Fludarabine phosphate in the treatment of chronic lymphocytic leukemia: Biology, clinical impact, and future directions

  • L. E. Robertson
  • Michael J. Keating
Part of the Cancer Treatment and Research book series (CTAR, volume 64)


After the significant antileukemic effect of the pyrimidine nucleoside, 1-β-D- arabinofuranosylcytosine (ara-C), was recognized, efforts were made to identify other clinically active arabinosyl nucleosides. The purine nucleoside analogue, 9-β-D-arabinofurano-syladenine (ara-A), was found to be of little therapeutic value due to its rapid inactivation by adenosine deaminase (ADA) [1]. This metabolic obstacle is overcome, however, by the 2-fluoro derivative of ara-A, 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), which is a relatively poor substrate for ADA [2] (figure 6-1). Because of the aqueous insolubility of the parent compound, F-ara-A, the more soluble 5′- monophosphate formulation, 9-β-D-arabinosylfuranosyl-2-fluoroadenine-5′- monophosphate (fludarabine phosphate, Fludara™ I.V.) has been used in clinical studies.


Chronic Lymphocytic Leukemia Chronic Lymphocytic Leukemia Patient Chronic Lymphocytic Leukemia Cell Deoxycytidine Kinase Untreated Chronic Lymphocytic Leukemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Brink JJ, LePage GA (1964). Metabolic effects of 9-D-arabinosyl purines in ascites tumor cells. Cancer Res 24: 312–318.PubMedGoogle Scholar
  2. 2.
    Montgomery JA, Hewson K (1969). Nucleosides of 2-fluoroadenosine. J Med Chem 12: 498–504.PubMedCrossRefGoogle Scholar
  3. 3.
    Brockman RW, Cheng Y-C, Schable FM Jr, et al. (1980). Metabolism and chemotherapeutic activity of 9-β-arabinofuranosyl-2-fluoroadenine against murine leukemia L1210 and evidence for its phosphorylation by deoxycytidine kinase. Cancer Res 40: 3610–3615.PubMedGoogle Scholar
  4. 4.
    Montgomery JA (1982). Has the well gone dry? The first Cain Memorial Award lecture. Cancer Res 42: 3911–3917.PubMedGoogle Scholar
  5. 5.
    Leiby JM, Snider KM, Kraut EH, et al. (1987). Phase II trial of 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-monophosphate in non-Hodgkin’s lymphoma: Prospective comparison of response with deoxycytidine kinase activity. Cancer Res 47: 2719–2722.PubMedGoogle Scholar
  6. 6.
    Kavanaugh JJ, Stringer CA, Copeland LJ, et al. (1986). Phase II trial of fludarabine in patients with epithelial ovarian cancer. Cancer Treatment Rep 70: 425–428.Google Scholar
  7. 7.
    Warrell RP, Berman E (1986). Phase I and II study of fludarabine phosphate in leukemia: Therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol 4: 74–79.PubMedGoogle Scholar
  8. 8.
    Spriggs DR, Stopa E, Mayer RJ, et al. (1986). Fludarabine phosphate (NSC312878) infusion for the treatment of acute leukemia: Phase I and neuropathological study. Cancer Res 46: 5953–5958.PubMedGoogle Scholar
  9. 9.
    Chun HG, Leyland-Jones B, Caryk SM, et al. (1986). Central nervous system toxicity of fludarabine phosphate. Cancer Treatment Rep 70: 1225–1228.Google Scholar
  10. 10.
    Grever MR, Kraut EH, Neidhart JA, et al. (1984). 2-Fluoro-ara-AMP: A phase I clinical investigation. Invest New Drugs 2: 116 (abstract).Google Scholar
  11. 11.
    Leiby JM, Grever MR, Staubus AE, et al. (1988). Phase I clinical investigation of fludarabine phosphate by a loading-dose and continuous-infusion schedule. J Natl Cancer Inst 80: 447–449.PubMedCrossRefGoogle Scholar
  12. 12.
