Usage
Clofarabine is prescribed for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia (ALL) after at least two prior regimens. Its pharmacological classification is antimetabolite, specifically a purine nucleoside analog. Clofarabine works by disrupting DNA synthesis and repair, leading to cancer cell death. It’s important to note that this indication is based upon response rate, and trials haven’t confirmed improvement in disease-related symptoms or survival.
Alternate Names
The International Nonproprietary Name (INN) is clofarabine. A popular brand name is Clolar®. Evoltra® is another brand name used internationally.
How It Works
Pharmacodynamics: Clofarabine is a prodrug metabolized intracellularly to clofarabine 5’-triphosphate, its active form. This metabolite incorporates into DNA, inhibiting DNA synthesis and repair mechanisms, ultimately triggering apoptosis (programmed cell death). Clofarabine is effective against both rapidly proliferating and quiescent leukemic cells.
Pharmacokinetics:
- Absorption: Administered intravenously.
- Metabolism: Intracellularly converted to clofarabine 5’-triphosphate. Limited hepatic metabolism occurs.
- Elimination: Predominantly renal excretion (49-60% of the dose excreted unchanged in urine). Non-hepatic elimination pathways are not fully understood.
Mode of Action: Clofarabine 5’-triphosphate gets incorporated into DNA, disrupting DNA polymerase and ribonucleotide reductase activities. This interference with DNA synthesis and repair ultimately leads to cell cycle arrest and apoptosis.
Receptor Binding/Enzyme Inhibition: Clofarabine 5’-triphosphate inhibits ribonucleotide reductase, a crucial enzyme for DNA synthesis.
Dosage
Standard Dosage
Adults: Clofarabine is not FDA-approved for adults over 21 with ALL. Studies have explored a dose of 40 mg/m² in adult patients with relapsed or refractory acute myeloid leukemia (AML) and ALL.
Children (1-21 years): 52 mg/m² administered as an intravenous infusion over 2 hours daily for 5 consecutive days. Repeat cycles every 2-6 weeks based on hematologic recovery (absolute neutrophil count ANC ≥ 0.75 × 10⁹/L) and return to baseline organ function. For children weighing < 20 kg, an infusion time > 2 hours should be considered to mitigate anxiety, irritability, and high peak plasma concentrations. Safety and efficacy haven’t been established in children younger than 1 year.
Special Cases:
- Elderly Patients: No specific dosage recommendations; adult data is limited.
- Patients with Renal Impairment: Contraindicated in severe renal impairment (serum creatinine ≥ 2 x upper limit of normal (ULN) for age). Use with caution in mild to moderate renal impairment; dose reduction may be necessary (e.g., 50% reduction for creatinine clearance 30-60 mL/min).
- Patients with Hepatic Dysfunction: Contraindicated in severe hepatic impairment. Use with caution in mild to moderate impairment.
- Patients with Comorbid Conditions: Consider comorbidities and potential drug interactions carefully.
Clinical Use Cases
The specific clinical use case for clofarabine is relapsed or refractory ALL in pediatric patients. Dosage remains consistent in this setting. Information on the use in intubation, surgical procedures, mechanical ventilation, ICU use, and other emergency situations isn’t available.
Dosage Adjustments
Reduce the dose by 25% in patients experiencing significant toxicities. Discontinue clofarabine if hypotension or capillary leak syndrome develops during administration, or if serum creatinine and bilirubin levels increase substantially.
Side Effects
Common Side Effects:
Nausea, vomiting, diarrhea, fever, neutropenia, headache, rash, itching, fatigue, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), anxiety, flushing, mucosal inflammation.
Rare but Serious Side Effects:
Severe myelosuppression, hemorrhage (cerebral, gastrointestinal, pulmonary), severe infections (sepsis), tumor lysis syndrome, capillary leak syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, renal dysfunction, liver dysfunction, cardiac effects (e.g., tachycardia, pericardial effusion), neurologic effects (e.g., seizures).
