Cladribine - Indications, Contraindications, and Precautions

Introduction:

Patients diagnosed with acute myeloid leukemia (AML) typically have a median age of 68 years. The age of patients with high-risk cytogenetics, gene overexpression that promotes treatment resistance, secondary AML after antecedent hematological disorders (sAML), and therapy-related AML (t-AML), which is more frequently seen in older patients, all change the AML landscape. Simultaneously, aged patients' capacity to endure intense chemotherapy (IC) significantly deteriorates due to age-related comorbidities and a decline in general health. Although it is generally established that chronological age alone is insufficient to bar a patient from IC, certain older persons may benefit from rigorous therapy in terms of survival.

A purine analog called Cladribine has actions on AML cells that are cytotoxic, proapoptotic, and antiproliferative. It also inhibits DNA (deoxyribonucleic acid) repair and functions as an epigenetic and hypomethylating agent. Cladribine can work in concert with other anti-leukemic medications, particularly anthracyclines, and cytarabine (by raising the intracellular concentration of the active metabolite in leukemic cells).

Furthermore, the P-glycoprotein, whose enhanced activity is recognized as one of the primary causes of drug resistance in AML, is only marginally necessary for its cellular outflow. This property of Cladribine seems to be particularly significant in elderly AML patients because of the P-glycoprotein's increased activity with age.

For Patients:

How to Use a Cladribine Vial?

A medical expert administers this drug by injecting it into a vein. The weight and treatment response will determine the appropriate dosage. This drug is used consistently for seven consecutive days or as the doctor prescribes. It is important to prevent the medicine from coming into contact with the mouth, nose, eyes, or skin. If one does manage to get the drug in such regions, immediately notify the doctor and flush with lots of water.

Effects on the body:

It is possible to experience nausea, vomiting, dizziness, headache, cough, diarrhea, joint and muscular discomfort, insomnia, stomach or abdominal pain, constipation, and pain, swelling or redness at the injection site. Inform the doctor or chemist immediately if any of these side effects persist or worsen.

Serious side effects are possible for those taking this medicine. The risk may be reduced by the doctor performing careful monitoring.

Call the doctor immediately if one experiences any severe adverse effects, such as pain, swelling, redness in the arms or legs, or shortness of breath.

Rarely will this medication cause a severe allergic reaction. In the event of notable adverse reaction symptoms, including rash, itching, or swelling (especially in the face, tongue, or throat), severe dizziness, or breathing difficulties, it is crucial to seek immediate medical attention.

Cladribine can occasionally result in a minor rash, which is often not dangerous. However, one might not be able to distinguish it from a rare inflammation that might indicate a severe allergic reaction. Immediately seek medical attention if one experiences any rash.

What Are the Precautions Related to Cladribine?

Inform the physician or pharmacist if one is allergic to Cladribine or has any other allergies before using this medication. To gather additional information, it is advisable to consult with the chemist regarding potential allergic reactions or other concerns that may arise from the inactive chemicals in this product.

Inform the doctor or chemist about all the medical conditions before taking this drug, especially any kidney, liver, nerve, muscle, blood, bone marrow, or current or recent infections.

The consumption of this medication may cause feelings of lightheadedness, which can be further intensified when alcohol or cannabis is also consumed. Refrain from operating machinery, driving, or engaging in activities that demand alertness until the person can do so safely. Limit alcohol consumption. If the person is a marijuana (cannabis) user, it is recommended to consult with the doctor. Prior to undergoing surgery, inform the surgeon or dentist about cannabis usage.

For Doctors:

What Is Cladribine?

A chemotherapy drug used to treat lymphoproliferative disorders, such as hairy-cell leukemia.

In individuals with relapsing forms of multiple sclerosis (MS) who have not reacted to or could not tolerate alternative MS medications, Cladribine is a purine antimetabolite used for treatment. This substance is a member of a group of organic substances called purine 2'-deoxyribonucleosides. These substances have a purine joined to a ribose that does not have a hydroxyl group at position 2.

