Usage
Nelarabine is prescribed for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in adult and pediatric patients aged 1 year and older. It is used when the disease hasn’t responded to or has relapsed after at least two other chemotherapy regimens. Pharmacologically, nelarabine is classified as an antineoplastic antimetabolite, specifically a nucleoside metabolic inhibitor. Its mechanism of action involves being a prodrug of 9-β-D-arabinofuranosylguanine (ara-G). Nelarabine is demethylated to ara-G, which is then phosphorylated intracellularly to ara-G triphosphate (ara-GTP). Ara-GTP inhibits DNA polymerase, leading to DNA synthesis inhibition and apoptosis in T-cells.
Alternate Names
The International Nonproprietary Name (INN) for nelarabine is “nelarabine”. A commonly known brand name is Arranon.
How It Works
Pharmacodynamics: Nelarabine primarily affects rapidly dividing cells, particularly T-lymphoblasts. Ara-G triphosphate (ara-GTP), the active metabolite, inhibits DNA polymerase and ribonucleotide reductase, disrupting DNA and RNA synthesis. This leads to cell cycle arrest and apoptosis, especially in T-cells.
Pharmacokinetics: Nelarabine is administered intravenously and is rapidly demethylated to ara-G. Ara-G is then phosphorylated intracellularly to its active form, ara-GTP. Peak plasma concentrations of ara-G are achieved at the end of infusion. Nelarabine and ara-G are partially metabolized and excreted primarily through the kidneys. Cytochrome P450 (CYP) enzymes play a minor role in nelarabine’s metabolism.
Mode of Action: Nelarabine’s mode of action involves intracellular conversion to ara-GTP, which competes with deoxyguanosine triphosphate (dGTP) for incorporation into DNA. This leads to chain termination and inhibits DNA synthesis. Ara-GTP also inhibits ribonucleotide reductase, reducing the availability of dGTP. These combined effects disrupt DNA replication and repair, leading to cell death.
Elimination Pathways: Nelarabine and its active metabolite, ara-G, are partially renally excreted and partially metabolized.
Dosage
Standard Dosage
Adults:
1500 mg/m² administered intravenously over 2 hours on days 1, 3, and 5 of a 21-day cycle.
Children (1 year and older):
650 mg/m² administered intravenously over 1 hour daily for 5 consecutive days, repeated every 21 days.
Special Cases:
- Elderly Patients: No specific dosage adjustment is recommended, but close monitoring is advised due to potential age-related decrease in renal function.
- Patients with Renal Impairment: For patients with creatinine clearance (CrCl) ≥ 50 mL/minute, no dosage adjustment is necessary. For CrCl < 50 mL/minute, no data exists to guide dosing; close monitoring is recommended.
- Patients with Hepatic Dysfunction: No specific dosage adjustment is available; close monitoring is necessary.
- Patients with Comorbid Conditions: Monitor closely for potential drug interactions and adjust concomitant medications as needed.
Clinical Use Cases
Nelarabine’s dosage is specifically designed for T-cell malignancies and doesn’t vary based on clinical settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. The standard dosage guidelines apply in these contexts.
Dosage Adjustments
Dosage must be discontinued at the first sign of neurological events of NCI Common Terminology Criteria Adverse Event (NCI CTCAE) grade 2 or greater. Delaying subsequent doses can be considered for other toxicities, including hematologic toxicity.
Side Effects
Common Side Effects
Nausea, vomiting, fatigue, fever, chills, headache, dizziness, peripheral neuropathy (numbness, tingling), decreased blood cell counts (neutropenia, thrombocytopenia, anemia), infections.
Rare but Serious Side Effects
Severe neurological reactions (seizures, somnolence, confusion, motor weakness, paralysis), Guillain-Barré syndrome-like symptoms, tumor lysis syndrome, severe infections.
Long-Term Effects
Chronic peripheral neuropathy, secondary malignancies.
