Clofarabine – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Clofarabine is metabolized intracellularly to the active 5′-monophosphate metabolite by deoxycytidine kinase and 5′-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5′-triphosphate also disrupts the integrity of the mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C, and apoptosis-inducing factor, leading to programmed cell death.

Clofarabine is a purine nucleoside antimetabolite that differs from other purine nucleoside analogs by the presence of chlorine in the purine ring and fluorine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells.

Indications

  • For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use.
  • Treatment of acute lymphoblastic leukemia (ALL) in pediatric patients who have relapsed or are refractory after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response. Safety and efficacy have been assessed in studies of patients ≤ 21 years old at initial diagnosis.
  • Clofarabine is approved to treat Acute lymphoblastic leukemia that has recurred (come back) or is refractory (does not respond to treatment) in children and young adults aged 1 to 21 years who have already had at least two other types of treatment.
  • Refractory Acute Lymphoblastic Leukemia (ALL)
  • Refractory Acute Myeloid Leukemia (AML)
  • Relapsed Acute Lymphoblastic Leukemia (ALL)
  • Refractory Langerhans cell histiocytosis

Use in Cancer

Clofarabine is approved to treat:

  • Acute lymphoblastic leukemia that has recurred (come back) or is refractory (does not respond to treatment) in children and young adults aged 1 to 21 years who have already had at least two other types of treatment.

Clofarabine is also being studied in the treatment of other types of cancer.

Contraindications

  • a bacterial infection
  • opportunistic fungal infection
  • dehydration
  • decreased function of bone marrow
  • anemia
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • capillary leak syndrome, is a condition where fluid leaks out of small blood vessels
  • low blood pressure
  • bleeding
  • inflammation of the small and large intestine
  • liver problems
  • the high amount of bilirubin in the blood
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • sepsis
  • chronic kidney disease stage 3A (moderate)
  • chronic kidney disease stage 3B (moderate)
  • an increased risk of developing an uncommon viral infection called an opportunistic infection

Dosage

Strengths: 1 mg/mL

Acute Lymphoblastic Leukemia

18 to less than 22 years:

  • 52 mg/m2 IV over 2 hours daily for 5 consecutive days of a 28-day cycle; repeat every 2 to 6 weeks
  • Subsequent cycles should begin no sooner than 14 days from day 1 of the previous cycle.
  • Subsequent cycles may be administered when the ANC is greater than or equal to 750/mm3.
  • Provide supportive care, such as IV fluids, antihyperuricemics, and alkalinization of urine throughout therapy to reduce the risk of tumor lysis and other adverse events.
  • Monitor renal, hepatic, and cardiac function during therapy.
  • Monitor patients taking medications known to affect blood pressure.
  • Discontinue therapy if hypotension develops during the 5 days of administration.

Acute Lymphoblastic Leukemia

1 year and older:

  • 52 mg/m2 IV over 2 hours daily for 5 consecutive days of a 28-day cycle; repeat every 2 to 6 weeks
  • Subsequent cycles should begin no sooner than 14 days from day 1 of the previous cycle.
  • Subsequent cycles may be administered when the ANC is greater than or equal to 750/mm3.
  • Provide supportive care, such as IV fluids, antihyperuricemics, and alkalinization of urine throughout therapy to reduce the risk of tumor lysis and other adverse events.
  • Monitor renal, hepatic, and cardiac function during therapy.
  • Monitor patients taking medications known to affect blood pressure.
  • Discontinue therapy if hypotension develops during the 5 days of administration.

Renal Dose Adjustments

  • Mild renal dysfunction (CrCl 60 to less than 90 mL/min): No adjustment is recommended.
  • Moderate renal dysfunction (CrCl 30 to less than 60 mL/min): Reduce the starting dose by 50%.
  • Severe renal dysfunction (CrCl less than 15 to less than 30 mL/min) and end-stage renal disease (CrCl less than 15 mL/min): Data not available

Dose Adjustments

Supportive Medications and Medications to Avoid:

  • Consider prophylactic antiemetic medications as this drug is moderately emetogenic.
  • Consider the use of prophylactic steroids to mitigate Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome (e.g., hypotension, tachycardia, tachypnea, pulmonary edema).
  • Minimize exposure to drugs with known renal toxicity during the 5 days of therapy since the risk of renal toxicity may be increased.
  • Consider avoiding the concomitant use of medications known to induce hepatic toxicity.

