Best Practice & Research Clinical Haematology
Volume 23, Issue 1 , Pages 85-96 , March 2010

Therapy of chronic lymphocytic leukaemia

  • Michael Hallek, MD (Director and Chair)

      Affiliations

    • Corresponding Author InformationTel.: +49 221 478 4400; Fax: +49 221 478 5455.

References 

  1. CLL trialists' collaborative group. Chemotherapeutic options in chronic lymphocytic leukemia. J Natl Cancer Inst. 1999;91:861–868
  2. O'Brien S, Kantarjian H, Keating MJ. Purine analogs in chronic lymphocytic leukemia and Waldenstrom's macroglobulinaemia. Ann Oncol. 1996;7(Suppl. 6):S27–S33
  3. Cheson B. The purine analogs – a therapeutic beauty contest. J Clin Oncol. 1992;10:352–355
  4. Anaissie EJ, Kontoyiannis DP, O'Brien S, et al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med. 1998;129(7):559–566
  5. Plunkett W, Gandhi V, Huang P, et al. Fludarabine: pharmacokinetics, mechanisms of action, and rationales for combination therapies. Semin Oncol. 1993;20(5 Suppl. 7):2–12
  6. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343(24):1750–1757
  7. Steurer M, Pall G, Richards S, et al. Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2006;3:CD004270
  8. Johnson S, Smith AG, Loffler H, 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. [see comments] Lancet. 1996;347(9013):1432–1438
  9. Leporrier M, Chevret S, Cazin 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(8):2319–2325
  10. Robak T, Blonski JZ, Kasznicki M, 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(8):2723–2729
  11. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 10;27(26):4378–4384
  12. Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001;98(5):1326–1331
  13. O'Brien S, Kantarijan H, Thomas D, et al. Rituximab dose-escalation trial in chronic lymphocytic leukaemia. J Clin Oncol. 2001;19:2165–2170
  14. Byrd J, Murphy T, Howard R, et al. Rituximab using a thrice-weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol. 2001;19:2153–2164
  15. Österborg A, Dyer MJ, Bunjes D, et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European study group of CAMPATH-1H treatment in chronic lymphocytic leukemia. J Clin Oncol. 1997;15(4):1567–1574
  16. Rai KR, Freter CE, Mercier RJ, et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002 Sep 15;20(18):3891–3897
  17. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002 May 15;99(10):3554–3561
  18. Stilgenbauer S, Dohner H. Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy. N Engl J Med. 2002 Aug 8;347(6):452–453
  19. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004 May 1;103(9):3278–3281
  20. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007 Dec 10;25(35):5616–5623
  21. Bellosillo B, Villamor N, Colomer D, et al. In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia. Blood. 1999;94(8):2836–2843
  22. Hallek M, Eichhorst BF. Chemotherapy combination treatment regimens with fludarabine in chronic lymphocytic leukemia. Hematol J. 2004;5(Suppl. 1):S20–S30
  23. Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006;107:885–891
  24. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US intergroup trial E2997. J Clin Oncol. 2007 Mar 1;25(7):793–798
  25. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007 Jul 21;370(9583):230–239
  26. Stilgenbauer S, Eichhorst BF, Busch R, et-al. Biologic and clinical markers for outcome after fludarabine (F) or F plus cyclophosphamide (FC) – comprehensive analysis of the CLL4 trial of the GCLLSG. ASH annual meeting abstracts. 2008 November 16, 2008;112(11):2089.
  27. Bosch F, Ferrer A, Lopez-Guillermo A, et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002 Dec;119(4):976–984
  28. Montillo M, Tedeschi A, O'Brien S, et al. Phase II study of cladribine and cyclophosphamide in patients with chronic lymphocytic leukemia and prolymphocytic leukemia. Cancer. 2003 Jan 1;97(1):114–120
  29. Robak T, Blonski JZ, Gora-Tybor J, et al. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006 Jul 15;108(2):473–479
  30. di Gaetano N, Xiao Y, Erba E, et al. Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. Br J Haematol. 2001;114(4):800–809
  31. Schulz H, Klein SH, Rehwald U, et al. Phase II study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia. Blood. 2002;100(9):3115–3120
  32. Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003 Jan 1;101(1):6–14
  33. Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005 Jan 1;105(1):49–53
  34. Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Aug 15;112(4):975–980
  35. Hallek M, Fingerle-Rowson G, Fink A-M, et-al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine and cyclophosphamide (FC) improves response rates and progression-free survival (PFS) of previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL). ASH annual meeting abstracts. 2008 November 16, 2008;112(11):325.
  36. Robak T, Moiseev SI, Dmoszynska A, et-al. Rituximab, fludarabine, and cyclophosphamide (R-FC) prolongs progression free survival in relapsed or refractory chronic lymphocytic leukemia (CLL) compared with FC alone: final results from the international randomized phase III REACH trial. ASH annual meeting abstracts. 2008 November 16, 2008;112(11):lba-1.
