Mechanisms of Action, Pharmacology, and Clinical Investigations
  • Varsha Gandhi
  • William Plunkett
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Clofarabine is a new dAdo analog that shows effectiveness in both adult and pediatric ALL and AML. The pharmacokinetic and pharmacodynamic profile of the drug in acute leukemias is favorable relative to fludarabine or cladribine and may have prognostic value for its clinical activity. The toxicity profile of this agent is different from other nucleoside analogs in that it clearly has clinical activity when used as a single agent against adult acute leukemias at tolerable doses. Further, therapeutic strategies combining clofarabine with DNA-damaging agents are likely to allow mechanismbased rationales to be evaluated with minimal likelihood of untoward toxicity. Exploration of additional schedules and combinations along with availability of an oral formulation strongly indicate promising possibilities with this agent.

Key Words

Acute leukemias cellular pharmacology cladribine clofarabine DNA polymerase DNA repair fludarabine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Schiffer CA. Acute myeloid leukemia in adults: where do we go from here? Cancer Chemother Pharmacol 2001;48(suppl 1):S45–S52.PubMedCrossRefGoogle Scholar
  2. 2.
    Plunkett W, Gandhi V. Purine and pyrimidine nucleoside analogs. In: Giaccone G, Schilsky R, Sondel P, eds. Cancer Chemotherapy and Biological Response Modifiers. Annual 19. Amsterdam: Elsevier Science; 2001:21–45.Google Scholar
  3. 3.
    Gandhi V, Plunkett W, Du M, Ayres M, Estey E. Prolonged infusion of gem-citabine: clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia. J Clin Oncol 2002;20:665–673.PubMedCrossRefGoogle Scholar
  4. 4.
    Wijermans P, Lübbert M, Verhoef G, et al. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syn drome: a multicenter phase II study in elderly patients. J Clin Oncol 2000;18:956–962.PubMedGoogle Scholar
  5. 5.
    Rizzeri DA, Bass AJ, Rosner GL, et al. Phase I evaluation of prolonged-infusion gemcitabine with mitoxantrone for relapsed or refractory acute leukemia. J Clin Oncol 2002;20:674–679.CrossRefGoogle Scholar
  6. 6.
    Silverman LR, Demakos EP, Bercedis L, et al. A randomized controlled trial of azacytidine in patients with myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol 2002;20:2429–2440.PubMedCrossRefGoogle Scholar
  7. 7.
    Giles F, Faderl S, Thomas D, et al. Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias. J Clin Oncol 2003;21:1050–1056.PubMedCrossRefGoogle Scholar
  8. 8.
    Krance RA, Hurwitz CA, Head DR, et al. Experience with 2-chlorodeoxyadeno-sine in previously untreated children with newly diagnosed acute myeloid leukemia and myelodysplastic diseases. J Clin Oncol 2001;19:2804–2811.PubMedGoogle Scholar
  9. 9.
    Rubnitz JE, Razzouk BI, Srivastava DK, Pui CH, Ribeiro RC, Santana VM. Phase II trial of cladribine and cytarabine in relapsed or refractory myeloid malignancies. Leuk Res 2004;28:349–352.PubMedCrossRefGoogle Scholar
  10. 10.
    Crews KR, Gandhi V, Srivastava DK, et al. An interim analysis of a continuous infusion vs a short daily infusion of cytarabine given in combination with cladribine for pediatric acute myeloid leukemia. J Clin Oncol 2002;20:4217–4224.PubMedCrossRefGoogle Scholar
  11. 11.
    Kornblau SM, Gandhi V, Andreeff HM, et al. Clinical and laboratory studies of 2-chlorodeoxyadenosine ± cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults. Leukemia 1996; 10:1563–1569.PubMedGoogle Scholar
  12. 12.
    Avramis VI, Wiersma S, Krailo MD, et al. Pharmacokinetic and pharmaco-dynamic studies of fludarabine and cytosine arabinoside administered as loading boluses followed by continuous infusions after a phase I/II study in pediatric patients with relapsed leukemias. The Children′s Cancer Group. Clin Cancer Res1998;4:45–52.PubMedGoogle Scholar
  13. 13.
    Marcucci G, Byrd JC, Dai G, et al. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood 2003; 101:425–432.PubMedCrossRefGoogle Scholar
  14. 14.