Indication:

As indicated by clinically significant anemia, neutropenia, thrombocytopenia, or other disease-related symptoms, for treating active hairy cell leukemia (leukemic reticuloendotheliosis). Low-grade non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and chronic lymphocytic leukemia (CLL) are also treated with this drug as alternatives.

Pharmacodynamics:

Antineoplastic Cladribine is a synthetic purine nucleoside having immunosuppressive properties. Only the chlorine atom at position 2 of the purine ring, which confers resistance to enzymatic breakdown by adenosine deaminase, distinguishes Cladribine structurally from deoxyadenosine. Due to this resistance, Cladribine has a longer-lasting cytotoxic effect on resting and proliferating lymphocytes than deoxyadenosine. One of the chemotherapeutic medications in the antimetabolites class is Cladribine. Antimetabolites prevent cells from creating and repairing DNA, two processes required for the development and proliferation of cancer cells.

Mechanism of Action:

Although it shares structural similarities with Pentostatin and Fludarabine, Cladribine works in a distinct way. Although the exact mechanism of action is not fully understood, evidence suggests that Cladribine undergoes phosphorylation by deoxycytidine kinase. This leads to the formation of cladribine triphosphate (CdATP), a nucleotide that accumulates and integrates into DNA in cells with high deoxycytidine kinase levels and low deoxynucleotide levels. Consequently, this process causes DNA strand breakage and hinders DNA synthesis and repair.

Asymmetry in triphosphorylated deoxynucleotide (dNTP) pools causes DNA strand breakage, suppression of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death. Cladribine, in contrast to other antimetabolite medications, has cytotoxic effects on both dormant and growing lymphocytes. However, it does result in cell accumulation at the G1/S phase junction, indicating that cytotoxicity is linked to processes essential for cell entry into the S phase. Additionally, it binds purine nucleoside phosphorylase (PNP), albeit there is no known connection between this binding and a specific mode of action.

Absorption:

34 % to 48 % of Cladribine is bioavailable.

Volume of Distribution:

For Patients with hematologic malignancies, the volume of distribution is 2.8 liters/kilograms (L/kg). It shows 10 % protein binding at 9 L/kg.

Metabolism:

Cladribine metabolized to 2-chloro-2'-deoxyadenosine-5'-triphosphate in all cells having deoxycytidine kinase activity.

Half-Life: 5.4 hours.

Clearance: Nearly 978 mL/h/kg.

Adverse Reactions:

Parenteral:

• Fever.

• Tiredness.

• Vomiting.

• Rash.

• Migraine.

• Decrease in appetite.

• Vomiting.

• Acute nephrotoxicity.

• Irreversible neurologic toxicity (paraparesis or quadriparesis).

Severe bone marrow suppression leading to neutropenia, anemia, and thrombocytopenia are all signs of overdosage.

Contraindications:

If a person has active cancer, HIV (human immunodeficiency virus), tuberculosis, chronic kidney disease, or hepatic cirrhosis, they should not use Cladribine. A history of using other immunosuppressants, such as Cyclophosphamide, Azathioprine, Methotrexate, or Mitoxantrone, is another contraindication to Cladribine. Men and women who are sexually active should receive counseling regarding the teratogenicity of cladribine and its effects on the viability and quality of sperm. Patients must be strongly advised to follow stringent guidelines for reliable contraception before, throughout, and after Cladribine treatment. Patients under 18 should not use Cladribine because it may negatively affect them.

Monitoring:

Before considering oral Cladribine as an MS disease-modifying medication, laboratory tests should be run for the following conditions: complete blood count with the differential, comprehensive metabolic panel, HIV screen, viral hepatitis panel, pregnancy test, and interferon-gamma release assay. Patients should not combine Cladribine with other immunosuppressive medications; thus, clinicians must closely check the medication history. Following each course of Cladribine over the following two years, MS patients will require complete blood counts with differential cell counts evaluated at months three and seven. After the first two years, routine blood tests may not be required if the medication is well tolerated.

Drug Interaction:

Abatacept: When Cladribine and Abatacept are combined, there is a chance that the risk or intensity of side effects will rise.

