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 Nelarabine

nelarabine is an arabinonucleoside antimetabolite with antineoplastic activity. Nelarabine is demethoxylated by adenosine deaminase to become biologically active 9-beta-D-arabinosylguanine (ara-G); ara-G incorporates into DNA, thereby inhibiting DNA synthesis and inducing an S phase-dependent apoptosis of tumor cells. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

According to http://en.wikipedia.org/wiki/Nelarabine, Nelarabine is a chemotherapy drug used in T-cell acute lymphoblastic leukemia. It was previously known as 506U78. Nelarabine is a purine nucleoside analog converted to its corresponding arabinosylguanine nucleotide triphosphate (araGTP), resulting in inhibition of DNA synthesis and cytotoxicity. Pre-clinical studies suggest that T-cells are particularly sensitive to nelarabine. In October 2005, it was approved by the FDA for T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma that has not responded to or has relapsed following treatment with at least two chemotherapy regimens. It was later approved in the European Union on August 22, 2007. Complete responses have been achieved with this medication. It is marketed in the US as Arranon and as Atriance in the EU by GlaxoSmithKline.

Drug Description

ARRANON (nelarabine) is a pro-drug of the cytotoxic deoxyguanosine analogue, 9-β-D-arabinofuranosylguanine (ara-G). The chemical name for nelarabine is 2-amino-9-β-D-arabinofuranosyl-6-methoxy-9H-purine. It has the molecular formula C11H15N5O5 and a molecular weight of 297.27. Nelarabine is slightly soluble to soluble in water and melts with decomposition between 209° and 217° C. ARRANON Injection is supplied as a clear, colorless, sterile solution in glass vials. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. ARRANON is intended for intravenous infusion. Hydrochloric acid and sodium hydroxide may have been used to adjust the pH. The solution pH ranges from 5.0 to 7.0.

Mechanism of Action

 Nelarabine is a pro-drug of the deoxyguanosine analogue 9-β-D-arabinofuranosylguanine (ara-G), a nucleoside metabolic inhibitor. Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G, mono-phosphorylated by deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the active 5'-triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death. Other mechanisms may contribute to the cytotoxic and systemic toxicity of nelarabine.

  1: Commander LA, Seif AE, Insogna IG, Rheingold SR. Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. Br J Haematol. 2010 May 26. [Epub ahead of print] PubMed PMID: 20528871.

2: Fullmer A, O'Brien S, Kantarjian H, Jabbour E. Novel therapies for relapsed acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2009 Jul;4(3):148-56. PubMed PMID: 20425428.

3: Yamauchi T, Nishi R, Kitazumi K, Nakano T, Ueda T. A new high-performance liquid chromatography method determines low production of 9-beta-D-arabinofuranosylguanine triphosphate, an active metabolite of nelarabine, in adult T-cell leukemia cells. Oncol Rep. 2010 Feb;23(2):499-504. PubMed PMID: 20043113.

4: Marks DI, Paietta EM, Moorman AV, Richards SM, Buck G, DeWald G, Ferrando A, Fielding AK, Goldstone AH, Ketterling RP, Litzow MR, Luger SM, McMillan AK, Mansour MR, Rowe JM, Tallman MS, Lazarus HM. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood. 2009 Dec 10;114(25):5136-45. Epub . PubMed PMID: 19828704; PubMed Central PMCID: PMC2792210.

5: DeAngelo DJ. Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. Review. PubMed PMID: 19825456.

6: Nelarabine: new drug. T-lymphoblastic leukaemia/lymphoma: more evaluation needed. Prescrire Int. 2009 Feb;18(99):3-5. PubMed PMID: 19382393.

7: Robak T, Korycka A, Lech-Maranda E, Robak P. Current status of older and new purine nucleoside analogues in the treatment of lymphoproliferative diseases. Molecules. 2009 Mar 23;14(3):1183-226. Review. PubMed PMID: 19325518.

8: Iino M. [Severe liver injury following nelarabine chemotherapy for T-cell lymphoblastic lymphoma]. Rinsho Ketsueki. 2009 Jan;50(1):49-51. Japanese. PubMed PMID: 19225230.

9: Sigalas P, Tourvas AD, Moulakakis A, Pangalis G, Kontopidou F. Nelarabine induced complete remission in an adult with refractory T-lineage acute lymphoblastic leukemia: A case report and review of the literature. Leuk Res. 2009 Jul;33(7):e61-3. Epub 2009 Jan 21. Review. PubMed PMID: 19157550.

10: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 May;30(4):313-31. PubMed PMID: 18773127.

11: Cohen MH, Johnson JR, Justice R, Pazdur R. FDA drug approval summary: nelarabine (Arranon) for the treatment of T-cell lymphoblastic leukemia/lymphoma. Oncologist. 2008 Jun;13(6):709-14. PubMed PMID: 18586926.