    Jehn U, Bartl R, Dietzfelbinger H, Haferlach T, Heinemann V. An update: 12-yr follow-up of patients with hairy cell leukemia following treatment with 2-chlorodeoxyadenosine. Leukemia 2004;18:1476–1481.PubMedCrossRefGoogle Scholar
  15. 15.
    Dimopoulos MA, Kantarjian H, Weber D, et al. Primary therapy of Waldenstrom′s macroglobulinemia with 2-chlorodeoxyadenosine. J Clin Oncol 1994; 12:2694–2698.PubMedGoogle Scholar
  16. 16.
    Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chloram-bucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000; 343:1750–1757.PubMedCrossRefGoogle Scholar
  17. 17.
    Tsimberidou AM, McLaughlin P, Younes A, et al. Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regi men in patients with stage IV indolent lymphoma. Blood 2002;100:4351–4357.PubMedCrossRefGoogle Scholar
  18. 18.
    Montgomery JA, Shortnacy-Fowler AT, Clayton SD, Riordan JM, Secrist JA III. Synthesis and biologic activity of 2′-fluoro-2-halo derivatives of 9-β-D-arabino-furanosyladenine. J Med Chem 1992;35:397–401.PubMedCrossRefGoogle Scholar
  19. 19.
    Parker WB, Shaddix SC, Chang CH, et al. Effects of 2-chloro-9-(2-deoxy-2-flu-oro-β-D-arabinofuranosyl) adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5′-trisphosphate. Cancer Res 1991;51:2386–2394.PubMedGoogle Scholar
  20. 20.
    Carson DA, Wasson DB, Esparza LM, Carrera CJ, Kipps TJ, Cottam HB. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2′-arabino-flu-oro-2′deoxyadenosine. Proc Natl Acad Sci USA 1992;89:2970–2974.PubMedCrossRefGoogle Scholar
  21. 21.
    Parker WB, Allan PW, Hassan AE, Secrist JA 3rd, Sorscher EJ, Waud WR. Antitumor activity of 2-fluoro-2′-deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase. Cancer Gene Ther 2003; 10:23–29.PubMedCrossRefGoogle Scholar
  22. 22.
    Parker WB, Shaddix SC, Rose LM, et al. Comparison of the mechanism of cytotoxicity of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine, 2-chloro-9-(2-deoxy-2-fluoro-β-D-ribofuranosyl)adenine, 2-chloro-9-(2-deoxy-2,2-difluoro-β-D-ribofuranosyl) adenine in CEM cells. Mol Pharmacol 1999;55:515–520.PubMedGoogle Scholar
  23. 23.
    Parker WB, Bapat AR, Shen JX, Townsend AJ, Cheng YC. Interaction of 2-halo-genated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase. Mol Pharmacol 1988;34:485–491.PubMedGoogle Scholar
  24. 24.
    Xie C, Plunkett W. Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine in human lymphoblastoid cells. Cancer Res 1995;55:2847–2852.PubMedGoogle Scholar
  25. 25.
    Xie KC, Plunkett W. Deoxynucleotide pool deletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblas toid cells with 2-chloro-(2-deoxy-fluoro-β-D-arabinofuranosyl)adenine. Cancer Res 1996;56:3030–3037.PubMedGoogle Scholar
  26. 26.
    Albertioni F, Hassan M, Silbering J, Liliemark J. Kinetics and metabolism of 2-chloro-2′-deoxyadenosine and 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine in the isolated perfused rat liver. Euro J Drug Metab Pharmcokinet 1995;20:225–232.CrossRefGoogle Scholar
  27. 27.
    Huang P, Plunkett W. Phosphorolytic cleavage of 2-fluoroadenine from 9-β-D-arabinofuranosyl-2-fluoroadenine by Escherichia coli. Biochem Pharmacol 1987;36:2945–2950.PubMedCrossRefGoogle Scholar
  28. 28.
    Sjoberg AH, Wang L, Eriksson S. Substrate specificity of human recombinant mitochondrial deoxyguanosine kinase with cytostatic and antiviral purine and pyrimidine analogs. Mol Pharmacol 1998;53:270–273.PubMedGoogle Scholar
  29. 29.
    Lotfi K, Mansson E, Spasokoukotskaja T, et al. Biochemical pharmacology and resistance to 2-chloro-2′-arabinofluoro-2′-deoxyadenosine, a novel analogue of cladribine in human leukemic cells. Clin Cancer Res 1999;5:2438–2444.PubMedGoogle Scholar
  30. 30.
