Continuing Education Activity

Cytarabine is a medication used in the management and treatment of leukemias and lymphomas. It belongs to the antimetabolic group of medications. This activity reviews the indications, action, and contraindications for cytarabine as a valuable agent in treating acute myeloid leukemia (and other leukemias). This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the treatment of patients with leukemia and related conditions.

Objectives:

• Identify the mechanism of action of cytarabine.
• Describe the potential adverse effects of cytarabine.
• Review the appropriate monitoring for patients receiving therapy with cytarabine.
• Summarize interprofessional team strategies for improving care coordination for patient safety in cases of cytarabine overdose and improve outcomes.

Indications

In the early 1950s, researchers discovered cytarabine as a nucleoside (containing arabinose sugar) in Cryptotethia crypta, a species of sponges. Cytarabine is an antimetabolite and an antineoplastic agent that belongs to the category of drugs known as anthracyclines. 

Cytarabine has both labeled and off-labeled indications. Labeled indications of cytarabine include the treatment of acute lymphoblastic leukemia, remission induction therapy in acute myeloid leukemia in adult and pediatric patients, the treatment of chronic myeloid leukemia (blast phase), and prophylaxis and treatment of meningeal leukemia. Some of the many off-labeled indications of cytarabine in adults include refractory chronic lymphocytic leukemia and refractory or relapsed Hodgkin disease. It is also an option for non-Hodgkin’s lymphoma and primary central nervous system (CNS) lymphoma.

Mechanism of Action

Cytarabine is a pyrimidine analog and is also known as arabinosylcytosine (ARA-C). It is converted into the triphosphate form within the cell and competes with cytidine to incorporate itself into the DNA. The sugar moiety of cytarabine hinders the rotation of the molecule within the DNA. The process of DNA replication ceases, specifically during the S phase of the cell cycle, making it a specific drug for rapidly dividing cells, such as those seen in cancer. DNA replication and repair also halts due to the inhibition of DNA polymerase by cytarabine. This drug must act for a time equivalent to one cell cycle to effectively inhibit the replication of tumor cells. Hence the bolus dose of cytarabine is given every 8 to 12 hours to maintain optimum intracellular levels.

Pharmacokinetics

The absorption of cytarabine is not effective when taken orally due to high first-pass metabolism. When administered subcutaneously, intrathecally, or intravenously, it has a high bioavailability. It has a low plasma protein binding capacity and, thus, a high volume of distribution. It can cross the blood-brain barrier and hence has an off-label use in primary CNS lymphomas. Cytarabine metabolism primarily occurs in the liver. It has an active metabolite- azacytidine triphosphate; and an inactive metabolite- uracil arabinoside, which is cleared by the kidney.

Administration

Dosage Forms

• Solution, Injection: 10 mg/ml, 20 mg/mL (25 mL), 100 mg/ml
• Intrathecal injection, liposomal: 50 mg/5ml

Administration - Rapid intravenous infusion, infuse over 1 to 3 hours intravenously or subcutaneously or intrathecally. 

Storage - Store at room temperature. 