Dose Modifications and Reinitiation of Therapy:
HEMATOLOGIC TOXICITY:

  • Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle and provided the patient ANC is 0.75 x 10(9)/L or greater.
  • If a patient experiences Grade 4 neutropenia (ANC less than 0.5 x 10(9)/L) lasting 4 weeks or more, reduce the dose by 25% for the next cycle.

NONHEMATOLOGIC TOXICITY:

  • Withhold therapy if the patient develops a clinically significant infection, until the infection is controlled, then restart at the full dose.
  • Withhold therapy for Grade 3 noninfectious nonhematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting controlled by antiemetic therapy); reinstitute therapy at a 25% dose reduction with resolution or return to baseline.
  • Discontinue therapy for Grade 4 noninfectious nonhematologic toxicity.
  • Discontinue therapy if a patient shows early signs or symptoms of SIRS or capillary leak (e.g., hypotension, tachycardia, tachypnea, pulmonary edema) occur, and provide supportive measures.
  • Discontinue therapy if Grade 3 or higher increases in creatinine or bilirubin are noted; reinstitute therapy at a 25% dose reduction, when the patient is stable and organ function has returned to baseline. If hyperuricemia is anticipated (tumor lysis), initiate measures to control uric acid.

Side Effects

The Most Common

  • nausea
  • vomiting
  • stomach pain
  • diarrhea
  • constipation
  • loss of appetite
  • weight loss
  • swelling of the inside of the mouth and nose
  • painful white patches in the mouth
  • headache
  • anxiety
  • depression
  • irritability
  • pain in the back, joints, arms, or legs
  • drowsiness
  • dry, itchy, or irritated skin
  • flushing
  • fast heartbeat
  • fast breathing
  • shortness of breath
  • dizziness
  • lightheadedness
  • fainting
  • decreased urination
  • sore throat, cough, fever, chills, and other signs of infection
  • pale skin
  • excessive tiredness
  • weakness
  • confusion
  • unusual bruising or bleeding
  • nosebleed
  • bleeding gums
  • blood in urine
  • small red or purple spots under the skin
  • yellowing of the skin or eyes
  • itching
  • red, warm, swollen, tender skin
  • uncontrollable shaking of a part of the body

More Common

  • Tumor lysis syndrome (TLS). Clofarabine quickly kills leukemia cells in the blood. The body may react to this. Signs include hyperkalemia, hyperuricemia, and hyperphosphatemia. TLS is very serious and can lead to death if it is not treated right away.
  • Systemic inflammatory response syndrome (SIRS): symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs.
  • Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enough red blood cells, white blood cells, and platelets. Serious side effects that can happen because of bone marrow suppression include severe infection (sepsis), bleeding, and anemia.
  • Effects on pregnancy and breastfeeding. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby.
  • Dehydration and low blood pressure. Clofarabine can cause vomiting and diarrhea which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased urination.
  • Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and nausea), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count, fever, and infection). Clofarabine can also cause tachycardia and can affect the liver and kidneys.
  • trouble breathing while lying down;
  • diarrhea that is watery or bloody;
  • little or no urination;
  • pain, blisters, bleeding, or severe rash on the palms of your hands or the soles of your feet;
  • low blood pressure–a light-headed feeling, like you might pass out;
  • signs of a liver problem–upper stomach pain, sudden swelling in your mid-section, dark urine, jaundice (yellowing of the skin or eyes);
  • signs of infection–fever, chills, tiredness, mouth and throat ulcers, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, shallow breathing;
  • signs of bleeding inside the body–sudden numbness or weakness (especially on one side of the body), severe headache, problems with vision or speech, chest pain, coughing up blood, blood in your urine, bloody or tarry stools; or
  • signs of tumor cell breakdown–tiredness, weakness, muscle cramps, nausea, vomiting, diarrhea, fast or slow heart rate, tingling in your hands and feet or around your mouth.