Abciximab: Combining Abciximab and Cladribine may enhance the likelihood or intensity of bleeding.

Abemaciclib: Cladribine's excretion rate may be slowed down by Abemaciclib, which could raise the serum level.

Acenocoumarol: When Acenocoumarol and Cladribine are combined, there is a potential increase in bleeding risk or severity.

Acetyldigitoxin: Acetyldigitoxin may lessen the cardiotoxic effects of Cladribine.

Acid Acetylsalicylic: When Acetylsalicylic Acid and Cladribine are combined, there is a potential increase in bleeding risk or severity.

Acipimox: When Cladribine and Acipimox are taken together, the risk or severity of myopathy, rhabdomyolysis, and myoglobinuria may rise.

Adalimumab: When using Adalimumab, the chance or severity of side effects may rise.

Do not take Echinacea (dietary supplement). If administered, Echinacea should only be given to individuals taking therapeutic immunosuppressants. Keep an eye out for any immunosuppressant efficacy reductions while taking them together.

Dosage Forms & Strengths

For Adult:

Injectable solution (generic formulation) 1 mg/mL tablets (10 mL single-use vials) administered for seven days through continuous IV (intravenous) infusion of 0.09 mg/kg every day.

Dosage Consideration:

1. Observe the CBC with differential.

2. Watch for signs and symptoms of infection and neurotoxicity; treat any infection before therapy if it exists; if this is not possible, explore alternate therapies.

3. Relapsing multiple sclerosis. Relapsing-remitting illness and active secondary progressive illness should be mentioned.

4. Use is typically advised for individuals who have not responded well to or cannot handle the alternative suggested medicine.

Two Yearly Therapy Sessions:

1.75 mg/kg/course orally, each divided into two treatment cycles; the maximum cumulative dose of 3.5 mg/kg (oral administration). Oral dosage each cycle based on weight for each treatment cycle:

• 40 mg first cycle; 40 mg second cycle for 40 kg to 50 kg.

• 50 mg first cycle: 50 mg second cycle for 50 kg to 60 kg.

• 60 mg first cycle; 60 mg second cycle for 60 kg to 70 kg.

• 70 mg first cycle; 70 mg second cycle for 70 kg to 80 kg.

• 80 mg first cycle; 70 mg second cycle for 80 kg to 90 kg.

• 90 mg first cycle; 80 mg second cycle for 90 kg to 100 kg.

• 100 mg first cycle; 90 mg second cycle for weights between 100 and 110 kg.

Do not take more than two pills per day; instead, take one or two tablets each day orally for successive four to five days.

Modifications to Dosage:

1. Renal Dysfunction:

Mild (Creatinine Clearance or CrCl 60-89 mL/min): No dosage modification is advised.

Not advised for moderate-to-severe (CrCl 60 mL/min).

2. Hepatic Dysfunction:

Mild: No dosage modification is advised.

Not advised for moderate-to-severe (Child-Pugh > 6).

Considerations for Dosing:

Restrictions on Use: Due to its safety profile, treatment is not advised for patients with clinically isolated syndrome (CIS).

Before Administration:

• Due to the possibility of malignancies, follow normal cancer screening recommendations.

• Pregnancies in women with reproductive potential should be avoided.

• Rule out HIV infection.

• Screening for tuberculosis.

• Hepatitis B and C testing.

• Consider delaying treatment until acute infections are under control after evaluating acute infections.

• Patients testing negative for antibodies to varicella-zoster virus are advised to get vaccinated.

• Four to six weeks before therapy, administer live-attenuated or live vaccines and deliver all vaccinations per recommended vaccination schedules. While receiving treatment and afterward, refrain from administering live or live-attenuated vaccinations to the patient if their white blood cell counts are not within normal ranges.

• To reduce the chance of developing progressive multifocal leukoencephalopathy (PML), obtain a baseline magnetic resonance imaging scan within three months of starting treatment. At the first indication of PML, stop the medication and have a proper diagnostic examination.

