Nelarabine, a prodrug of the deoxyguanosine analog 9-β-D-arabinofuranosylguanine (ara-G), is an antimetabolite antineoplastic agent.1, 2, 5
Nelarabine is used for the treatment of acute T-cell lymphocytic (lymphoblastic) leukemia (ALL) and T-cell lymphoblastic lymphoma in patients whose disease is refractory to or has relapsed after at least 2 prior chemotherapy regimens.1, 2, 4 Nelarabine is designated an orphan drug by the US Food and Drug Administration (FDA) for use in these conditions.6 Nelarabine became commercially available in the US under the principles and procedures of the accelerated review policy of the FDA, which allows approval based on analysis of surrogate markers of response rather than clinical end points.5 The current indication for nelarabine is based on induction of complete responses; randomized clinical trials showing increased survival or other clinical benefits have not been conducted to date.1
Safety and efficacy of nelarabine were evaluated in an open-label, single-arm, multicenter trial in 39 adults with relapsed or refractory T-cell ALL or T-cell lymphoblastic lymphoma.1, 7
Among the 28 trial patients (mean age: 34 years, range: 16-65 years; 82% male; 61% white) with disease that was refractory to or had relapsed after at least 2 prior induction regimens, nelarabine (1500 mg/m2 IV over 2 hours on days 1, 3, and 5, with treatment cycles repeated every 21 days) resulted in a complete response rate of 18%, a rate of complete response without full hematologic recovery of 4%, a duration of response (complete or complete without full hematologic recovery) of 4 to longer than 195 weeks, and a median overall survival of about 21 weeks.1, 2
Safety and efficacy of nelarabine also were evaluated in an open-label, single-arm, multicenter trial in 84 children and young adults 21 years of age and younger (mean age: about 12 years) with relapsed or refractory T-cell ALL or T-cell lymphoblastic lymphoma.1, 2, 3, 7 Among the 39 trial patients with disease that was refractory to or had relapsed after at least 2 prior induction regimens, nelarabine (650 mg/m2 IV over 1 hour daily for 5 consecutive days and repeated every 21 days) resulted in a complete response rate of 13%, a rate of complete response without full hematologic recovery of 10%, a duration of response (complete or complete without full hematologic recovery) of about 3-9 weeks, and a median overall survival of about 13 weeks.1, 2
Nelarabine is administered by IV infusion over 2 hours in adults and over 1 hour in children.1 Nelarabine injection should not be diluted prior to administration.1 The appropriate dose of nelarabine should be withdrawn from the required number of vials and transferred into empty polyvinylchloride (PVC) infusion bags or glass containers prior to administration.1 The drug should be inspected visually for particulate matter and discoloration prior to administration.1
Appropriate measures (e.g., administration of IV fluids, allopurinol, and alkalinization of urine) should be taken to prevent hyperuricemia of tumor lysis syndrome.1 (See Tumor Lysis Syndrome under Warnings/Precautions: Warnings, in Cautions.)
