Clofarabine – Uses, Dosage, Side Effects, Interaction

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.

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

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.

References