Cladribine

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Cladribine
Cladribine.svg
Clinical data
Trade namesLeustatin, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa693015
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration
Intravenous, subcutaneous (liquid)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100% (i.v.); 37 to 51% (Orally)[3]
Protein binding25% (range 5-50%)[2]
MetabolismMostly via intracellular kinases; 15-18% is excreted unchanged[2]
Elimination half-lifeTerminal elimination half-life: Approximately 10 hours after both intravenous infusion an subcutaneous bolus injection[2]
ExcretionUrinary[2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.164.726 Edit this at Wikidata
Chemical and physical data
FormulaC10H12ClN5O3
Molar mass285.687 g/mol
3D model (JSmol)
  (verify)

Cladribine, sold under the brand name Leustatin and Mavenclad among others, is a medication used to treat hairy cell leukemia (HCL, leukemic reticuloendotheliosis), B-cell chronic lymphocytic leukemia and relapsing-remitting multiple sclerosis.[4][5] Its chemical name is 2-chloro-2'-deoxyadenosine (2CdA).

As a purine analog, it is a synthetic chemotherapy agent that targets lymphocytes and selectively suppresses the immune system. Chemically, it mimics the nucleoside adenosine. However, unlike adenosine it is relatively resistant to breakdown by the enzyme adenosine deaminase, which causes it to accumulate in cells and interfere with the cell's ability to process DNA. Cladribine is taken up cells via a transporter. Once inside a cell cladribine is activated mostly in lymphocytes, when it is triphosphorylated by the enzyme deoxyadenosine kinase (dCK). Various phosphatases dephosphorylate cladribine. Activated, triphosphorylated, cladribine is incorporated into mitochondrial and nuclear DNA, which triggers apoptosis. Non-activated cladribine is removed quickly from all other cells. This means that there is very little non-target cell loss.[4][6]

Medical uses[edit]

Cladribine is used for as a first and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukemia and is administered by intravenous or subcutaneous infusion.[5][7]

Since 2017, cladribine is approved as an oral formulation (10 mg tablet) for the treatment of RRMS in Europe, UAE, Argentina, Chile, Canada and Australia. Merck KGaA will be filing the product for registration in different countries around the globe, including the US, where the NDA application was accepted in late July 2018.

Some investigators have used the parenteral formulation orally to treat patients with HCL. It is important to note that approximately 40% of oral cladribine in bioavailable orally. It used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease[8] and Langerhans cell histiocytosis,[9]

Cladribine can cause fetal harm when administered to a pregnant woman and is listed by the FDA as Pregnancy Category D; safety and efficacy in children has not been established.[7]

Adverse effects[edit]

Injectable cladribine suppresses the body's ability to make new lymphocytes, natural killer cells and neutrophils (called Myelosuppression); data from HCL studies showed that about 70% of people taking the drug had fewer white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anemic; and about 10% of people had too few platelets.[7]

At the dosage used to treat HCL in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.[7]

In comparison, in MS, cladribine is associated with a 6% rate of severe lymphocyte suppression (lymphopenia) (levels lower than 50% of normal). Other common side effects include headache (75%), sore throat (56%), common cold-like illness (42%) and nausea (39%)[10]

Mechanism of Action[edit]

As a purine analogue, it is taken up into rapidly proliferating cells like lymphocytes to be incorporated into DNA synthesis. Unlike adenosine, cladribine has a chlorine molecule at position 2, which renders it partially resistant to breakdown by adenosine deaminase (ADA). In cells it is phosphorylated into its toxic form, deoxyadenosine triphosphate, by the enzyme deoxycytidine kinase (DCK). This molecule is then incorporated into the DNA synthesis pathway, where it causes strand breakage. This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis).[11] This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment[12]

Within the lymphocyte pool, cladribine targets B cells more than T cells. Both HCL and B-cell chronic lymphocytic leukaemia are types of B cell blood cancers. In MS, its effectiveness may be due to its ability to effectively deplete B cells, in particular memory B cells[13] In the pivotal phase 3 clinical trial of oral cladribine in MS, CLARITY, cladribine selectively depleted 80% of peripheral B cells, compared to only 40-50% of total T cells.[14] More recently, cladribine has been shown to induce long term, selective suppression of certain subtypes of B cells, especially memory B cells.[15]

Another family of enzymes, the 5´nucleotidase (5NCT) family, is also capable of dephosphorylating cladribine, making it inactive. The most important subtype of this group appears to be 5NCT1A, which is cytosolically active and specific for purine analogues. When DCK gene expression is expressed as a ratio with 5NCT1A, the cells with the highest ratios are B cells, especially germinal centre and naive B cells.[15] This again helps to explain which B cells are more vulnerable to cladribine-mediated apoptosis.

