Seminars in Hematology
Volume 41, Issue 3 , Pages 224-233 , July 2004

Advances in chemotherapy for chronic lymphocytic leukemia

  • C.-M Wendtner

      Affiliations

    • Medical Clinic I, University of Cologne, Cologne, Germany
  • ,
  • B.F Eichhorst

      Affiliations

    • Medical Clinic III, University of Munich, Munich, Germany
  • ,
  • M.J Hallek

      Affiliations

    • Medical Clinic I, University of Cologne, Cologne, Germany
    • Corresponding Author InformationAddress correspondence to M.J. Hallek, MD, Klinik I für Innere Medizin, Klinikum der Universität zu Köln, Joseph-Stelzmann-Strasse 9, Haus 16, D-50924 Köln, Germany

References 

  1. Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, et al.  Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia (Long-term follow-up of an Eastern Cooperative Oncology Group randomized trial). J Clin Oncol. 1991;9:770–776
  2. Saven A, Lemon RH, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol. 1995;13:570–574
  3. Tallman MS, Hakimian D, Zanzig C, Hogan DK, Rademaker A, Rose E, et al.  Cladribine in the treatment of relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 1995;13:983–988
  4. Dillman RO, Mick R, McIntyre OR. Pentostatin in chronic lymphocytic leukemia (A phase II trial of Cancer and Leukemia Group B). J Clin Oncol. 1989;7:433–438
  5. Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, et al.  Fludarabine (A new agent with major activity against chronic lymphocytic leukemia). Blood. 1989;74:19–25
  6. Israels LG, Galton DAG, Till M, Wiltshaw E. Clinical evaluation of CB 1348 in malignant lymphoma and related diseases. Ann NY Acad Sci. 1958;68:915–925
  7. Begleiter A, Mowat M, Israels LG, Johnston JB. Chlorambucil in chronic lymphocytic leukemia (Mechanism of action). Leuk Lymphoma. 1996;23:187–201
  8. Montserrat E, Fontanilles M, Estape J. Treatment of chronic lymphocytic leukemia (A preliminary report of Spanish (PETHEMA) trials). Leuk Lymphoma. 1991;5(suppl):89–91
  9. Sawitsky A, Rai KR, Glidewell O, Silver RT. Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia. Blood. 1977;50:1049–1059
  10. Jaksic B, Brugiatelli M, Krc I, Losonczi H, Hoowiecki J, Planinc-Peraica A, et al.  High dose chlorambucil versus Binet’s modified cyclophosphamide, doxorubicin, vincristine, and prednisone regimen in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (Results of an international multicenter randomized trial. International Society for Chemo-Immunotherapy, Vienna). Cancer. 1997;79:2107–2114
  11. Jaksic B, Brugiatelli M. High dose continuous chlorambucil vs intermittent chlorambucil plus prednisone for treatment of B-CLL IGCI CLL-01 trial. Nouv Rev Fr Hematol. 1988;30:437–442
  12. Han T, Ezdinli EZ, Shimaoka K, Desai DV. Chlorambucil vs combined chlorambucil-corticosteroid therapy in chronic lymphocytic leukemia. Cancer. 1973;31:502–508
  13. Montserrat E, Rozman C. Chronic lymphocytic leukaemia treatment. Blood Rev. 1993;7:164–175
  14. Hansen MM, Andersen E, Birgeus H, Christensen BE, Christensen TG, Gisler C. CHOP versus prednisone + chlorambucil in chronic lymphocytic leukemia (Preliminary results of a randomized multicenter study). Nouv Rev Fr Hematol. 1998;30:433–436
  15. CLL Trialists Collaborative Group . Chemotherapeutic options in chronic lymphocytic leukemia (A meta-analysis of the randomized trials). J Natl Cancer Inst. 1999;91:861–868