    Keating MJ, Kantarjian H, Talpaz M, et al. (1989). Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 74: 19–25.PubMedGoogle Scholar
  13. 13.
    Grever MR, Kopecky KJ, Coltman CA, et al. (1988). Fludarabine monophosphate: A potentially useful agent in chronic lymphocytic leukemia. Nouv Rev Fr Hematol 30: 457–459.PubMedGoogle Scholar
  14. 14.
    Puccio CA, Mittelman A, Lichtman SM (1991). A loading dose/continuous infusion schedule of fludarabine phosphate in chronic lymphocytic leukemia. J Clin Oncol 9: 1562–1569.PubMedGoogle Scholar
  15. 15.
    Avramis VI, Plunkett W (1983). Metabolism of 9-β-D-arabinosyl-2-fluoroadenine-5′-phosphate by mice bearing P388 leukemia. Cancer Drug Deliv 1: 1–10.PubMedCrossRefGoogle Scholar
  16. 16.
    Noker PE, Duncan GF, El Dareer SM, et al. (1983). Disposition of 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-phosphate in mice and dogs. Cancer Treatment Rep 67: 445–456.Google Scholar
  17. 17.
    Sirotnak FM, Chello PL, Dorick DM, et al. (1983). Specificity of systems mediating transport of adenosine, 9-β-D-arabinofuranosyl-2-fluoroadenine, and other purine nucleoside analogues in L1210 cells. Cancer Res 43: 104–109.PubMedGoogle Scholar
  18. 18.
    Barrueo JR, Jacobsen DM, Chang CH, et al. (1987). Proposed mechanism of therapeutic selectivity of 9-β-D-arabinofuranosyl-2-fluoroadenine against murine leukemia based upon lower capacities for transport and phosphorylation in proliferating intestinal epithelium compared to tumor cells. Cancer Res 47: 700–706.Google Scholar
  19. 19.
    Danhauser L, Plunkett W, Keating M, et al. (1986). 9-β-D-Arabinofuranosyl-2-fluoro-adenine 5′-monophosphate pharmacokinetics in plasma and tumor cells of patients with relasped leukemia and lymphoma. Cancer Chemother Pharmacol 18: 145–152.PubMedCrossRefGoogle Scholar
  20. 20.
    Kemana A, Keating MJ, Plunkett W (1991). Plasma and cellular bioavailability of oral fludarabine. Blood 77: 199a (abstract).Google Scholar
  21. 21.
    Malspeis L, DeSouza JJV, Staubus AE, et al. (1984). Pharmacokinetics of 2-F-ara-AMP in man during a phase I clinical trial. Invest New Drugs 2: 116 (abstract).Google Scholar
  22. 22.
    Dow LW, Bell DE, Poulakos L, et al. (1980). Differences in metabolism and cytotoxicity between 9-β-D-arabinofuranosyl-adenine and l-β-D-arabinofuranosyl-2-fluoradenine in human leukemic lymphoblasts. Cancer Res 40: 1405–1410.PubMedGoogle Scholar
  23. 23.
    Brockman RW, Cheng Y-C, Schabel FM Jr, et al. (1980). Metabolism and chemotherapeutic activity of 9-β-D-arabinofuranosyl-2-fluoroadenine against murine leukemia L1210 and evidence for its phosphorylation by deoxycytidine kinase. Cancer Res 40: 3610–3615.PubMedGoogle Scholar
  24. 24.
    Lilliemark JO, Plunkett W (1986). Regulation of 1-β-D-arabinofurano-sylcytosine 5′-triphosphate accumulation in human leukemia cells by deoxycytidine 5′-triphosphate. Cancer Res 46: 1079–1083.Google Scholar
  25. 25.
    Avramis VI, Plunkett W (1983). 2-Fluoro-ATP: a toxic metabolite of 9-β-D-arabinofuranosyl-2-fluoroadenine. Biochem Biophys Res Commun 113: 35–43.PubMedCrossRefGoogle Scholar
  26. 26.