Adverse Drug Reactions (ADR)
Severe neurotoxicity, rhabdomyolysis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Contraindications
Hypersensitivity to nelarabine, concurrent intrathecal chemotherapy or craniospinal radiation.
Drug Interactions
Pentostatin, other myelosuppressive agents, live vaccines, deferiprone.
Pregnancy and Breastfeeding
Nelarabine is contraindicated during pregnancy. It can cause fetal harm. Effective contraception should be used during treatment and for at least 3 months after the last dose for men and 6 months after the last dose for women. Breastfeeding is contraindicated while taking nelarabine.
Drug Profile Summary
- Mechanism of Action: Prodrug of ara-G, inhibits DNA polymerase and ribonucleotide reductase, leading to apoptosis in T-cells.
- Side Effects: Myelosuppression, neurotoxicity, nausea, vomiting, fatigue.
- Contraindications: Hypersensitivity, pregnancy, breastfeeding, concurrent intrathecal chemotherapy or craniospinal radiation.
- Drug Interactions: Pentostatin, myelosuppressive agents.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Adults: 1500 mg/m² IV over 2 hours on days 1, 3, and 5 of a 21-day cycle. Children: 650 mg/m² IV over 1 hour daily for 5 days, repeated every 21 days.
- Monitoring Parameters: Complete blood counts, renal and liver function tests, neurological assessment.
Popular Combinations
Nelarabine is sometimes used in combination with other chemotherapy agents like cyclophosphamide and etoposide (NECTAR regimen) for relapsed or refractory T-ALL/T-LBL, though the efficacy and safety data is still limited.
Precautions
- General Precautions: Monitor for neurotoxicity, myelosuppression, tumor lysis syndrome, and infections. Pre-hydration and allopurinol may be necessary.
- Specific Populations:
- Pregnant Women: Contraindicated.
- Breastfeeding Mothers: Contraindicated.
- Children & Elderly: Close monitoring for toxicity is crucial.
- Lifestyle Considerations: Avoid driving or operating machinery if experiencing dizziness or drowsiness.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Nelarabine?
A: Adults: 1500 mg/m² IV over 2 hours on days 1, 3, and 5 of a 21-day cycle. Children: 650 mg/m² IV over 1 hour daily for 5 days, repeated every 21 days.
Q2: What is the primary dose-limiting toxicity of Nelarabine?
A: Neurotoxicity, including peripheral neuropathy, seizures, and altered mental status.
Q3: What are the most common side effects of Nelarabine?
A: Myelosuppression (neutropenia, thrombocytopenia, anemia), infections, nausea, vomiting, fatigue, and peripheral neuropathy.
A: Primarily through demethylation to ara-G and subsequent phosphorylation to ara-GTP. Renal excretion plays a major role in elimination.
Q5: What are the contraindications for using Nelarabine?
A: Hypersensitivity to nelarabine, concurrent intrathecal chemotherapy or craniospinal radiation, pregnancy, and breastfeeding.
Q6: Are there any specific drug interactions with Nelarabine?
A: Concomitant use with pentostatin is not recommended. Caution is advised with other myelosuppressive agents and live vaccines.
Q7: What should be monitored in patients receiving Nelarabine?
A: Complete blood counts, renal and liver function tests, neurological status, and signs of tumor lysis syndrome.
Q8: What is the mechanism of action of Nelarabine?
A: Nelarabine is a prodrug of ara-G, which is converted to ara-GTP, an inhibitor of DNA polymerase and ribonucleotide reductase. This leads to DNA and RNA synthesis inhibition, causing apoptosis in T-cells.
Q9: Can Nelarabine be used during pregnancy or breastfeeding?
A: No, Nelarabine is contraindicated during pregnancy and breastfeeding due to the risk of fetal harm.
Q10: What is the recommended administration route for Nelarabine?
A: Intravenous infusion. It should not be diluted prior to administration.