The usual precautions for handling and preparing solutions of cytotoxic drugs should be observed when preparing or administering nelarabine.1
The optimal duration of treatment in adult or pediatric patients has not been clearly established.1 In clinical trials, treatment generally was continued until evidence of disease progression, unacceptable toxicity, bone marrow transplantation, or lack of clinical benefit was observed or until patients became candidates for bone marrow transplantation.1
Nelarabine should be discontinued in patients experiencing neurotoxicity of NCI Common Toxicity Criteria grade 2 or greater.1 (See Neurotoxicity under Warnings/Precautions: Warnings, in Cautions.) Dosage may be delayed for other toxicity (e.g., hematologic toxicity).1
The recommended adult dosage of nelarabine for the treatment of relapsed or refractory T-cell ALL or T-cell lymphoblastic lymphoma is 1500 mg/m2 given by IV infusion over 2 hours on days 1, 3, and 5 and then every 21 days thereafter.1, 2
The recommended pediatric dosage of nelarabine for the treatment of relapsed or refractory T-cell ALL or T-cell lymphoblastic lymphoma is 650 mg/m2 IV over 1 hour daily for 5 consecutive days and then every 21 days thereafter.1, 2
Dosage adjustment is not necessary in patients with mild renal impairment (creatinine clearance of 50 mL/minute or greater).1 Insufficient data are available to support a dosage recommendation for patients with moderate to severe renal impairment (creatinine clearance of less than 50 mL/minute) or hepatic impairment.1
Known hypersensitivity to nelarabine or any ingredient in the formulation.1
Nelarabine should be used under the supervision of a qualified clinician experienced in therapy with antineoplastic agents.1
Neurotoxicity, usually manifested by somnolence, confusion, seizures, peripheral neuropathy (ranging from numbness and paresthesias to motor weakness and paralysis), ataxia, and hypoesthesia (which may be severe and irreversible), is the dose-limiting toxicity of nelarabine.1, 2, 3, 5
Severe neurotoxic effects also have included coma, status epilepticus, craniospinal demyelination, and ascending peripheral neuropathy (similar in presentation to Guillain-Barré syndrome).1
Patients who have received prior or concomitant intrathecal chemotherapy or prior craniospinal irradiation may be at increased risk for nelarabine-induced neurotoxicity.1 Patients should be closely monitored for neurologic toxicity, and the drug should be discontinued in patients experiencing neurologic events of NCI Common Toxicity Criteria grade 2 or greater.1
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity demonstrated in animals.1 No studies to date in humans.1 Pregnancy should be avoided during therapy.1 If used during pregnancy or the patient becomes pregnant while receiving nelarabine, apprise of potential fetal hazard.1
The principal manifestations of hematologic toxicity include leukopenia, thrombocytopenia, anemia, and neutropenia.1
Appropriate measures (e.g., hydration, urinary alkalinization, allopurinol) to prevent hyperuricemia should be used in patients at risk for tumor lysis syndrome.1
The manufacturer recommends that live virus vaccines be avoided during therapy with the drug.1
Complete blood cell counts, including platelet count, should be performed at regular intervals in all patients receiving nelarabine.1 Patients receiving nelarabine should be closely monitored for adverse neurologic effects; the drug should be discontinued in patients experiencing neurotoxic events of NCI Common Toxicity grade 2 or greater.1
Category D.1 (See Users Guide.) (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
Not known whether nelarabine or ara-G is distributed into human milk; discontinue nursing during nelarabine therapy.1
Safety and efficacy for treatment of relapsed or refractory T-cell ALL and T-cell lymphoblastic lymphoma have been established in patients 2.5-21 years of age.1 (See Pediatric Patients under Acute Lymphocytic Leukemia: Acute T-cell Leukemia, in Uses.)
Experience in those 65 years of age and older insufficient to determine whether they respond differently from younger adults.1 Incidence of adverse neurologic effects appears to increase with increasing age, especially in those 65 years of age and older.1 Renal impairment, which occurs more commonly in geriatric patients, may result in reduced clearance of ara-G.1
Nelarabine has not been studied in patients with hepatic impairment.1 Because of the possibility of an increased risk of adverse reactions, closely monitor patients with severe hepatic impairment (serum bilirubin greater than 3 mg/dL).1
Clearance of ara-G is reduced in patients with decreased renal function.1 Because of the possibility of an increased risk of adverse reactions, closely monitor patients with severe renal impairment (creatinine clearance of less than 30 mL/minute).1
