Q: What is cladribine?
A: Cladribine (2-chloro-2′-deoxyadenosine, 2-CDA, Mavenclad®) is a treatment with two oral 4-5 day courses over 2 years. A parenteral formulation was studied in the 1990s and demonstrated efficacy in reducing disease activity and slowing disease progression1-3. Oral cladribine gained approval by the European Medicines Agency (EMA) in June 2017 for highly active relapsing MS4,5 after alleviation of initial concerns of potential adverse effects. Cladribine was approved by the FDA for use in the United States in March 2019.
Q: How does cladribine work?
A: Cladiribine causes transient depletion of lymphocytes with a greater impact on B (particularly memory cells6) than T cells7followed by immune reconstitution. It is a synthetic purine nucleoside analog prodrug. Upon entry into lymphocytes by purine nucleoside transporters, the first phosphorylation to the active drug 2-chlorodeoxyadenosine triphosphate is by deoxycytidine kinase (DCK). The active drug is dephosphorylated by 5ʹ-nucleotidase (5’-NTase) and is resistant to deamination by adenosine deaminase. As lymphocytes have high DCK and low 5ʹNTase levels, the drug accumulates, inhibits DNA synthesis and repair in dividing lymphocytes, and reduces intracellular NAD and ATP in quiescent lymphocytes. This leads to death of proliferating and resting lymphocytes. Because the ratio of DCK/5’NTase is lower in other cell types and tissues, the selectivity of cladribine to lymphocytes reduces the incidence of adverse effects.
Q: How effective is cladribine for relapsing MS?
A: Cladribine has the potential for a persistent effect without continued treatment. Combined data from the 2-year phase III CLARITY showed that compared to placebo, cladribine reduces annualized relapse rate (-57.6%4), 3-month confirmed disability worsening 4,8,9, and increased the proportion of patients free from disease activity at 2 years (44% vs 16%). A post-hoc MRI study showed reductions in gadolinium-enhancing (GdE) lesions (86%) and active T2 lesions (73%)4. There was a decrease in mean annualized percent brain volume change between months 6 and 24 (-0.56 vs -0.70%)10. In terms of quality-of-life, “self-care” showed improvement in persons taking cladribine compared to placebo11.
The CLARITY extension study12 showed promise for a sustained effect of the drug: patients who initially received either 3.5 mg/kg or 5.25 mg/kg and later were randomized (2:1) to 3.5 mg/kg or placebo; 75% patients were relapse free. Treatment beyond 2-years was not associated with further clinical benefit. However, a subset of individuals who were more than 43 weeks from their last dose and had discontinued therapy showed greater MRI activity9.
In a post-hoc analysis of CLARITY and a phase 2B trial, patients with high disease activity had greater benefits compared to patients without. There was a reduction in the 6-month confirmed EDSS worsening by 47% compared to placebo and an 82% risk reduction of disability progression vs placebo13.
Q: How is cladribine administered?
A: The total cladribine dose is 3.5 mg/kg over two years administered as 1.75 mg/kg per year. The 1.75 mg/kg courses are administered over 4-5 days during weeks 1 and 5 of the first year and weeks 48 and 52 of the second year. The drug is available in 10 mg tablets which should not be crushed or chewed, must be taken with water, and can be taken independent of food intake. Hands should be dry when opening the blister-pack and washed thoroughly after taking the tablet.
Q: For whom should cladribine be considered?
A: Cladribine is an option for patients with relapsing remitting MS, particularly those with highly active disease, and can be appealing given a potential for a short oral treatment course.
Q: Can cladribine be used as initial MS therapy?
A: Cladribine is a reasonable option for first-line therapy in patients with highly active disease.
Q: Can patients switch from a previously-available therapy to cladribine?
A: Patients with breakthrough disease activity on other disease modifying therapies can consider switching to cladribine provided their pre-testing labs are within normal limits and no contraindications exist.
Q: Is cladribine effective in progressive MS?
A: There has not been any benefit on disability accumulation in patients with a progressive course14.