Although cladribine is selective for B cells, the long term suppression of memory B cells, which may contribute to its effect in MS, is not explained by gene or protein expression. Instead, cladribine appears to deplete the entire B cell department. However, while naive B cells rapidly more quickly from lymphoid organs, the memory B cell pool repopulates very slowly from the bone marrow.

History[edit]

Ernest Beutler and Dennis A. Carson had studied adenosine deaminase deficiency and recognized that because the lack of adenosine deaminase led to the destruction of B cell lymphocytes, a drug designed to inhibit adenosine deaminase might be useful in lymphomas. Carson then synthesized cladribine, and through clinical research at Scripps starting in the 1980s, Beutler tested it as intravenous infusion and found it was especially useful to treat hairy cell leukemia (HCL). No pharmaceutical companies were interested in selling the drug because HCL was an orphan disease, so Beutler's lab synthesized and packaged it and supplied it to the hospital pharmacy; the lab also developed a test to monitor blood levels. This was the first treatment that led to prolonged remission of HCL, which was previously untreatable.[16]:14–15

In February 1991 Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market and by December of that year J&J had filed an NDA; cladrabine was approved by the FDA in 1993 for HCL as an orphan drug,[17] and was approved in Europe later that year.[18]:2

The subcutaneous formulation was developed in Switzerland in the early 1990s and it was commercialized by Lipomed GmbH in the 2000s.[18]:2[19]

Multiple sclerosis[edit]

In the mid-1990s Beutler, in collaboration with Jack Sipe, a neurologist at Scripps, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drug's immunosuppressive effects. Sipe's insight into MS, and Beutler's interest in MS due to his sister's having had it, led a very productive collaboration.[16]:17[20] Ortho-Clinical, a subsidiary of J&J, filed an NDA for cladribine for MS in 1997 but withdrew it in the late 1990s after discussion with the FDA proved that more clinical data would be needed.[21][22]

Ivax acquired the rights for oral administration of cladribine to treat MS from Scripps in 2000,[23] and partnered with Serono in 2002.[22] Ivax was acquired by Teva in 2006,[24][25] and Merck KGaA acquired control of Serono's drug business in 2006.[26]

An oral formulation of the drug with cyclodextrin was developed[27]:16 and Ivax and Serono, and then Merck KGaA conducted several clinical studies. Merck KGaA submitted an application to the European Medicines Agency in 2009, which was rejected in 2010, and an appeal was denied in 2011.[27]:4–5 Likewise Merck KGaA's NDA with the FDA rejected in 2011.[28] The concerns were that several cases of cancer had arisen, and the ratio of benefit to harm was not clear to regulators.[27]:54–55 The failures with the FDA and the EMA were a blow to Merck KGaA and were one of a series of events that led to a reorganization, layoffs, and closing the Swiss facility where Serono had arisen.[29][30] However, several MS clinical trials were still ongoing at the time of the rejections, and Merck KGaA committed to completing them.[28] A meta-analysis of data from clinical trials showed that cladiribine did not increase the risk of cancer at the doses used in the clinical trials.[31]

In 2015 Merck KGaA announced it would again seek regulatory approval with data from the completed clinical trials in hand,[29] and in 2016 the EMA accepted its application for review.[32] On June 22, 2017, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the treatment of relapsing forms of multiple sclerosis.[33]

Finally, after all these problems it was approved in Europe on August 2017 for highly active RRMS.[34]

Efficacy[edit]

Cladribine is an effective treatment for relapsing remitting MS, with a reduction in the annual rate of relapses of 54.5%.[10] These effects may be sustained up to 4 years after initial treatment, even if no further doses are given.[35] Thus, cladribine is considered to be a highly effective immune reconstitution therapy in MS.. Similar to alemtuzumab, cladribine is given as two courses approximately one year apart. Each course consists of 4-5 tablets given over a week in the first month, followed by a second dosing of another 4-5 tablets the following month[36] During this time and after the final dose patients are monitored for adverse effects and signs of relapse.