    Plunkett W, Chubb S, Alexander L, et al. (1980). Comparison of the toxicity and metabolism of 9-β-D-arabinofuranosyl-2-fluoroadenine and 9-β-D-arabinofuranosyladenine in human lymphoblastoid cells. Cancer Res 40: 2349–2355.PubMedGoogle Scholar
  27. 27.
    Huang P, Plunkett W (1991). Action of 9-β-D-arabinosyl-2-fluoroadenine on RNA metabolism. Mol Pharmacol 39: 449–455.PubMedGoogle Scholar
  28. 28.
    Tseng W-C, Derse D, Cheng Y-C, et al. (1982). In vitro biological activity of 9-β-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. Mol Pharmacol 21: 474–477.PubMedGoogle Scholar
  29. 29.
    White EL, Shaddix DSC, Brockman RW, et al. (1982). Comparison of the actions of 9-β-D-arabinofuranosyl-2-fluoroadenine and 9-β-D-arabinofuranosyladenine on target enzymes from mouse tumor cells. Cancer Res 42: 2260–2264.PubMedGoogle Scholar
  30. 30.
    Catopano CV, Chandler KB, Fernandes DJ (1991). Inhibition of primer RNA formation in CCRF-CEM leukemia cells by fludarabine triphosphate. Cancer Res 51: 1829–1835.Google Scholar
  31. 31.
    Yang S-W, Huang P, Plunkett W, Becker FF, Chan JYH (1992). Dual mode of inhibition of purified DNA ligase I from human cells by 9-β-D-arabinofuranosyl-2-fluoroadenine triphosphate. J Biol Chem 267: 2345–2349.PubMedGoogle Scholar
  32. 32.
    Chang C-H, Cheng Y-C (1980). Effects of deoxyadenosine triphosphate and 9-β-D-arabinofuranosyladenine-5′-triphosphate on human ribonculeotide reductase from Molt-4F cells and the concept of’ self-potentiation.’ Cancer Res 40: 3555–3558.Google Scholar
  33. 33.
    Sato A, Montgomery JA, Cory JG (1984). Synergistic inhibition of leukemia L1210 cell growth in vitro by combinations of 2-fluoroadenine and hydroxyurea or 2,3-dihydro-lH-pyrazole[2,3-a]imidazole. Cancer Res 44: 3286–3290.PubMedGoogle Scholar
  34. 34.
    Huang P, Chubb S, Plunkett W (1990). Termination of DNA synthesis by 9-β-D-arabinofuranosyl-2-fluoroadenine. J Biol Chem 27: 16617–16625.Google Scholar
  35. 35.
    Johnstone AP, Williams GT (1982). Role of DNA breaks and ADP-ribosyl transferase activity in eukaryotic diffentiatial demonstrated in human lymphocytes. Nature 300: 368–370.PubMedCrossRefGoogle Scholar
  36. 36.
    Greer WL, Kaplan JG (1983). DNA strand breaks in murine lymphocytes: Induction by purine and pyrimidine analogues. Biochem Biophys Res Commun 115: 834–840.PubMedCrossRefGoogle Scholar
  37. 37.
    Seto S, Carrera CJ, Kubota M, Wasson DB, Carson DA (1985). Mechanisms of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing lymphocytes. J Clin Invest 75: 377–381.PubMedCrossRefGoogle Scholar
  38. 38.
    Carson DA, Seto S, Wasson B, et al. (1986). DNA strand breaks, NAD metabolism, and programmed cell death. Exp Cell Res 164: 273–281.PubMedCrossRefGoogle Scholar
  39. 39.
    Nieman PE, Thomas SJ, Long G (1991). Induction of apoptosis during normal and neoplastic B-cell development in the bursa of fabricius. Proc Natl Acad Sci USA 88: 5857–5861.CrossRefGoogle Scholar
  40. 40.