12: Korycka A, Lech-Marańda E, Robak T. Novel purine nucleoside analogues for hematological malignancies. Recent Pat Anticancer Drug Discov. 2008 Jun;3(2):123-36. Review. PubMed PMID: 18537755.

13: Cooper TM. Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther Clin Risk Manag. 2007 Dec;3(6):1135-41. PubMed PMID: 18516261; PubMed Central PMCID: PMC2387290.

14: Curbo S, Karlsson A. Nelarabine: a new purine analog in the treatment of hematologic malignancies. Rev Recent Clin Trials. 2006 Sep;1(3):185-92. Review. PubMed PMID: 18473971.

15: Galmarini CM, Popowycz F, Joseph B. Cytotoxic nucleoside analogues: different strategies to improve their clinical efficacy. Curr Med Chem. 2008;15(11):1072-82. Review. PubMed PMID: 18473803.

16: Chen AI, Advani RH. Beyond the guidelines in the treatment of peripheral T-cell lymphoma: new drug development. J Natl Compr Canc Netw. 2008 Apr;6(4):428-35. PubMed PMID: 18433608.

17: Bayés M, Rabasseda X. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 Jan-Feb;30(1):67-99. PubMed PMID: 18389098.

18: Sanford M, Lyseng-Williamson KA. Nelarabine. Drugs. 2008;68(4):439-47. Review. PubMed PMID: 18318562.

19: Gandhi V, Tam C, O'Brien S, Jewell RC, Rodriguez CO Jr, Lerner S, Plunkett W, Keating MJ. Phase I trial of nelarabine in indolent leukemias. J Clin Oncol. 2008 Mar 1;26(7):1098-105. PubMed PMID: 18309944.

20: Cheson BD. Clinical management of T-cell malignancies: current perspectives, key issues, and emerging therapies. Semin Oncol. 2007 Dec;34(6 Suppl 5):S3-7. Review. PubMed PMID: 18086345.

21: Larson RA. Three new drugs for acute lymphoblastic leukemia: nelarabine, clofarabine, and forodesine. Semin Oncol. 2007 Dec;34(6 Suppl 5):S13-20. Review. PubMed PMID: 18086342.

22: Buie LW, Epstein SS, Lindley CM. Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. Review. PubMed PMID: 18035189.

23: Choi J, Foss F. Efficacy of low dose clofarabine in refractory precursor T- acute lymphoblastic leukemia. Yale J Biol Med. 2006 Dec;79(3-4):169-72. PubMed PMID: 17940627; PubMed Central PMCID: PMC1994805.

24: Apostolidou E, Swords R, Alvarado Y, Giles FJ. Treatment of acute lymphoblastic leukaemia : a new era. Drugs. 2007;67(15):2153-71. Review. PubMed PMID: 17927282.

25: Alvarado Y, Welch MA, Swords R, Bruzzi J, Schlette E, Giles FJ. Nelarabine activity in acute biphenotypic leukemia. Leuk Res. 2007 Nov;31(11):1600-3. Epub 2007 May 18. PubMed PMID: 17512588.

26: Beesley AH, Palmer ML, Ford J, Weller RE, Cummings AJ, Freitas JR, Firth MJ, Perera KU, de Klerk NH, Kees UR. In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia. Br J Haematol. 2007 Apr;137(2):109-16. PubMed PMID: 17391490.

27: DeAngelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, Gockerman JP, Mitchell BS, Appelbaum FR, Larson RA. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood. 2007 Jun 15;109(12):5136-42. Epub 2007 Mar 7. PubMed PMID: 17344466; PubMed Central PMCID: PMC1941786.

28: Czuczman MS, Porcu P, Johnson J, Niedzwiecki D, Kelly M, Hsi ED, Cook JR, Canellos G, Cheson BD; Cancer and Leukemia Group B. Results of a phase II study of 506U78 in cutaneous T-cell lymphoma and peripheral T-cell lymphoma: CALGB 59901. Leuk Lymphoma. 2007 Jan;48(1):97-103. PubMed PMID: 17325852.

29: Kurtzberg J. The long and winding road of the clinical development of Nelarabine. Leuk Lymphoma. 2007 Jan;48(1):1-2. PubMed PMID: 17325839.

30: Watanabe A. [Recent advance in treatment of childhood acute lymphoblastic leukemia]. Gan To Kagaku Ryoho. 2007 Feb;34(2):150-5. Japanese. PubMed PMID: 17301519.

31: Hussar DA. New drugs 07, part I. Nursing. 2007 Feb;37(2):51-8; quiz 59-60. PubMed PMID: 17273084.

32: Robak T, Lech-Maranda E, Korycka A, Robak E. Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Curr Med Chem. 2006;13(26):3165-89. PubMed PMID: 17168705.