  16. Keating MJ, O‘Brien S, Lerner S, Koller C, Beran M, Robertson LE, et al.  Long term follow-up of patient with CLL receiving fludarabine regimens as initial therapy. Blood. 1998;92:65–71
  17. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, et al.  Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet. 1996;347:1432–1438
  18. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, et al.  Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343:1750–1757
  19. Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, et al.  Randomized comparison of fludarabine, CAP, and CHOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001;98:2319–2325
  20. Keating MJ, O’Brien S, Kantarjian H, Plunkett W, Estey E, Koller C, et al.  Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent. Blood. 1993;81:2878–2884
  21. Eichhorst BF, Busch R, Stauch M, Kneba M, Ritgen M, Söling U, et al.  Fludarabine induces higher response rates in first line therapy of older patients with advanced chronic lymphocytic leukemia than chlorambucil (Interim analysis of a phase III study of the German CLL Study Group). Blood. 2003;102:109; (abstr)
  22. Boogaerts MA, Van Hoof A, Catovsky D, Kovacs M, Montillo M, Zinzani PL, et al.  Activity of oral fludarabine phosphate in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2001;19:4252–4258
  23. Robak T, Blasinska-Morawiec M, Blonski JZ, Krykowski E, Komarnicki M, Trepinska E, et al.  The effect of 2-h infusion of 2-chlorodeoxyadenosine (cladribine) with prednisone in previously untreated B-cell chronic lymphocytic leukaemia. Eur J Cancer. 1997;33:2347–2351
  24. Robak T, Blonski JZ, Kasznicki M, Blasinska-Morawiec M, Krykowski E, Dmoszynska A, et al.  Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia (Report of a prospective, randomized, multicenter trial). Blood. 2000;96:2723–2729
  25. Dillman RO, Mick R, McIntyre OR. Pentostatin in chronic lymphocytic leukemia (A phase II trial of Cancer and Leukemia Group B). J Clin Oncol. 1989;7:433–438
  26. Ho AD, Thaler J, Stryckmans P, Coiffier B, Luciani M, Sonneveld P, et al.  Pentostatin in refractory chronic lymphocytic leukemia (A phase II trial of the European Organization for Research and Treatment of Cancer). J Natl Cancer Inst. 1990;82:1416–1420
  27. Plunkett W, Gandhi V, Huang P, Robertson LE, Yang LY, Gregoire V, et al.  Fludarabine (Pharmacokinetics, mechanisms of action, and rationales for combination therapies). Semin Oncol. 1993;20:2–12
  28. O‘Brien S. Clinical challenges in chronic lymphocytic leukemia. Semin Hematol. 1998;35:22–26
  29. O’Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ, et al.  Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:1414–1420
  30. Eichhorst BF, Hopfinger G, Pasold R, Hensel M, Söling U, Siehl S, et al.  Fludarabine plus cyclophosphamide (FC) induces higher remission rates and longer progression free survival (PFS) than fludarabine (F) alone in first line therapy of advanced chronic lymphocytic leukemia (CLL) (Results of a phase III study (CLL4 protocol) of the German CLL Study Group (GCLLSG)). Blood. 2003;102:72; (abstr)
  31. Hallek M, Schmitt B, Wilhelm M, Busch R, Krober A, Fostitsch HP, et al.  Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL) (Results of a phase II study of the German CLL Study Group). Br J Haematol. 2001;114:342–348
  32. Bosch F, Ferrer A, Lopez-Guillermo A, Gine E, Bellosillo B, Villamor N, et al.  Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukemia. Br J Haematol. 2002;119:976–984