    Gandhi V, Robertson LE, Plunkett W. 2-Chloro-2′-fluoro-arabinosyladenine: pharmacokinetics and action in chronic lymphocytic leukemia cells. Proc Am Assoc Clin Oncol 1993;34:414.Google Scholar
  31. 31.
    Lindemalm S, Liliemark J, Gruber A, et al. Comparison of cytotoxicity of 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine (clofarabine) with cladribine in mononuclear cells from patients with acute myeloid and chronic lymphocytic leukemia. Haematologica 2003;88:324–332.PubMedGoogle Scholar
  32. 32.
    Huang, P, Chubb S, Plunkett W. Termination of DNA synthesis by 9-β-D-arabi-nofuranosyl-2-fluoroadenine: a mechanism for cytotoxicity. J Biol Chem 1990; 265:16,617–16,625.PubMedGoogle Scholar
  33. 33.
    Huang P, Plunkett W. Action of 9-β-D-arabinofuranosyl-2-fluoroadenine on RNA metabolism. Mol Pharmacol 1991;39:449–455.PubMedGoogle Scholar
  34. 34.
    Chang CH, Cheng YC. Effects of deoxyadenosine triphosphate and 9-beta-D-arabi-nofuranosyl-adenine 5′-triphosphate on human ribonucleotide reductase from Molt-4F cells and the concept of “self-potentiation”. Cancer Res. 1980;40:3555–3558.PubMedGoogle Scholar
  35. 35.
    Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu Rev Biochem 2004; 73:87–106.PubMedCrossRefGoogle Scholar
  36. 36.
    Leoni LM, Chao Q, Cottam HB, et al. Induction of an apoptotic program in cell-free extracts by 2-chloro-2′-deoxyadenosine 5′-triphosphate and cytochrome c. Proc Natl Acad Sci USA1998;95:9567–9571.PubMedCrossRefGoogle Scholar
  37. 37.
    Genini D, Budihardjo I, Plunkett W, et al. Nucleotide requirements for the in vitro activation of the apoptosis protein-activating factor-1-mediated caspase pathway. J Biol Chem 2000;275:29–34.PubMedCrossRefGoogle Scholar
  38. 38.
    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. Blood2000;96:3537–3543.PubMedGoogle Scholar
  39. 39.
    Takahashi T, Shimizu M, Akinaga S. Mechanisms of the apoptotic activity of Cl-F-araA in a human T-ALL cell line, CCRF-CEM. Cancer Chemother Pharmacol 2002;50:193–201.PubMedCrossRefGoogle Scholar
  40. 40.
    Waud WR, Schmid SM, Harrison SD Jr, Secrist JA III, Montgomery JA. Preclinical antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine. (Cl-F-ara-A). Nucleosides Nucleotides Nucleic Acids 2000;19:447–460.PubMedCrossRefGoogle Scholar
  41. 41.
    Takahashi T, Kanazawa J, Akinaga S, Tamaoki T, Okabe M. Antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine, a novel deoxyadeno-sine analog, against human colon tumor xenografts by oral administration. Cancer Chemother Pharmacol 1999;43:23 3–240.CrossRefGoogle Scholar
  42. 42.
    Qian M, Wang X, Shanmuganathan K, Chu CK, Gallo JM. Pharmacokinetics of the anticancer agent 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine in rats. Cancer Chemother Pharmacol 1994;33:484–488.PubMedGoogle Scholar
  43. 43.
    Kantarjian H, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine (chloro-2′-fluoro-deoxy-9-beta-D-arabinofuranosyladenine) in patients with solid and hematologic cancers. J Clin Oncol 2003;21:1167–1173.PubMedCrossRefGoogle Scholar
  44. 44.
    Chiao N, Bumgardner A, Duvic M. Clofarabine-induced acral erythema during the treatment of patients with myelodysplasia and acute leukemia: report of two cases. Leuk Lymphoma 2003;44:1405–1407.PubMedCrossRefGoogle Scholar
  45. 45.
    Gandhi V, Kantarjian H, Faderl S, et al. Pharmacokinetics and pharmacodynam-ics of plasma clofarabine and cellular clofarabine triphosphate in patients with acute leukemias. Clin Cancer Res 2003;9:6335–6342.PubMedGoogle Scholar
  46. 46.