What side effects and safety issues does cladribine have?
- Mild-moderate lymphopenia: Lymphopenia occurred 21.6 vs 1.8% in CLARITY15. Lymphocyte levels returned to normal in 75% patients at 3 years following 2 courses16. Grade 3 lymphopenia (between 200-500 cells/μL) occurred in approximately a quarter of patients taking cladribine in CLARITY and grade 4 (< 200 cells/μL) occurred in 0.7% recipients (typically those that had grade 3 in the first course8,15). Persistence was uncommon in CLARITY and all cases recovered in the extension study (mean time 41 days). Lymphopenia was dose dependent, grade 3 or 4 lymphopenia occurring in 44.9% in the 5.25 mg/kg group compared to 25.6% 3.5 mg/kg group (CLARITY). A rapid decline in lymphocyte count occurs with a nadir at weeks 9 and 60 with a median change from baseline of -46% and -56% respectively4.
- Pancytopenia: a mild decrease in neutrophil, hemoglobin/red blood cell, and platelet counts can occur in some patients (give percentages) but most levels still remain within normal limits4,15.
- Infections: Although the overall incidence of infections was comparable between placebo and cladribine, viral upper respiratory (3.0 vs 1.1%), vaginal (1.9 vs 0.2%), and dermatomal herpes zoster (1.9 vs 0%) infections were greater in patients taking cladribine. Progressive multifocal leukoencephalopathy (PML) has not been reported in patients with MS taking cladribine but has been reported with cladribine use for other conditions 17,18. Long-term data noted below suggest that dermatomal herpes zoster was the only infection with a higher incidence in a pooled analysis of multiple studies.
- Malignancies: Cladribine was initially approved in Australia as Movectro in 2010 but its license was rejected by the EMA in 2013 due to concern about cancer risk 19,20. In CLARITY, the incidence of malignancies (1.4% vs 0 in placebo) were comparable to other DMTs. There were 3 cases of cancer in the 3.5 mg/kg arm (melanoma, pancreatic cancer, and ovarian cancer) and 1 case of choriocarcinoma 9 months after the end of the study with 5 mg/kg4. Long-term data noted below suggest there is not a higher incidence of malignancy.
- Another common side-effect in ORACLE and CLARITY was alopecia (3.5 vs 1.1% in placebo).
Q: What is the available long-term data on cladribine?
A: An observational study (PREMIERE) on subjects who have participated in cladribine clinical trials for 8 years following enrollment is ongoing to collect data pertaining to adverse effects and pregnancy outcomes. Serious adverse drug reactions pooled from CLARITY, CLARITY Extension, and ORACLE-MS studies as well as the PREMIERE registry (n=923 patients receiving 3.5 mg/kg) showed greater number of adverse effects (predominantly lymphopenia) 103.29 vs 94.26 per 100 person-years (PY)] and dermatomal herpes zoster (0.83 vs 0.20 per 100PY)21. Post-approval sources (8/2017-7/2018) did not identify any new safety or tolerability signals not already recognized in the two year extension22.
Additionally, parenteral cladribine is used for leukemia without evidence of secondary malignancies23.
Q: What testing is recommended with cladribine?
Pretesting prior to initiating
- Renal function to asses creatinine clearance (> 60 mL/min)
- Complete blood count with differentiation. Normal lymphocyte counts are required prior to starting.
- Screening for latent or active hepatitis B and C
- Screening for tuberculosis: interferon gamma release assay or purified protein derivative skin test
- Screening for the presence of adequate varicella-zoster virus IgG titers.
- Baseline MRI brain within 3 months of starting therapy
- Renal function to asses creatinine clearance (> 60 mL/min)
- Complete blood count with differentiation. Lymphocyte count ≥ 800 cells/μL in year 2 of dosing. The 2nd year treatment should be delayed by up to 6 months if recovery is necessary and stopping treatment if recovery is not seen by 6 months15. If the lymphocyte count is < 500 cells/μL, counts should be actively monitored until they increases. Awareness of an increased risk for dermatomal herpes zoster if lymphocytes < 500 cells/μL and prophylaxis if < 200 cells/μL
- MRI brain at 6 month intervals to monitor for evidence of disease activity
Q: Are there any restrictions on who can take cladribine?