  33. Schmitt BF, Burkhard O, Schlag R, Hopfinger G, Stauch M, Bergmann M, et al.  Fludarabine, mitoxantrone and cyclophosphamide combination therapy in relapsed chronic lymphocytic leukaemia (CLL) with or without G-CSF (Results of a first interim analysis of a phase III study of the German CLL Study Group (GCLLSG)). Blood. 2002;100:364; (abstr)
  34. Robertson LE, O’Brien S, Kantarjian H, Koller C, Beran M, Andreeff M, et al.  Fludarabine plus doxorubicin in previously treated chronic lymphocytic leukemia. Leukemia. 1995;9:943–945
  35. Rummel MJ, Kafer G, Pfreundschuh M, Jager E, Reinhardt U, Mitrou PS, et al.  Fludarabine and epirubicin in the treatment of chronic lymphocytic leukaemia (A German multicenter phase II study). Ann Oncol. 1999;10:183–188
  36. Rummel MJ, Gamm H, Rost A, Gruenhagen U, Wojatschek C, Jäger E, et al.  Fludarabine versus fludarabine plus epirubicin in the treatment of chronic lymphocytic leukemia (CLL)—Results of a randomized phase-III multicenter study. Blood. 2002;102:437; (abstr)
  37. O’Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, et al.  Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993;82:1695–1700
  38. Anaissie EJ, Kontoyiannis DP, O’Brien S, Kantarjian H, Robertson L, Lerner S, et al.  Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med. 1998;129:559–566
  39. Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, et al.  Impact of therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia (Intergroup Study Cancer and Leukemia Group B 9011). J Clin Oncol. 2001;19:3611–3621
  40. Gandhi V, Robertson LE, Keating MJ, Plunkett W. Combination of fludarabine and arabinosylcytosine for treatment of chronic lymphocytic leukemia (Clinical efficacy and modulation of arabinosylcytosine pharmacology). Cancer Chemother Pharmacol. 1994;34:30–36
  41. Mauro FR, Foa R, Meloni G, Gentile M, Giammartini E, Giannarelli D, et al.  Fludarabine, ara-C, novantrone and dexamethasone (FAND) in previously treated chronic lymphocytic leukemia patients. Haematologica. 2002;87:926–933
  42. Van Den Neste E, Bontemps F, Delacauw A, Cardoen S, Louviaux I, Scheiff JM, et al.  Potentiation of antitumor effects of cyclophosphamide derivatives in B-chronic lymphocytic leukemia cells by 2-chloro-2′-deoxyadenosine. Leukemia. 1999;13:918–925
  43. Robak T, Blonski JZ, Kasznicki M, Gora-Tybor J, Dwilewicz-Trojaczek J, Stella-Holowiecka B, et al.  Cladribine combined with cyclophosphamide is highly effective in the treatment of chronic lymphocytic leukemia. Hematol J. 2002;3:244–250
  44. Montillo M, Tedeschi A, O’Brien S, Di Raimondo F, Lerner S, Ferrajoli A, et al.  Phase II study of cladribine and cyclophosphamide in patients with chronic lymphocytic leukemia and prolymphocytic leukemia. Cancer. 2003;97:114–120
  45. Tefferi A, Li CY, Reeder CB, Geyer SM, Allmer C, Levitt R, et al.  A phase II study of sequential combination chemotherapy with cyclophosphamide, prednisone, and 2-chlorodeoxyadenosine in previously untreated patients with chronic lymphocytic leukemia. Leukemia. 2001;15:1171–1175
  46. Robak T, Blonski JZ, Kasznicki M, Gora-Tybor I, Dwilewicz-Trojaczek J, Boguradzki P, et al.  Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia. Leukemia. 2001;15:1510–1516
  47. Robak T, Gora-Tybor J, Lech-Maranda E, Blonski JZ, Kasznicki M. Cladribine in combination with mitoxantrone and cyclophosphamide(CMC) in the treatment of heavily pre-treated patients with advanced indolent lymphoid malignancies. Eur J Haematol. 2001;66:188–194