Adverse effects reported in 5% or more of adults receiving nelarabine include anemia,1, 2 thrombocytopenia,1, 2 neutropenia,1, 2 febrile neutropenia,1 somnolence,1, 2 dizziness,1 peripheral neurologic disorders,1 peripheral neuropathy,1, 2 peripheral motor neuropathy,1 peripheral sensory neuropathy,1 hypoesthesia,1, 2 headache,1, 2 paresthesia,1 ataxia,1 depressed level of consciousness,1 tremor,1 fatigue,1 pyrexia,1 asthenia,1 confusion,1 insomnia, 1 depression,1 muscular weakness,1 myalgia,1 arthralgia,1 back pain,1 extremity pain,1 abnormal gait,1 nausea,1 diarrhea,1 vomiting,1 constipation,1 abdominal pain,1 anorexia,1 stomatitis,1 abdominal distension,1 sinus tachycardia, 1 peripheral edema,1 edema,1 pain,1 rigors,1 chest pain,1 noncardiac chest pain,1 infection,1 pneumonia,1 sinusitis,1 increased serum AST concentrations,1 dehydration,1 hyperglycemia,1 cough,1 dyspnea,1 pleural effusion,1 epistaxis,1 exertional dyspnea,1 wheezing,1 petechiae,1 and hypotension.1, 2, 3
Adverse effects reported in 5% or more of pediatric patients receiving nelarabine include anemia,1, 2 neutropenia,1, 2 thrombocytopenia,1, 2 leukopenia,1, 2 headache,1, 2 peripheral neurologic disorders,1 peripheral neuropathy,1, 2, 3 peripheral sensory neuropathy,1 somnolence,1, 2 hypoesthesia,1 seizures,1 increased serum transaminase concentrations,1 hyperbilirubinemia,1 hypoalbuminemia,1 hypokalemia,1 hypocalcemia,1 increased serum creatinine concentrations,1 hypoglycemia,1 hypomagnesemia,1 vomiting,1 asthenia,1 and infection.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Nelarabine does not appear to substantially inhibit any of the cytochrome P-450 (CYP) isoenzymes, including 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro (at concentrations up to 100 µM).1
In a limited number of patients with refractory leukemia, fludarabine did not affect the pharmacokinetics of nelarabine, ara-G, or ara-GTP.1
Nelarabine, a prodrug of the deoxyguanosine analog ara-G, is an antimetabolite antineoplastic agent.1, 2, 5 Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G, monophosphorylated by deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the active 5'-triphosphate, ara-GTP.1, 2, 5 Ara-GTP accumulates in leukemic blasts and is incorporated into DNA, inducing fragmentation and apoptosis.1, 2, 5 Other mechanisms may contribute to the pharmacologic and toxicologic effects of the drug.1, 5
Nelarabine and ara-G are extensively distributed throughout the body and are not substantially bound to human plasma proteins (less than 25%).1 Following IV administration of nelarabine in adult patients with refractory leukemia or lymphoma, nelarabine and ara-G are rapidly eliminated from the plasma with a half-life of about 30 minutes and 3 hours, respectively.1 Mean clearance of nelarabine is about 30% higher in pediatric patients than in adult patients, while clearance of ara-G is similar in the two groups.1 Nelarabine and ara-G are partially (5-10 and 20-30%, respectively, of the administered dose) excreted by the kidneys.1
Risk of somnolence; avoid driving or operating machinery.1
Importance of patients notifying clinicians if they develop new or worsening symptoms of peripheral neuropathy (e.g., tingling or numbness in fingers, hands, toes, or feet; difficulty with fine motor coordination tasks such as buttoning clothing; unsteadiness while walking; weakness arising from a low chair or climbing stairs; increased tripping over uneven surfaces).1
Importance of patients notifying clinicians immediately if they develop seizures.1
Importance of patients notifying clinicians if fever or other symptom of infection, unusual bleeding or bruising, breathing difficulty, excessive fatigue, pallor, GI effects (e.g., nausea, vomiting, diarrhea, constipation), headache, drowsiness, or blurred vision occurs.1
Importance of advising women to use an effective method of contraception and to avoid breast-feeding while undergoing nelarabine therapy.1 Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV use | 5 mg/mL (250 mg) |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 1, 2006. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. GlaxoSmithKline. Arranon® (nelarabine) injection prescribing information. Research Triangle Park, NC; 2005 Oct.
2. Anon. Nelarabine (Arranon) for T-cell acute lymphoblastic leukemia. Med Lett Drugs Ther . 2006; 48:14-5. [PubMed 16467734]
3. Berg SL, Blaney SM, Devidas M et al. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol . 2005; 23:3376-82. [PubMed 15908649]
4. Childhood acute lymphoblastic leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2006 Feb 17.
5. Kisor DF. Nelarabine: a nucleoside analog with efficacy in T-cell and other leukemias. Ann Pharmacother . 2005; 39:1056-63. [PubMed 15870141]
6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; 2006 Mar 21. From FDA website ([Web]). Accessed 2006 Apr 3.
7. GlaxoSmith Kline, Research Triangle Park, NC: Personal communication