  37. Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498–503
  38. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446–5456
  39. Bosch F, Abrisqueta P, Villamor N, et-al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) is a highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. ASH annual meeting abstracts. 2008;112: 2097.
  40. Reynolds C, Di Bella N, Lyons RM, et-al. Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia. ASH annual meeting abstracts. 2008;112:327.
  41. Fischer K, Stilgenbauer S, Schweighofer CD, et-al. Bendamustine in combination with rituximab (BR) for patients with relapsed chronic lymphocytic leukemia (CLL): a multicentre phase II trial of the German CLL study group (GCLLSG). ASH annual meeting abstracts. 2008 November 16, 2008;112(11):330.
  42. Kennedy B, Rawstron A, Carter C, et al. Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood. 2002;99(6):2245–2247
  43. Elter T, Borchmann P, Schulz H, et al. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol. 2005 Oct 1;23(28):7024–7031
  44. Elter T, James R, Stilgenbauer S, et-al. Chemoimmuno-therapy with fludarabine, cyclophosphamide and alemtuzumab in patients with relapsed/refractory CLL: interim analysis of the CLL2L trial of the German CLL study group. ASH annual meeting abstracts. 2008 November 16, 2008;112(11):3170.
  45. Lepretre S, Aurran T, Mahé B, et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine (F), cyclophosphamide (C), and mabcampath (CAM) (FCCAM) in previously untreated patients (pts) with advanced B-chronic lymphocytic leukemia (B-CLL): experience on safety and efficacy within a randomised multicenter phase III trial of the French Cooperative Group on CLL and WM (FCGCLL/WM) and the “Groupe Ouest-Est d'Etudes des Leucémies Aigües et autres Maladies du Sang” (GOELAMS): CLL2007FMP (for medically fit patients) (abstr. 7.5). Haematologica. 2009;94(s3):S67
  46. Faderl S, Thomas DA, O'Brien S, et al. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003 May 1;101(9):3413–3415
  47. Byrd JC, O'Brien S, Flinn IW, et al. Phase 1 study of lumiliximab with detailed pharmacokinetic and pharmacodynamic measurements in patients with relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4448–4455
  48. Byrd JC, Castro J, O'Brien S, et-al. Comparison of results from a phase 1/2 study of lumiliximab (anti-CD23) in combination with FCR for patients with relapsed CLL with published FCR results. ASH annual meeting abstracts. 2006 November 16, 2006;108(11):32.
  49. Wierda W, O'Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070–4078
  50. O'Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007 Mar 20;25(9):1114–1120
  51. Chanan-Khan A, Miller KC, Musial L, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343–5349
  52. Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):399–404
  53. Schweighofer CD, Ritgen M, Eichhorst BF, et al. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009 Jan;144(1):95–98
  54. Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005 Feb 28;23:2971–2979
  55. Montillo M, Cafro AM, Tedeschi A, et al. Safety and efficacy of subcutaneous Campath-1H for treating residual disease in patients with chronic lymphocytic leukemia responding to fludarabine. Haematologica. 2002;87(7):695–700discussion
  56. O'Brien SM, Kantarjian HM, Thomas DA, et al. Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer. 2003 Dec 15;98(12):2657–2663
  57. Abrams ST, Lakum T, Lin K, et al. B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CbetaII. Blood. 2007 Feb 1;109(3):1193–1201
  58. Wendtner CM, Ritgen M, Schweighofer CD, et al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission–experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093–1101
  59. Boettcher S, Fischer K, Stilgenbauer S, et-al. Quantitative MRD assessments predict progression free survival in CLL patients treated with fludarabine and cyclophosphamide with or without rituximab – a prospective analysis in 471 patients from the randomized GCLLSG CLL8 trial. ASH annual meeting abstracts. 2008 November 16, 2008;112(11):326.
  60. Rawstron AC, Villamor N, Ritgen M, et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007 May;21(5):956–964
  61. Extermann M, Overcash J, Lyman GH, et al. Comorbidity and functional status are independent in older patients. J Clin Oncol. 1998;16(4):1582–1587
  62. Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German chronic lymphocytic leukemia study group. J Clin Oncol. 2009 Jul 13;
  63. Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia. 2007 Jan;21(1):12–17
  64. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009 Oct 15;114(16):3382–3391
  65. Knauf WU, Lissichkov T, Aldaoud A, et-al. Bendamustine versus chlorambucil in treatment-naive patients with B-cell chronic lymphocytic leukemia (B-CLL): results of an international phase III study. ASH annual meeting abstracts. 2007 November 16, 2007;110(11):2043.

PII: S1521-6926(09)00103-0

doi: 10.1016/j.beha.2009.12.002

Best Practice & Research Clinical Haematology
Volume 23, Issue 1 , Pages 85-96 , March 2010

Article Tools

* Image Usage & Resolution