33: Ravandi F, Gandhi V. Novel purine nucleoside analogues for T-cell-lineage acute lymphoblastic leukaemia and lymphoma. Expert Opin Investig Drugs. 2006 Dec;15(12):1601-13. Review. PubMed PMID: 17107284.

34: [Glaxo Smith Kline. A large oncology pipeline]. Med Monatsschr Pharm. 2006 Oct;29(10):385-6. German. PubMed PMID: 17058903.

35: Koenig R. The legacy of great science: the work of Nobel Laureate Gertrude Elion lives on. Oncologist. 2006 Oct;11(9):961-5. PubMed PMID: 17030634.

36: Murphy MJ. Milestones in oncology: introducing a new section. Oncologist. 2006 Oct;11(9):960. PubMed PMID: 17030633.

37: Cohen MH, Johnson JR, Massie T, Sridhara R, McGuinn WD Jr, Abraham S, Booth BP, Goheer MA, Morse D, Chen XH, Chidambaram N, Kenna L, Gobburu JV, Justice R, Pazdur R. Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma. Clin Cancer Res. 2006 Sep 15;12(18):5329-35. PubMed PMID: 17000665.

38: Gandhi V, Plunkett W. Clofarabine and nelarabine: two new purine nucleoside analogs. Curr Opin Oncol. 2006 Nov;18(6):584-90. Review. PubMed PMID: 16988579.

39: Berg SL, Brueckner C, Nuchtern JG, Dauser R, McGuffey L, Blaney SM. Plasma and cerebrospinal fluid pharmacokinetics of nelarabine in nonhuman primates. Cancer Chemother Pharmacol. 2007 May;59(6):743-7. Epub 2006 Sep 5. PubMed PMID: 16953392.

40: Kline J, Larson RA. Nelarabine in the treatment of refractory T-cell malignant diseases. Expert Opin Pharmacother. 2006 Sep;7(13):1791-9. Review. PubMed PMID: 16925505.

41: Roecker AM, Allison JC, Kisor DF. Nelarabine: efficacy in the treatment of clinical malignancies. Future Oncol. 2006 Aug;2(4):441-8. Review. PubMed PMID: 16922610.

42: Kisor DF. Nelarabine use in leukemias. Drugs Today (Barc). 2006 Jul;42(7):455-65. Review. PubMed PMID: 16894400.

43: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2006 Jun;28(5):323-43. PubMed PMID: 16845450.

44: Lech-Maranda E, Korycka A, Robak T. Pharmacological and clinical studies on purine nucleoside analogs--new anticancer agents. Mini Rev Med Chem. 2006 May;6(5):575-81. Review. PubMed PMID: 16719832.

45: Hussar DA. New drugs: abatacept, sorafenib, and nelarabine. J Am Pharm Assoc (2003). 2006 Mar-Apr;46(2):300-3. PubMed PMID: 16602235.

46: New drug to treat rare leukemia and lymphoma. FDA Consum. 2006 Jan-Feb;40(1):4-5. PubMed PMID: 16532541.

47: Gandhi V, Keating MJ, Bate G, Kirkpatrick P. Nelarabine. Nat Rev Drug Discov. 2006 Jan;5(1):17-8. PubMed PMID: 16485343.

48: Nelarabine (Arranon) for T-cell acute lymphoblastic leukemia. Med Lett Drugs Ther. 2006 Feb 13;48(1228):14-5. PubMed PMID: 16467734.

49: Robak T, Korycka A, Kasznicki M, Wrzesien-Kus A, Smolewski P. Purine nucleoside analogues for the treatment of hematological malignancies: pharmacology and clinical applications. Curr Cancer Drug Targets. 2005 Sep;5(6):421-44. Review. PubMed PMID: 16178817.

50: Kurtzberg J, Ernst TJ, Keating MJ, Gandhi V, Hodge JP, Kisor DF, Lager JJ, Stephens C, Levin J, Krenitsky T, Elion G, Mitchell BS. Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol. 2005 May 20;23(15):3396-403. PubMed PMID: 15908652.

51: Berg SL, Blaney SM, Devidas M, Lampkin TA, Murgo A, Bernstein M, Billett A, Kurtzberg J, Reaman G, Gaynon P, Whitlock J, Krailo M, Harris MB; Children's Oncology Group. 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 May 20;23(15):3376-82. PubMed PMID: 15908649.

52: Kisor DF. Nelarabine: a nucleoside analog with efficacy in T-cell and other leukemias. Ann Pharmacother. 2005 Jun;39(6):1056-63. Epub 2005 May 3. Review. PubMed PMID: 15870141.

53: Szafraniec SI, Stachnik KJ, Skierski JS. New nucleoside analogs in the treatment of hematological disorders. Acta Pol Pharm. 2004 May-Jun;61(3):223-32. Review. PubMed PMID: 15481249.

