebo: 1.34/year (95% CI 0.90-1.93) Phase III, No difference in EDSS scores between randomized, treatment groups placebo-controlled, double-blind study (Rice et al., 2000) Note. C1= confidence interval; CPMS = chronic progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis, SPMS = secondary progressive multiple sclerosis; PPMS = primary progressive multiple sclerosis; EDSS = expanded disability status scale; SNRS = Scripps neurologic rating scale. Table 2. Secondary Endpoints in the CLARITY Trial * Proportion of patients relapse-free over 96 weeks * Sustained disability progression * Number of active lesions * Number of T2 lesions over 96 weeks * Number of T1 Gd+ enhanced lesions over 96 weeks * Hematologic, clinical chemistry safety assessment, and adverse events * Quality of life * Health resource utilization Table 3. Pretreatment Blood Count Criteria for Cladribine in Multiple Sclerosis Platelet count before monthly courses of cladribine must be * [greater than or equal to] 200,000 or * 150,000-200,000 and represent >50% of the previous pretreatment platelet count or * 125,000-150,000 and represent [greater than or equal to] 80% of the previous pretreatment platelet count. Absolute granulocyte count must be * >1000. Hemoglobin level must not have declined * >1.5 g/dl from previous monthly pretreatment level or * >3 g/dl from baseline blood count. Note. From "Cladribine for multiple sclerosis: Review and current status," by J. C. Sipe, 2005, Expert Review of Neurotherapeutics, 5, pp. 721-727. Copyright 2005 by Future Drugs Ltd. Reprinted with permission.