Rare

  • loss of appetite
  • mouth sores, sore throat
  • muscle aches
  • nausea
  • pain, redness or blistering of hands and feet
  • rash
  • sleepiness
  • vomiting
  • weakness
  • changes in blood pressure
  • diarrhea, nausea, and vomiting lasting more than 24 hours
  • the feeling of being unwell
  • fluid accumulating in the lungs (e.g., shortness of breath, rapid breathing, chest pain)
  • muscle and joint pain
  • inflammation in the digestive system (e.g., abdominal pain, fever, vomiting, diarrhea)
  • rapid heartbeat
  • shortness of breath
  • signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
  • signs of bleeding (e.g., bloody nose, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
  • signs of depression (e.g., poor concentration, changes in weight, changes in sleep, decreased interest in activities, thoughts of suicide)
  • signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
  • signs of fluid gathering around the heart (e.g., chest pain, shortness of breath when lying down, painful breathing, fainting, dizziness)
  • signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
  • signs of a serious allergic reaction (e.g., abdominal cramps, difficulty breathing, nausea and vomiting, or swelling of the face and throat)
  • signs of severe bleeding (e.g., vomit resembling coffee grounds in texture and color, black tarry stools)

Drug Interaction

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Pregnancy and Lactation

FDA Pregnancy Category D

Pregnancy

Collar (clofarabine) may cause fetal harm when administered to a pregnant woman. Clofarabine was teratogenic in rats and rabbits. Developmental toxicity (reduced fetal body weight and increased post-implantation loss) and increased incidences of malformations and
variations (gross external, soft tissue, skeletal and retarded ossification) were observed in rats receiving 54 mg/m2 /day (approximately equivalent to the recommended clinical dose on an mg/m2 basis), and in rabbits receiving 12 mg/m2 /day (approximately 23% of the recommended clinical dose on an mg/m2 basis). There are no adequate and well-controlled studies on pregnant women using clofarabine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving
treatment with clofarabine. All patients should be advised to use effective contraceptive measures to prevent pregnancy.

Lactation

It is not known whether clofarabine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for clofarabine in animal studies and the potential for serious adverse reactions, women treated with clofarabine should not nurse. Female patients should be advised to avoid breastfeeding during treatment with Clolar.

How should this medicine be used?

Clofarabine comes as a solution to be injected into a vein. Clofarabine is administered by a doctor or nurse. It is usually given once a day for 5 days in a row. This dosing cycle may be repeated once every 2 to 6 weeks, depending on your response to the medication.

It will take at least 2 hours for you to receive each dose of clofarabine. Tell your doctor or another healthcare provider right away if you feel anxious or restless while you are receiving the medication.

What special precautions should I follow?

Before using clofarabine,

  • tell your doctor and pharmacist if you are allergic to clofarabine or any other medications.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention medications for high blood pressure and heart disease. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had kidney or liver disease.
  • tell your doctor if you are pregnant or plan to become pregnant. Clofarabine may harm the fetus. You should use birth control to prevent pregnancy during your treatment with clofarabine. Talk to your doctor about the types of birth control that will work for you. If you become pregnant while using clofarabine, call your doctor.
  • tell your doctor if you are breastfeeding. You should not breastfeed during your treatment with clofarabine.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving clofarabine.
  • you should know that clofarabine may cause a skin condition called hand-foot syndrome. If you develop this condition, you may experience tingling of the hands and feet, and then reddening dryness, and flaking of the skin on the hands and feet. If this happens, ask your doctor to recommend a lotion that you can apply to these areas. You will need to apply the lotion lightly and avoid rubbing the areas forcefully. Your doctor may also prescribe medication to relieve these symptoms.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021673s024lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-673_Clolar.cfm
  3. https://www.cancer.gov/about-cancer/treatment/drugs/clofarabine
  4. https://go.drugbank.com/drugs/DB00631
  5. https://en.wikipedia.org/wiki/Clofarabine
  6. https://medlineplus.gov/druginfo/meds/a607012.html
  7. https://www.drugs.com/mtm/clofarabine.html
  8. https://pubchem.ncbi.nlm.nih.gov/compound/Clofarabin
  9. https://pubchem.ncbi.nlm.nih.gov/compound/Clofarabine-triphosphate#section=Chemical-Co-Occurrences-in-Literature
  10. https://www.webmd.com/drugs/2/drug-92460/clofarabine-intravenous/details/list-contraindications
  11. ChemIDplus Chemical Information Classification
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