Dosing: Adult

1. Acute lymphoblastic leukemia (off-label dosing):
   • Induction regimen, relapsed or refractory- Administer 3,000 mg/sq.meter of cytarabine over 3 hours by intravenous infusion daily for five days in combination with idarubicin for three days.[1]
   • Dose-intensive regimen- 3,000 mg/sq.meter of cytarabine over 2 hours by intravenous infusion. This dose is to be given every 12 hours on days 2 and 3 (4 doses/cycle) of even-numbered cycles in combination with methotrexate.[2]
2. Acute myeloid leukemia (remission induction chemotherapy):
   • Administer standard dose 100 mg/sq.meter/day of cytarabine by continuous intravenous infusion for 7 days or give 200 mg/sq.meter/day by continuous intravenous infusion for 7 days(as 100 mg/m2 over 12 hours every 12 hours).[3]
3. Acute myeloid leukemia consolidation therapy (off-label use):
   • 5+2 regimen: Administer 100 mg/sq.meter/day of cytarabine for five days by intravenous infusion in combination with daunorubicin or idarubicin, or mitoxantrone.[3][4]
4. Acute myeloid leukemia salvage treatment (off-label use):
   • CLAG-M regimen: Administer 2,000 mg/sq.meter/day of cytarabine by intravenous infusion over 4 hours for five days in combination with cladribine, G-CSF, and mitoxantrone.[5]
5. Acute promyelocytic leukemia consolidation therapy (off-label use):
   • First consolidation course: Administer 200 mg/sq.meter/day of cytarabine by intravenous infusion for seven days in combination with daunorubicin.[6]
   • Second consolidation course:
     • If age is ≤60 years and low risk (WBC <10,000/cubic mm), then administer 1,000 mg/sq.meter of cytarabine every 12 hours for four days (8 doses) by intravenous infusion.
     • If age is <50 years and high risk (WBC ≥10,000/cubic mm), then administer 2,000 mg/sq.meter of cytarabine every 12 hours for five days (10 doses) by intravenous infusion.
     • If age is 50 to 60 years and high risk (WBC ≥10,000/cubic mm), then administer 1500 mg/sq.meter of cytarabine every 12 hours for five days (10 doses) by intravenous infusion.
     • If age is >60 years and high risk (WBC ≥10,000/cubic mm) then administer 1,000 mg/sq.meter every 12 hours for four days (8 doses) by intravenous infusion.
6. Acute promyelocytic leukemia induction (off-label dosing):
   • Administer 200 mg/sq.meter/day of cytarabine by continuous intravenous infusion for seven days, beginning on the third day of treatment in combination with tretinoin and daunorubicin.[6][7]

Adverse Effects

Myelosuppression is the most dreaded adverse effect of cytarabine and can present as acute and severe pancytopenia with striking megaloblastic changes.[8] Other, less life-threatening symptoms include irritation at the site of administration, gastrointestinal disturbances, stomatitis, conjunctivitis, reversible hepatic enzyme elevation, and dermatitis. Severe hypersensitivity, such as anaphylaxis, occurs on rare occasions but is a strong indication for discontinuation of cytarabine therapy. Cerebral and cerebellar toxicity may follow an intrathecal administration of cytarabine. Manifestations of cerebellar toxicity include ataxia and slurred speech, while that of cerebral toxicity are seizures and dementia.[9][10] 

Cytarabine might affect the cardiovascular system also, causing angina pectoris and even pericarditis. Cytarabine syndrome is a rare illness produced shortly after administration of cytarabine, characterized by non-specific symptoms like fever, malaise, rash, joint pain, and muscle pain, and is manageable with corticosteroids. Severe symptoms tend to occur more commonly in patients with renal impairment as the renal clearance of the drug decreases.

Contraindications

Cytarabine is contraindicated in patients who have had a hypersensitivity reaction to it or any of the fundamental ingredients used in the preparation of the drug. With active meningeal infections, liposomal cytarabine is also contraindicated.

Monitoring

As cytarabine affects various organs, a panel of tests is necessary to monitor the patients. These are:

• Liver function tests
• Complete blood count
• Differential WBC count
• Platelet count
• Serum creatinine
• Blood urea nitrogen (BUN)
• Serum uric acid

Toxicity

Toxicity caused by cytarabine can classify into either low dose or high dose toxicity. The only noteworthy low-dose toxicity is myelosuppression, while corneal toxicity is frequent with high doses of cytarabine. Continuous infusion may prove more toxic than the typical intermittent dosage. Considerable cardiac toxicity has been observed only in the standard induction schedules.[11]

Enhancing Healthcare Team Outcomes

It is an observation that in delivering therapeutic drugs, incorrect doses of drugs are sometimes administered.[12] Lack of proper care during intrathecal administration of cytarabine in pediatric patients can lead to overdose. Previously cerebrospinal fluid exchange was recommended if such an incident occurred. Contrary to this belief, there have been recent reports that if there is prompt identification of such an error, then management via a cerebrospinal fluid exchange is not necessary.[13][14] In the above case reports, hydrocortisone was administered, and the patient received adequate supportive care. All patients were neurologically stable at the time of overdose. They did not show any signs of cytarabine toxicity or complications and quickly recovered.

Given the critical nature of the illnesses for which cytarabine is given, an interprofessional, coordinated team approach to therapy and monitoring is absolutely essential. This team includes specialists, mid-level practitioners, family clinicians, oncology specialty-trained nurses, and pharmacists, preferably with oncology specialization. By working collaboratively and engaging in open information-sharing regarding the latest information on the patient's case, patient outcomes can be optimized, and adverse events minimized when utilizing cytarabine therapy. [Level 5]