Seminars in Oncology
Volume 34 , Pages S13-S20 , December 2007

Three New Drugs for Acute Lymphoblastic Leukemia: Nelarabine, Clofarabine, and Forodesine

  • Richard A. Larson

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Richard A. Larson, MD, Section of Hematology/Oncology, The University of Chicago, 5841 S Maryland Ave, MC-2115, Chicago, IL 60637.
    • Dr Larson has served as a consultant to GlaxoSmithKline and BioCryst Pharmaceuticals.

References 

  1. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354:166–178
  2. Goekbuget N, Arnold R, Buechner T, et al. Intensification of induction and consolidation improves only subgroups of adult ALL: Analysis of 1200 patients in the GMALL study 05/93. Blood. 2001;98(suppl 1):802a;(abstr 3338)
  3. Lambe CU, Averett DR, Paff MT, et al. 2-amino-6-methoxypurine arabinoside: An agent for T-cell malignancies. Cancer Res. 1995;55:3352–3356
  4. Rodriguez CO, Mitchell BS, Ayres M, et al. Arabinosylguanine is phosphorylated by both cytoplasmic deoxycytidine kinase and mitochondrial deoxyguanosine kinase. Cancer Res. 2002;62:3100–3105
  5. Verhoef V, Frinland A. Metabolic basis of arabinonucleoside selectivity for human leukemic T- and B-lymphoblasts. Cancer Res. 1985;45:3646–3650
  6. Rodriguez CO, Stellrecht CM, Gandhi V. Mechanisms for T-cell selective cytotoxicity of arabinosylguanine. Blood. 2003;102:1842–1848
  7. Kurtzberg J, Ernst TJ, Keating MJ, et al. Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol. 2005;23:3396–3403
  8. Gandhi V, Plunkett W, Rodriguez CO, et al. Compound GW506U78 in refractory hematologic malignancies: Relationship between cellular pharmacokinetics and clinical response. J Clin Oncol. 1998;16:3607–3615
  9. Kisor DF, Plunkett W, Kurtzberg J, et al. 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;18:995–1003
  10. Gandhi V, Plunkett W, Weller S, et al. Evaluation of the combination of nelarabine and fludarabine in leukemias: Clinical response, pharmacokinetics, and pharmacodynamics in leukemic cells. J Clin Oncol. 2001;19:2142–2152
  11. Kisor DF. Nelarabine: A nucleoside analogue with efficacy in T-cell and other leukemias. Ann Pharmacother. 2005;39:1056–1062
  12. Cohen MH, Johnson JR, Massie T, et al. Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma. Clin Cancer Res. 2006;12:5329–5335
  13. 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;23:3376–3382
  14. DeAngelo D, Yu D, Johnson JL, et al. 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;109:5136–5142
  15. Goekbuget N, Arnold R, Atta J, et al. Compound GW506U78 has high single-drug activity and good feasibility in heavily pretreated relapsed T-lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LBL) and offers the option for cure with stem cell transplantation (SCT). Blood. 2005;106(suppl 1):47a;(abstr 150)
  16. Kline J, Larson RA. Nelarabine in the treatment of refractory T-cell malignant diseases. Expert Opin Pharmacother. 2006;7:1791–1799
  17. Jeha S, Kantarjian H. Clofarabine for the treatment of acute lymphoblastic leukemia. Expert Rev Anticancer Ther. 2007;7:113–118
  18. Kline JP, Larson RA. Clofarabine in the treatment of acute myeloid leukemia and acute lymphoblastic leukemia: A review. Expert Opin Pharmacother. 2005;6:2711–2718
  19. Carson DA, Wasson DB, Esparza LM, et al. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2’-arabino-fluoro-2’-deoxyadenosine. Proc Natl Acad Sci U S A. 1992;89:2970–2974
  20. Xie KC, Plunkett W. Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine. Cancer Res. 1995;56:3030–3037
  21. Genini D, Adachi S, Chao Q, et al. Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood. 2000;96:3537–3543