  48. Bremer K. High rates of long-lasting remissions after 5-day bendamustine chemotherapy cycles in pre-treated low-grade non-Hodgkin‘s lymphomas. J Cancer Res Clin Oncol. 2002;128:603–609
  49. Aivado M, Schulte K, Henze L, Burger J, Finke J, Haas R. Bendamustine in the treatment of chronic lymphocytic leukemia (Results and future perspectives). Semin Oncol. 2002;29(suppl 13):19–22
  50. Bergmann M, Herold M, Wilhelm M, Emmerich B, Boening L, Hallek M. High efficacy and better hematological safety of reduced dose of bendamustin in extendedly pretreated patients with advanced, relapsed or refractory B-CLL (Phase I/II study of the German CLL Study Group). Proc Am Soc Clin Oncol. 2003;22:590; (abstr)
  51. Kath R, Blumenstengel K, Fricke HJ, Höffken K. Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia. J Cancer Res Clin Oncol. 2001;127:48–54
  52. Chow KU, Boehrer S, Geduldig K, Krapohl A, Hoelzer D, Mitrou PS, et al.  In vitro induction of apoptosis of neoplastic cells in low-grade non-Hodgkin‘s lymphomas using combinations of established cytotoxic drugs with bendamustine. Haematologica. 2001;86:485–493
  53. Weide R, Heymanns J, Gores A, Koppler H. Bendamustine mitoxantrone and rituximab (BMR) (A new effective regimen for refractory or relapsed indolent lymphomas). Leuk Lymphoma. 2002;43:327–331
  54. Konig A, Schwartz GK, Mohammad RM, Al-Katib A, Gabrilove JL. The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines. Blood. 1997;90:4307–4312
  55. Byrd JC, Shinn C, Waselenko JK, Fuchs EJ, Lehman TA, Nguyen PL, et al.  Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood. 1998;92:3804–3816
  56. Byrd JC, Shinn C, Willis CR, Flinn IW, Lehman T, Sausville E, et al.  UCN-01 induces cytotoxicity toward human CLL cells through a p53-independent mechanism. Exp Hematol. 2001;29:703–708
  57. Drexler HG, Gignac SM, Jones RA, Scott CS, Pettit GR, Hoffbrand AV. Bryostatin 1 induces differentiation of B-chronic lymphocytic leukemia cells. Blood. 1989;74:1747–1757
  58. Mohammad RM, Katato K, Almatchy VP, Wall N, Liu KZ, Schultz CP, et al.  Sequential treatment of human chronic lymphocytic leukemia with bryostatin 1 followed by 2-chlorodeoxyadenosine (preclinical studies). Clin Cancer Res. 1998;4:445–453
  59. Roberts JD, Feldman EJ, Smith MR, Grant S. Phase I trial of bryostatin 1 (NSC 339555) and fludarabine in patients with chronic lymphocytic leukemia and indolent non-Hodgkin‘s lymphoma. Blood. 2002;100:385; (abstr)
  60. Byrd JC, Shinn C, Ravi R, Willis CR, Waselenko JK, Flinn IW, et al.  Depsipeptide (FR901228) (A novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemia cells). Blood. 1999;94:1401–1408
  61. Bruner RJ, Marcucci G, Binkley P, Xiao J, Chan K, Parthun M, et al.  Phase I trial of the histone deacetylase inhibitor depsipeptide (FR901228) in fludarabine refractory chronic lymphocytic leukemia. Blood. 2002;100:385; (abstr)
  62. Aron JL, Parthun MR, Marcucci G, Kitada S, Mone AP, Davis ME, et al.  Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8-mediated apoptosis and down-regulation of c-FLIP protein. Blood. 2003;102:652–658
  63. Frankel SR. Oblimersen sodium (G3139 Bcl-2 antisense oligonucleotide) therapy in Waldenstrom‘s macroglobulinemia (A targeted approach to enhance apoptosis). Semin Oncol. 2003;30:300–304
  64. Rai KR, O‘Brien S, Cunningham C, Turkina AG, Ochoa L, Frankel SR, et al.  Genasense (Bcl-2 Antisense) monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia (Phase I and II results). Blood. 2002;100:384; (abstr)