Long-Term Effects:
Potential long-term effects are not well-defined due to the nature of the disease and treatment. Secondary malignancies and organ damage are potential long-term risks with chemotherapy.
Adverse Drug Reactions (ADR):
Severe myelosuppression, capillary leak syndrome, tumor lysis syndrome, hepatotoxicity, renal dysfunction, severe infections.
Contraindications
Hypersensitivity to clofarabine, severe renal impairment, severe hepatic impairment, breastfeeding.
Drug Interactions
Clofarabine has shown limited interaction potential in vitro. It’s not expected to significantly inhibit or induce CYP450 enzymes. However, concomitant use of nephrotoxic or hepatotoxic drugs should be avoided. Consult drug interaction resources for specific interactions.
Pregnancy and Breastfeeding
Clofarabine is contraindicated during pregnancy and breastfeeding due to its teratogenic potential. Effective contraception is crucial during treatment and for 6 months (females) or 3 months (males) after the last dose. Breastfeeding should be discontinued before, during, and after treatment.
Drug Profile Summary
- Mechanism of Action: Purine nucleoside analog that inhibits DNA synthesis and repair, inducing apoptosis.
- Side Effects: Myelosuppression, nausea, vomiting, diarrhea, infections, rash, hand-foot syndrome. Serious side effects include hemorrhage, capillary leak syndrome, tumor lysis syndrome.
- Contraindications: Hypersensitivity, severe renal/hepatic impairment, pregnancy, breastfeeding.
- Drug Interactions: Limited potential; avoid nephrotoxic and hepatotoxic drugs.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Children (1-21 years): 52 mg/m² IV over 2 hours daily for 5 days, repeated every 2-6 weeks.
- Monitoring Parameters: Complete blood counts, renal and liver function tests, electrolyte levels, signs of infection and bleeding.
Popular Combinations
Clinical trials have explored clofarabine in combination with other chemotherapeutic agents like daunorubicin or cytarabine in AML. However, currently, Clolar® is approved as monotherapy for relapsed or refractory ALL.
Precautions
- General Precautions: Monitor closely for myelosuppression, infections, bleeding, tumor lysis syndrome, capillary leak syndrome, hepatic and renal dysfunction.
- Specific Populations: Refer to sections on dosage adjustments for renal/hepatic impairment. Contraindicated in pregnancy and breastfeeding.
- Lifestyle Considerations: Address potential impact on quality of life due to side effects.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Clofarabine in children with relapsed or refractory ALL?
A: 52 mg/m² IV infusion over 2 hours daily for 5 consecutive days, repeated every 2-6 weeks depending on hematologic recovery and organ function.
Q2: Is Clofarabine approved for use in adults?
A: Clofarabine is not FDA-approved for adults over 21 with ALL. Research is ongoing in adult AML and ALL populations, but standard dosing isn’t established.
Q3: What are the most common side effects of Clofarabine?
A: Myelosuppression (neutropenia, thrombocytopenia, anemia), nausea, vomiting, diarrhea, infections, rash, and hand-foot syndrome.
Q4: What are the absolute contraindications to Clofarabine?
A: Hypersensitivity to clofarabine, severe renal impairment, severe hepatic impairment, and breastfeeding.
A: It is intracellularly metabolized to its active form, clofarabine 5’-triphosphate. Limited hepatic metabolism occurs.
Q6: How should Clofarabine be administered?
A: By intravenous infusion over 2 hours (longer duration may be considered for younger children).
Q7: What monitoring is necessary during Clofarabine treatment?
A: Frequent complete blood counts, monitoring of renal and hepatic function, electrolyte levels, and vigilant observation for signs of infection and bleeding.
Q8: Can Clofarabine be used during pregnancy?
A: No, Clofarabine is contraindicated in pregnancy due to its teratogenic effects.
Q9: What is the mechanism of action of Clofarabine?
A: Clofarabine inhibits DNA synthesis and repair by incorporating its active metabolite into DNA, leading to cancer cell death.