https://www.merckneurology.co.uk/wp-content/uploads/2017/08/mavenclad-table-1.jpg

Safety[edit]

Compared to alemtuzumab, cladribine is associated with a lower rate of severe lymphopenia. It also appears to have a lower rate of common adverse events, especially mild to moderate infections[10][35] As cladribine is not a recombinant biological therapy, it is not associated with the development of antibodies against the drug, which might reduce the effectiveness of future doses. Also, unlike alemtuzumab, cladribine is not associated with secondary autoimmunity.[37]

This is probably due to the fact cladribine more selectively targets B cells. Unlike alemtuzumab, cladribine is not associated with a rapid repopulation of the peripheral blood B cell pool, which then ´overshoots´ the original number by up to 30%.[38] Instead, B cells repopulate more slowly, reaching near normal total B cells numbers at 1 year. This phenomenon and the relative sparing of T cells, some of which might be important in regulating the system against other autoimmune reactions, is thought to explain the lack of secondary autoimmunity.

Use in clinical practice[edit]

The decision to start cladribine in MS depends on the degree of disease activity (as measured by number of relapses in the past year and T1 gadolinium-enhancing lesions on MRI), the failure of previous disease-modifying therapies, the potential risks and benefits and patient choice.

In the UK, the National Institute for Clinical Excellence (NICE) recommends cladribine for treating highly active RRMS in adults if the persons has:

rapidly evolving severe relapsing–remitting multiple sclerosis, that is, at least 2 relapses in the previous year and at least 1 T1 gadolinium-enhancing lesion at baseline MRI or

relapsing–remitting multiple sclerosis that has responded inadequately to treatment with disease-modifying therapy, defined as 1 relapse in the previous year and MRI evidence of disease activity.[39]

People with MS require counselling on the intended benefits of cladribine in reducing the risk of relapse and disease progression, versus the risk of adverse effects such as headaches, nausea and mild to moderate infections. Women of childbearing age also require counselling that they should not conceive while taking cladribine, due to the risk of harm to the fetus.

Cladribine, as the 10 mg oral preparation Mavenclad, is administered as two courses of tablets approximately one year apart. Each course consists of four to five treatment days in the first month, followed by an additional four to five treatment days in the second month. The recommended dose of Mavenclad is 3.5 mg/kg over 2 years, given in two treatment courses of 1.75 mg/kg/year. Therefore, the number of tablets administered on each treatment day depends on the person's weight. A full guide to the dosing strategy can be found below:

https://www.merckneurology.co.uk/mavenclad/mavenclad-efficacy/

After treatment, people with MS are monitored with regular blood tests, looking specifically at the white cell count, renal and liver function. Patients should be followed up regularly by their treating neurologist to assess efficacy, and should be able to contact their MS service in the case of adverse effects or relapse. After the first two years of active treatment no further therapy may need to be given, as cladribine has been shown to be efficacious for up to last least four years after treatment. However, if patients fail to respond, options include switching to other highly effective disease-modifying therapies such as alemtuzumab, fingolimod or natalizumab.

Research directions[edit]

Cladribine has been studied as part of a multi-drug chemotherapy regimen for drug-resistant T-cell prolymphocytic leukemia.[40]

References[edit]

  1. ^ Drugs.com International trade names for Cladribine Page accessed Jan 14, 2015
  2. ^ a b c d "PRODUCT INFORMATION LITAK© 2 mg/mL solution for injection" (PDF). TGA eBusiness Services. St Leonards, Australia: Orphan Australia Pty. Ltd. 10 May 2010. Retrieved 27 November 2014.
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  19. ^ EMA 2004 Litak: Background Information one the Procedure
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  32. ^ Press release
  33. ^ Merck. "Cladribine Tablets Receives Positive CHMP Opinion for Treatment of Relapsing Forms of Multiple Sclerosis". www.prnewswire.co.uk. Retrieved 2017-08-22.
  34. ^ Cladribine approved in Europe, Press Release
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  40. ^ Hasanali, Zainul S.; Saroya, Bikramajit Singh; Stuart, August; Shimko, Sara; Evans, Juanita; Shah, Mithun Vinod; Sharma, Kamal; Leshchenko, Violetta V.; Parekh, Samir (24 June 2015). "Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia". Science Translational Medicine. 7 (293): 293ra102. doi:10.1126/scitranslmed.aaa5079. ISSN 1946-6234. PMC 4807901. PMID 26109102.