  22. Gandhi V, Kantarjian H, Faderl S, et al. Pharmacokinetics and pharmacodynamics of plasma clofarabine and cellular clofarabine triphosphate in patients with acute leukemias. Clin Cancer Res. 2003;9:6335–6342
  23. Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol. 2003;21:1167–1173
  24. Bonate PL, Craig A, Gaynon P, et al. Population pharmacokinetics of clofarabine, a second generation nucleoside analog, in pediatric patients with acute leukemia. J Clin Pharm. 2004;44:1309–1322
  25. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102:2379–2386
  26. Burnett AK, Russell N, Kell JW, et al. A phase 2 evaluation of single agent clofarabine as first line treatment for older patients with AML who are not considered fit for intensive chemotherapy. Blood. 2004;104(suppl 1):248a;(abstr 869)
  27. Jeha S, Gandhi V, Chan KW, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004;103:784–789
  28. Jeha S, Razzouk BI, Rytting ME, et al. Phase II trials of clofarabine in relapsed or refractory pediatric leukemia. Blood. 2004;104(suppl 1):196a;(abstr 684)
  29. Jeha S, Gaynon PS, Razzouk B, et al. Phase II study of clofarabine in pediatric patients with relapsed or refractory acute lymphoblastic leukemia. J Clin Oncol. 2006;24:1917–1923
  30. Faderl S, Gandhi V, Keating M, et al. The role of clofarabine in hematologic and solid malignancies—Development of a next-generation nucleoside analog. Cancer. 2005;103:1985–1995
  31. Faderl S, Gandhi V, O’Brien S, et al. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005;105:940–947
  32. Faderl S, Verstovsek S, Cortes C, et al. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older. Blood. 2006;108:45–51
  33. Ravandi F, Gandhi V. Novel purine nucleoside analogues for T-cell lineage acute lymphoblastic leukaemia and lymphoma. Expert Opin Invest Drugs. 2006;15:1601–1613
  34. Galmarini CM. Drug evaluations: Forodesine—PNP inhibitor for the treatment of leukemia, lymphoma, and solid tumor. IDrugs. 2006;9:712–722
  35. Gandhi V, Kilpatrick JM, Plunkett W, et al. A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine). Blood. 2005;106:4253–4260
  36. Bantia S, Anath SL, Parker CD, et al. Mechanism of inhibition of T-acute lymphoblastic leukemia by PNP inhibitor—BCX-1777. Int Immunopharmacol. 2003;3:879–887
  37. Furman RR, Gandhi V, Bennett JC, et al. Intravenous forodesine (BCX-1777), a novel purine nucleoside phosphorylase (PNP) inhibitor, demonstrates clinical activity in phase I/II studies in patients with B-cell acute lymphoblastic leukemia. Blood. 2004;104(suppl 1):750a;(abstr 2743)
  38. Ritchie E, Gore L, Roboz GJ, et al. Phase II study of forodesine, a PNP inhibitor, in patients with relapsed or refractory B-lineage acute lymphoblastic leukemia. Blood. 2006;108(suppl 1):533a;(abstr 1881)
  39. Isola L, Furman RR, Gandhi V, et al. Antileukemic activity and pharmacodynamics of intravenous forodesine (BXC-1777), a novel purine nucleoside phosphorylase (PNP) inhibitor, in phase I/II trials in patients with advanced T-cell malignancies. Blood. 2004;104(suppl 1):208b;(abstr 4501)
  40. Furman RR, Gore L, Ravandi F, et al. Forodesine IV (BXC-1777) is clinically active in relapsed/refractory T-cell leukemia: Results of a phase IIA study. Blood. 2006;108(suppl 1):524a;(abstr 1851)
  41. Duvic M, Forero-Torres A, Foss F, et al. Oral forodesine (BXC-1777) is clinically active in refractory cutaneous T-cell lymphoma: Results of a phase I/II study. Blood. 2006;108(suppl 1):698a;(abstr 2467)

PII: S0093-7754(07)00220-5

doi: 10.1053/j.seminoncol.2007.11.002

Seminars in Oncology
Volume 34 , Pages S13-S20 , December 2007

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