    McConkey DJ, Hortzell P, Amador-Perez JF, et al. (1989). Calcium-dependent killing of immature thymocytes by stimulation via the CD3/T-cell receptor complex. J Immunol 143: 1801–1806.PubMedGoogle Scholar
  41. 41.
    Collins RJ, Vershuer LA, Hormon BV, et al. (1989). Spontaneous programmed death (apoptosis) of B-chronic lymphocytic leukemia cells following culture in vitro. Br J Haematol 71: 343–350.PubMedCrossRefGoogle Scholar
  42. 42.
    McConkey DJ, Aguilar-Santelises M, Hartzell P, et al. (1991). Induction of DNA fragmentation in chronic B-lymphocytic leukemia cells. J Immunol 146: 1272–1276.Google Scholar
  43. 43.
    Wyllie AH (1980). Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 555–556.Google Scholar
  44. 44.
    Robertson LE, Chubb S, Hittelman W, et al. (1991). Programmed death (apoptosis) in chronic lymphocytic leukemia after chlorodeoxyadenosine and fludarabine. Blood 77: 173a (abstract).Google Scholar
  45. 45.
    Carrera CJ, Terai C, Piro L, Saven A, Beutler E, Carson D (1991). 2-CDA chemotherapy triggers programmed cell death in normal and malignant lymphocytes. Int J Purine Res (Suppl) 2: 38.Google Scholar
  46. 46.
    Robertson LE, Chubb S, Meyn RE, Spry M, Ford R, Hittleman WN, Plunkett W (1993). Induction of apoptotic cell death in chronic lymphocytic leukemia by 2-chloro-21-desxyaderosine and 9-β-D-arabinosyl-2-fluoroadenine. Blood 81.Google Scholar
  47. 47.
    Keating MJ, Scouros M, Murphy S, et al. (1988). Multiple-agent chemotherapy (POACH) in previously treated and untreated patients with chronic lymphocytic leukemia. Leukemia 2: 157–164.PubMedGoogle Scholar
  48. 48.
    Keating MJ, Kantarjian H, O’Brien S, et al. (1991). Fludarabine: A new agent with marked cytoreduction activity in chronic lymphocytic leukemia. J Clin Oncol 9: 44–49.PubMedGoogle Scholar
  49. 49.
    Cheson BD, Bennett JM, Rai KR, et al. (1988). Guidelines for clinical protocols for chronic lymphocytic leukemia (CLL): Recommendations of the NCI-sponsored working group. Am J Hematol 29: 152–163.PubMedCrossRefGoogle Scholar
  50. 50.
    Keating MJ, Hester JP, McCredie KB, et al. (1990). Long-term results of CAP therapy in chronic lymphocytic leukemia. Leuk Lymphoma 2: 391–397.CrossRefGoogle Scholar
  51. 51.
    Han T, Ezdinli EZ, Shimaoka K, et al. (1973). Chlorambucil vs. combined chlorambucil-corticosteroid therapy in chronic lymphocytic leukemia. Cancer 31: 502–508.Google Scholar
  52. 52.
    Sawitsky A, Rai KR, Glidewell O, et al. (1977). Comparison of daily versus intermittant chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia. Blood 50: 1049–1059.PubMedGoogle Scholar
  53. 53.
    Anaissie E, Kontoyiannis DP, Kantarjian H, Elting L, Robertson LE, Keating M (1992). Listeriosis in patients with chronic lymphocytic leukemia treated with fludarabine and prednisone. Ann Intern Med 117: 466–469.PubMedGoogle Scholar
  54. 54.
    Keating MJ (1990). Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Semin Oncol 17(5) (Suppl 8):49.PubMedGoogle Scholar
  55. 55.
    Plunkett W, Adams T, Keating MJ (1986). Pharmacologic basis for the therapeutic index of high-dose ara-C: Implications for combinations. Proc Am Assoc Cancer Res 27: 174 (abstract).Google Scholar
  56. 56.