A: The drug is contraindicated15 in patients with:
- moderate/severe renal (creatinine clearance < 60 mL/min) or hepatic (Child-Pugh score > 6) impairment
- concurrently receiving immunosuppressive/myelosuppresive agents (e.g. methotrexate, cyclophosphamide, cyclosporine, azathioprine, chronic steroids); are immunocompromised
- HIV or chronic infection (tuberculosis or hepatitis)
- active malignancies
- hereditary problems of fructose intolerance (each tablet contains sorbitol 64 mg)
Cladribine should not be taken during pregnancy and breastfeeding (see below).
Q: What are reproductive concerns related to cladribine?
A: Cladribine should be used cautiously in women of childbearing age and their male partners. Cladribine is contraindicated during pregnancy and is presumed to be highly teratogenic. Pregnancy is not recommended for at least 6 months following the last dose15. Cladribine may affect the efficacy of oral contraceptives so barrier protection should be used during and for at least 4 weeks following the oral course15.
Male patients should take precautions to prevent pregnancy of their partner during treatment and for at least 6 months after the last dose as cladribine interferes with DNA synthesis and can cause adverse effects on sperm (gametogenesis).
Breastfeeding is contraindicated during the oral course and for 1 week after the last dose. Fertility is not thought to be affected.
Q: Is cladribine safe for children?
A: Oral cladribine for MS has not been studied in a patients < 18 years old or < 40 kg (88 lbs).
Q: Is cladribine safe for the elderly?
A: Clinical studies with oral cladribine in MS did not include patients > 65 years old. Care should be taken to evaluate co-morbidities that may impair liver and kidney function, affect blood counts and the immune system, or concomitant drugs that may change the bioavailability of cladribine.
Q: Can cladribine be used in combination with other MS therapies?
A: Although cladribine is not recommended for concurrent use with other disease modifying therapies, short courses of systemic corticosteroids may be used to treat relapses15.
Q: Can cladribine be combined with MS symptom medications?
A: Yes, but cladribine should be taken ≥ 3 hours from other oral drugs (see below).
Q: Can cladribine be combined with medications for other conditions?
A: When taking cladribine tablets, their administration should be separated by ≥ 3 hours from other oral drugs to ovoid increased bioavailability from drug-hydroxypropylbetadex complexes (solubility enhancing agent in cladribine tablets)15.
Caution should be used with other medications that can affect blood counts such as carbamazepine.
Medications that inhibit/induce certain protein transporters may increase/decrease bioavailability of cladribine should be avoided during the oral course24:
- inhibit breast cancer resistance protein (BCRP) by eltrombopag
- inhibit equilibrative nucleoside transporter and concentrative nucleoside transporter by cilostazol, dilazep, nifedipine, nimodipine, reserpine, and sulindac
- induce BCRP or P-glycoprotein-related by corticosteroids, rifampicin, St. John’s wort
Cladribine should not be started within 6 weeks of live or attenuated live vaccination and avoided during and after treatment if white blood cell counts are not within normal limits due to a risk of active vaccine infection.
Blood transfusions should be irradiated of cellular blood components to prevent transfusion-related graft-versus-host disease and a hematologist should be consulted.
Q: What can be done if patients on cladribine have breakthrough activity?
A: All patients who have a relapse either during or following treatment can be treated with systemic corticosteroids. Switching to an alternative therapy may be considered in patients with breakthrough activity before the second course of cladribine or within a year of completing their second course. In patients who exhibit activity a year beyond the second course, can be considered either for re-dosing with 1.75 mg/kg per year or a switch to an alternative therapy. Prior to starting another disease modifying therapy, lymphocyte counts and contraindications should be reviewed.
Approach last updated: February 11, 2019
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