  65. Banerjee D. Genasense (Gena Inc.). Curr Opin Invest Drugs. 2001;2:574–580
  66. O’Brien S, Kantarjian H, Beran M, Koller C, Talpaz M, Lerner S, et al.  Fludarabine and granulocyte colony-stimulating factor (G-CSF) in patients with chronic lymphocytic leukemia. Leukemia. 1997;11:1631–1635
  67. Flinn IW, Byrd JC, Morrison C, Jamison J, Diehl LF, Murphy T, et al.  Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood. 2000;96:71–75
  68. Siakantaris MP, Angelopoulou MK, Vassilakopoulos TP, Dimopoulo MN, Kontopidou FN, Pangalis GA. Correction of disease related anaemia of B-chronic lymphoproliferative disorders by recombinant human erythropoietin (Maintenance is necessary to sustain response). Leuk Lymphoma. 2000;40:141–147
  69. Osterborg A, Brandberg Y, Molostova V, Iosava G, Abdulkadyrov K, Hedenus M, et al.  Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol. 2002;20:2486–2494
  70. Pangalis GA, Siakantaris MP, Angelopoulou MK, Vassilakopoulos TP, Dimopoulou MN, Kyrtsonis MC, et al.  Downstaging Rai stage III B-chronic lymphocytic leukemia patients with the administration of recombinant human erythropoietin. Haematologica. 2002;87:500–506
  71. Ludwig H, Rai K, Blade J, Dammacco F, Degos L, Itri L, et al.  Management of disease-related anemia in patients with multiple myeloma or chronic lymphocytic leukemia (Epoetin treatment recommendations). Hematol J. 2002;3:121–130
  72. Extermann M. Measuring comorbidity in older cancer patients. Eur J Cancer. 2000;36:453–471
  73. Bernardi D, Milan I, Balzarotti M, Spina M, Santoro A, Tirelli U. Comprehensive geriatric evaluation in elderly patients with lymphoma (Feasibility of a patient-tailored treatment plan). J Clin Oncol. 2003;24:754–756
  74. Kennedy B, Rawstron A, Carter C, Ryan M, Speed K, Lucas G, et al.  Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood. 2002;99:2245–2247
  75. Keating M, Manshouri T, O‘Brien S, Wierda W, Kantarijan H, Washington L, et al.  A high proportion of molecular remission can be obtained with a fludarabine, cyclophosphamide, rituximab combination (FCR) in chronic lymphocytic leukaemia. Blood. 2002;100:205; (abstr)
  76. Cazin B, Maloum K, Divine M, Lepretre S, Travade P, Delmer A, et al.  Oral fludarabine and cyclophosphamide in previously untreated chronic lymphocytic leukaemia (CLL) (Preliminary data on 75 patients). Blood. 2002;100:200; (abstr)
  77. Flinn IW, Jemiai Y, Bennett JM, Falkson CI, Flynn P, Pundaleeka S, et al.  Fludarabine and cyclophosphamide achieves high complete response rate in patients with previously untreated chronic lymphocytic leukemia (ECOG 1997). Blood. 2001;98:150; (abstr)
  78. O‘Brien S, Kantarjian H, Keating MJ. Purine analogs in chronic lymphocytic leukemia and Waldenstrom‘s macroglobulinemia. Ann Oncol. 1996;7(suppl):27–33
  79. Giles FJ, O’Brien S, Santini V, Gandhi V, Plunkett W, Seymour JF, et al.  Sequential cis-platinum and fludarabine with or without arabinosyl cytosine in patients failing prior fludarabine therapy for chronic lymphocytic leukemia (A phase II study). Leuk Lymphoma. 1999;36:57–65 cytic leukemia: A phase II study. Leuk Lymphoma 36:57–65, 1999

 Supported in part by the Deutsche Krebshilfe, the Bundesministerium für Bildung und Forschung (BMBF), and the Kompetenznetz Leukämien.

PII: S0037-1963(04)00091-5

doi: 10.1053/j.seminhematol.2004.05.004

Seminars in Hematology
Volume 41, Issue 3 , Pages 224-233 , July 2004