• Check for liver damage; measure total bilirubin, alkaline phosphatase, and aminotransferase serum levels.

Blood Count:

Before beginning the first treatment course, lymphocytes must be within normal limits, and before starting the second treatment session, they must have at least 800 cells per milliliter.

• To allow for the recovery of lymphocytes to at least 800 cells per microliter, the second treatment course may be postponed for up to six months; if the patient's recovery takes more than six months, additional treatment should not be given.

• Before beginning the first and second treatments, have a CBC with a differential that includes the lymphocyte count.

• Obtain a CBC with differential, including a lymphocyte count, two and six months following the commencement of the treatment course. If the lymphocyte count at the second month is less than 200 cells/mcL, monitor every month until month six and then occasionally, going forward, as clinically recommended.

• Administer antiherpes medication to those who have lymphocytes.

• Give patients with lymphocyte counts under 200 cells per milliliter (mcL) antiherpes prophylaxis.

Cautions:

• Monitoring renal and hepatic function is advised when using the powerful chemotherapy drug Cladribine, particularly in people with kidney or liver failure.

• Patients with a significant tumor burden are advised to take Allopurinol and receive IV hydration to avoid tumor lysis syndrome.

• It has been demonstrated that suppressing rapidly producing cells, such as testicular cells, might harm fertility.

• Given the known myelosuppressive effects of therapy, practitioners should carefully weigh the risks and benefits of delivering this medication to patients with active infections, given that fever with or without neutropenia is typically noted during the first month of treatment.

• The manufacturer reports no nephrotoxicity at doses approved for hairy cell leukemia; nevertheless, high doses (four to nine times the recommended amount) have been linked to nephrotoxicity.

• Routine evaluation of peripheral blood counts, especially during the therapy.

Warnings:

Cladribine (Parenteral):

• The medication needs to be delivered under the guidance of a skilled cancer chemotherapy doctor.

• Although it is typically reversible and appears to be dose-dependent, bone marrow suppression is possible.

• Standard Cladribine dosing regimens have also been linked to severe neurological toxicity; continuous high doses of four to nine times the dose recommended for hairy cell leukemia have been linked to serious acute nephrotoxicity and neurological toxicity leading to irreversible paraparesis and quadriparesis.

• High doses (four to nine times the therapeutic dose for hairy cell leukemia) have been linked to acute nephrotoxicity, especially when combined with nephrotoxic drugs.

Lactation and Pregnancy:

Pregnancy is contraindicated in pregnant women, and men and women who are sexually active and do not intend to use effective contraception. Additionally, there is insufficient information on the potential developmental danger of treatment in pregnant women.

Reproductive Capacity:

In addition to using effective contraception during therapy and at least six months after the last dosage in each treatment course, females of reproductive potential should also use a barrier technique both during therapy and at least four weeks following the last dose in each treatment course.

Male patients with reproductive potential should take precautions to prevent their partner from becoming pregnant while receiving treatment and for at least six months after the final dose since Cladribine interferes with DNA synthesis and could negatively affect human gametogenesis.

Lactation:

Due to the possibility of major adverse responses in breastfed infants, lactation therapy is contraindicated in breastfeeding women. Women are advised to stop breastfeeding during treatment and for ten days after the final dosage. Currently, there is insufficient information regarding the presence of Cladribine in human milk, its effects on breastfed infants, or its influence on milk production.

Conclusion:

Younger AML patients' outcomes have improved by adding Cladribine to conventional IC in both frontline and relapsed or refractory scenarios. The subgroup of treatment-naive physically fit AML patients over 60 with good or intermediate cytogenetics showed an advantage in overall survival (OS) from adding Cladribine to Daunorubicin and cytarabine induction in the randomized phase II study. As a salvage therapy for relapsed or refractory AML, a novel combination of Cladribine with granulocyte colony-stimulating factor, LD-AC (low-dose cytarabine), and Aclarubicin has recently demonstrated remarkable efficacy. This regimen may be a practical therapeutic choice for older AML patients because of the reduced hematological toxicity.