54: Parker WB, Secrist JA 3rd, Waud WR. Purine nucleoside antimetabolites in development for the treatment of cancer. Curr Opin Investig Drugs. 2004 Jun;5(6):592-6. Review. PubMed PMID: 15242246.

55: Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2003 Nov;25(9):747-71. PubMed PMID: 14685303.

56: Rodriguez CO Jr, Stellrecht CM, Gandhi V. Mechanisms for T-cell selective cytotoxicity of arabinosylguanine. Blood. 2003 Sep 1;102(5):1842-8. Epub 2003 May 15. PubMed PMID: 12750168.

57: Rodriguez CO Jr, Mitchell BS, Ayres M, Eriksson S, Gandhi V. Arabinosylguanine is phosphorylated by both cytoplasmic deoxycytidine kinase and mitochondrial deoxyguanosine kinase. Cancer Res. 2002 Jun 1;62(11):3100-5. PubMed PMID: 12036920.

58: Jones D, Vega F, Sarris AH, Medeiros LJ. CD4-CD8-"Double-negative" cutaneous T-cell lymphomas share common histologic features and an aggressive clinical course. Am J Surg Pathol. 2002 Feb;26(2):225-31. PubMed PMID: 11812944.

59: Adams DJ, Levesque MC, Weinberg JB, Smith KL, Flowers JL, Moore J, Colvin OM, Silber R. Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes. Leukemia. 2001 Dec;15(12):1852-9. PubMed PMID: 11753605.

60: Johnson SA. Nucleoside analogues in the treatment of haematological malignancies. Expert Opin Pharmacother. 2001 Jun;2(6):929-43. Review. PubMed PMID: 11585009.

61: Gandhi V, Plunkett W, Weller S, Du M, Ayres M, Rodriguez CO Jr, Ramakrishna P, Rosner GL, Hodge JP, O'Brien S, Keating MJ. Evaluation of the combination of nelarabine and fludarabine in leukemias: clinical response, pharmacokinetics, and pharmacodynamics in leukemia cells. J Clin Oncol. 2001 Apr 15;19(8):2142-52. PubMed PMID: 11304766.

62: Larson RA. Recent clinical trials in acute lymphocytic leukemia by the Cancer and Leukemia Group B. Hematol Oncol Clin North Am. 2000 Dec;14(6):1367-79, x. Review. PubMed PMID: 11147228.

63: Rodriguez CO Jr, Plunkett W, Paff MT, Du M, Nowak B, Ramakrishna P, Keating MJ, Gandhi V. High-performance liquid chromatography method for the determination and quantitation of arabinosylguanine triphosphate and fludarabine triphosphate in human cells. J Chromatogr B Biomed Sci Appl. 2000 Aug 18;745(2):421-30. PubMed PMID: 11043760.

64: Kalil N, Cheson BD. Management of chronic lymphocytic leukaemia. Drugs Aging. 2000 Jan;16(1):9-27. Review. PubMed PMID: 10733261.

65: Kisor DF, Plunkett W, Kurtzberg J, Mitchell B, Hodge JP, Ernst T, Keating MJ, Gandhi V. Pharmacokinetics of nelarabine and 9-beta-D-arabinofuranosyl guanine in pediatric and adult patients during a phase I study of nelarabine for the treatment of refractory hematologic malignancies. J Clin Oncol. 2000 Mar;18(5):995-1003. PubMed PMID: 10694549.

66: Mahmoudian M, Eaddy J, Dawson M. Enzymic acylation of 506U78 (2-amino-9-beta-D-arabinofuranosyl-6- methoxy-9H-purine), a powerful new anti-leukaemic agent. Biotechnol Appl Biochem. 1999 Jun;29 ( Pt 3):229-33. PubMed PMID: 10334953.

67: Aguayo A, Cortes JE, Kantarjian HM, Beran M, Gandhi V, Plunkett W, Kurtzberg J, Keating MJ. Complete hematologic and cytogenetic response to 2-amino-9-beta-D-arabinosyl-6-methoxy-9H-guanine in a patient with chronic myelogenous leukemia in T-cell blastic phase: a case report and review of the literature. Cancer. 1999 Jan 1;85(1):58-64. Review. PubMed PMID: 9921974.

68: Gandhi V, Plunkett W, Rodriguez CO Jr, Nowak BJ, Du M, Ayres M, Kisor DF, Mitchell BS, Kurtzberg J, Keating MJ. Compound GW506U78 in refractory hematologic malignancies: relationship between cellular pharmacokinetics and clinical response. J Clin Oncol. 1998 Nov;16(11):3607-15. PubMed PMID: 9817282.

69: Ho PT, Cheson BD, Phillips PH. Clinical trials referral resource. Clinical trials using compound 506U78. Oncology (Williston Park). 1996 Dec;10(12):1831-2. PubMed PMID: 9063861.