    Gandhi V, Nowak B, Keating MJ, et al. (1989). Modulation of arabinosyl-cytosine metabolism by arabinosyl-2-fluoroadenine in lymphocytes from patients with chronic lymphocytic leukemia: Implications for combination therapy. Blood 74: 2070–2075.PubMedGoogle Scholar
  57. 57.
    International Workshop on Chronic Lymphocytic Leukemia (1989). Chronic lymphocytic leukemia: Recommendations for diagnosis, staging, and response criteria. Ann Intern Med 110: 236–238.Google Scholar
  58. 58.
    Robertson LE, Huh YO, Butler JJ, Pugh WC, Hirsch-Ginsberg C, Stass S, kantarjian H, Keating MJ (1992). Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, immunophenotypic, and molecular analysis. Blood 80: 29–36.PubMedGoogle Scholar
  59. 59.
    Robertson L, Huh Y, Hirsch-Ginsberg C, et al. (1990). Clinical, immunophenotypic, and molecular analysis of the completeness of response in chronic lymphocytic leukemia after fludarabine. Blood 76: 314a.Google Scholar
  60. 60.
    Pangalis GA, Griva E (1988). Recombinant alfa-2b-interferon therapy in untreated, stages A and B chronic lymphocytic leukemia. A preliminary report. Cancer 61: 869–872.PubMedCrossRefGoogle Scholar
  61. 61.
    Rozman C, Montserrat E, Vinolas N, et al. (1988). Recombinant alpha 2-interferon in the treatment of B chronic lymphocytic leukemia in early stages. Blood 71: 1295–1298.PubMedGoogle Scholar
  62. 62.
    Ziegler-Heitbrock HW, Schlag R, Flieger D, Thiel E (1989). Favorable response of early stage B CLL patients to treatment with IFN-alpha 2. Blood 73: 1426–1430.PubMedGoogle Scholar
  63. 63.
    Vadhan-Raj S, Velasquez WS, Butler JJ, et al. (1990). Stimulation of myelopoiesis in chronic lymphocytic leukemia and in other lymphoproliferative disorders by recombinant human granulocyte-macrophage colony-stimulating factor. Am J Hematol 33: 189–197.PubMedCrossRefGoogle Scholar
  64. 64.
    Elias L, Stock-Novack L, Grever M, et al. (1991). A phase I trial of combination fludarabine plus chlorambucil in chronic lymphocytic leukemia. Proc Am Soc Clin Oncol 10: 221 (abstract).Google Scholar
  65. 65.
    The French Cooperative Group on Chronic Lymphocytic Leukemia (1989). Long-term results of the CHOP regimen in Stage C chronic lymphocytic leukemia. Br J Haematol 73: 334–340.CrossRefGoogle Scholar
  66. 66.
    Gregoire V, Hunter N, Milas L, Brock WA, Plunkett WK, Hittelman WN (1992). Enhancement of radiation response by fludarabine in murine tumor models. Proc Am Assoc Cancer Res 33: 512 (abstract).Google Scholar
  67. 67.
    Yang LY, Trujillo JM, Keating MJ, Plunkett W (1992). Effect of fludarabine on the tumoricidal synergy produced by the combination of arabinosylcytosine and cisplatin in human LoVo colon carcinoma cells. Proc Am Assoc Cancer Res 33: 443 (abstract).Google Scholar
  68. 68.
    Gandhi V, Plunkett W (1988). Modulation of arabinosylnucleoside metabolism by arabinosylnucleotides in human leukemia cells. Cancer Res 48: 3290–3294.Google Scholar
  69. 69.
    Gandhi V, Kemena A, Keating MJ, et al. (1992). Fludarabine infusion potentiates arabinosyl-cytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia. Cancer Res 52: 897–903.PubMedGoogle Scholar
  70. 70.
    Bandini G, Michallet M, Rosit G, et al. (1991). Bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplant 7: 251–253.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • L. E. Robertson
  • Michael J. Keating

There are no affiliations available

Personalised recommendations