    Kantarjian HM, Estey E, Plunkett W, et al. Phase I-II and cellular pharmacology study of high dose cytosine arabinoside in refractory leukemia. Am J Med1986;81:387–394.PubMedCrossRefGoogle Scholar
  47. 47.
    Gandhi V, Plunkett W, Du M, Ayres M, Estey EH. Prolonged infusion of gemc-itabine: clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia. J Clin Oncol 2002;20:665–673.PubMedCrossRefGoogle Scholar
  48. 48.
    Kantarjian H, Gandhi V, Cortes J, et al. Phase II clinical and pharmacology study of clofarabine inpatients with refractory or relapsed acute leukemias. Blood 2003;102:2379–2386.PubMedCrossRefGoogle Scholar
  49. 49.
    Gandhi V, Plunkett W, Weller S, et al. Evaluation of the combination of nelarabine and fludarabine in leukemias: clinical response, pharmacokinetics and pharmaco-dynamics in leukemia cells. J Clin Oncol 2001;19:2142–2152.PubMedGoogle Scholar
  50. 50.
    Gandhi V, Kemena A, Keating MJ, Plunkett W. Cellular pharmacology of flu darabine triphosphate in chronic lymphocytic leukemia cells during fludarabine therapy. Leukemia Lymphoma 1993;10:49–56.PubMedCrossRefGoogle Scholar
  51. 51.
    Albertioni F, Lindemalm S, Reichelova V, et al. Pharmacokinetics of cladribine in plasma and its 5′-monophosphate and 5′-triphosphate in leukemic cells of patients with chronic lymphocytic leukemia. Clin Cancer Res 1998;4:653–658.PubMedGoogle Scholar
  52. 52.
    Gandhi V, Estey E, Keating MJ, Plunkett W. Fludarabine potentiates metabolism of arabinosylcytosine in patients with acute myelogenous leukemia during ther apy. J Clin Oncol 1993;11:116–124.PubMedGoogle Scholar
  53. 53.
    Kemena A, Gandhi V, Shewach D, Keating MJ, Plunkett W. Inhibition of fludara bine metabolism by arabinosylcytosine during therapy. Cancer Chemother Pharmacol 1992;31:193–199.PubMedCrossRefGoogle Scholar
  54. 54.
    Gandhi V, Estey E, Keating MJ, Chucrallah A, Plunkett W. Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: Pharmaco-kinetic, pharmacodynamic, and molecular interactions. Blood 1996;87:156–164.Google Scholar
  55. 55.
    Cunningham CC, Nemunaitis J, Senzer N, et al. A phase I dose-finding and safety study of clofarabine in patients with advanced solid malignancies. Proc Am Soc Clin Oncol 2003;22:151;. Abstract 605.Google Scholar
  56. 56.
    Spasokoukotskaja T, Sasvari-Szekely M, Hullan L, Albertioni F, Eriksson S, Staub M. Activation of deoxycytidine kinase by various nucleoside analogues. Adv Exp Med Biol 1998;431:641–645.PubMedGoogle Scholar
  57. 57.
    Cooper T, Ayres M, Nowak B, Gandhi V. Biochemical modulation of cytarabine triphosphate by clofarabine. Cancer Chemother Pharmacol 2005;55:361–368.PubMedCrossRefGoogle Scholar
  58. 58.
    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.PubMedCrossRefGoogle Scholar
  59. 59.
    Yamauchi T, Nowak B, Keating MJ, Plunkett W. DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhi bited by fludarabine and clofarabine. Clin Cancer Res 2001;7:3580–3589.PubMedGoogle Scholar
  60. 60.
    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.PubMedCrossRefGoogle Scholar
  61. 61.
    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 Pharmacol 2004;44:1309–1322.PubMedCrossRefGoogle Scholar
  62. 62.
    Jeha S, Razzouk B, Gaynon P, et al. Clofarabine therapy for the treatment of relapsed or refractory pediatric acute leukemias. Proc Am Soc Clin Oncol 2004; 22:796.Google Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Varsha Gandhi
    • 1
  • William Plunkett
    • 1
  1. 1.Department of Experimental TherapeuticsThe University of Texas, M. D., Anderson Cancer CenterHoustonUSA

Personalised recommendations