Pharmacology Update: Nelarabine Injection (Arranon®)
Pharmacology Update
Nelarabine Injection (Arranon®)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.
The FDA has approved nelarabine for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic leukemia (T-LBL). Nelarabine was approved under the FDA’s accelerated approval program. It received an Orphan Designation because it is for a rare disease affecting less than 200,000 in the United States. Nelarabine is marketed by GlaxoSmithKline as Arranon®.
Indications
Nelarabine is indicated for the treatment of patients with T-ALL and T-LBL who have not responded to or have relapsed following treatment with at least 2 chemotherapeutic regimens.1
Dosage
The recommended adult dose is 1,500 mg/m2 given intravenously over 2 hours on days 1, 3, and 5 every 21 days. The recommended pediatric dose is 650 mg/m2 over 1 hour for 5 consecutive days and repeated every 21 days. Standard hydration, urine alkalinization and prophylaxis with allopurinol are necessary to prevent hyperuricemia of tumor lysis syndrome. Nelarabine should be discontinued for grade 2 or greater neurological toxicity and dose may be delayed for hematological toxicity.1
Potential Advantages
In clinical trials complete response and complete response without hematologic recovery was 21% in adults and 23% in pediatric patients.1 No significant drug-drug interactions involving cytochrome P450 isoenzymes have been reported.
Potential Disadvantages
Major side effects were neurological in nature and are the dose-limiting toxicities. These include somnolence, confusion, convulsions, ataxia, paresthesia, and hypoesthesia. Leukopenia, thrombocytopenia, anemia, and neutropenia including febrile neutropenia have been associated with nelarabine. Grade 4 neutropenia has been reported in 62% of pediatric subjects and 49% of adult subjects. Monitoring of complete blood counts and platelets are recommended.1Median overall survival appears to be limited, 13.1 (95% CI, 8.7-17.4) weeks for patients less than 21 years of age and 20.6 (95% CI, 10.4-36.4) weeks for adult patients.1
Comments
Nelarabine is a prodrug of 9-D-arabinofuranosylguanine (ara-G). After entry into the cell it is demethylated by adenosine deaminase and activated by phosphorylation by deoxycytidine kinase or deoxyguanosine kinase. This active form is incorporated into cellular DNA resulting in inhibition of DNA synthesis and ultimately to cell death. Nelarabine is more toxic to T lymphoblasts than deoxyguanine and is resistant to degradation by purine nucleoside phosphorylase.2 It was evaluated in 2 open-label, single-arm studies with refractory or relapsing disease. Complete response and complete response without hematologic recovery was 23% for children and young adults (n = 39) and 21% in adults (n = 28). Complete response was defined as bone marrow blast counts 5%, no evidence of disease, and full recovery of peripheral blood counts. Median overall survival durations were 13.1 and 20.6 weeks respectively. In a study involving children and young adults with T-cell malignancies, subjects with first relapse responded better than those with second or subsequent relapses.2 A 55% response rate (complete and partial) was observed in those with T-ALL 25% bone marrow blasts with or without extramedullary relapse other than CNS, in first relapse or refractory to initial induction therapy. This compares to 27% in patients with second or subsequent relapse. Severe neurologic events and myelosuppression were the most common adverse events associated with nelarabine. The duration of treatment has not been clearly established. In clinical trials treatment continued until there is disease progression, unacceptable toxicity, no apparent benefit, or the patient became a candidate for bone marrow transplant.1
Clinical Implications
Approximately 1600 patients are diagnosed with T-ALL/T-LBL annually in the United States. It is estimated that about 500 have relapsed or refractory disease.3Nelarabine offers single agent therapy for those with refractory and relapsing disease.
References
1. Arranon® Product Information. GlaxoSmithKline. October 2005.
2. Berg SL, 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;23:3376-3382.
3. FDA News Release. FDA Approves Arranon for Rare Leukemia and Lymphoma Drug Approved Under Agency’s Orphan Drug and Accelerated Approval Programs. www.fda.gov/bbs/topics/NEWS/2005/NEW01251.html.
The FDA has approved nelarabine for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic leukemia (T-LBL). Nelarabine was approved under the FDAs accelerated approval program. It received an Orphan Designation because it is for a rare disease affecting less than 200,000 in the United States. Nelarabine is marketed by GlaxoSmithKline as Arranon®.Subscribe Now for Access
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