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Changing paradigms in the treatment of chronic lymphocytic leukemia

Abstract

Progress in our understanding of chronic lymphocytic leukemia and its treatment has resulted in a more tailored approach to patient management, with different therapeutic regimens for different patient populations. The current standard of care has evolved from single-agent therapy with chlorambucil or cyclophosphamide, through the introduction of purine analogs to the more recent introduction of chemoimmunotherapy. Selection of appropriate initial therapy should be based primarily on patient characteristics such as age, performance status and the expected clinical course of the leukemia based on established risk factors. Achieving a complete and durable response is the major goal for fit patients; chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab would be advantageous. Alternatively, in unfit patients, controlling symptoms is the essential treatment goal and a regimen with a more favorable toxicity profile should be applied. This manuscript reviews the data that has lead to current treatment choices, advises on tailored therapies and discusses emerging trends. Data for this review was identified by a search of electronic information including Medline and PubMed databases, conference proceedings and trial registers. Critical analysis of extracted data was undertaken with attention to trial phase, treatment schedules and end points, including response rates, follow-up times, progression-free survival and overall survival.

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References

  1. Dighiero G, Hamblin TJ . Chronic lymphocytic leukaemia. Lancet 2008; 371: 1017–1029.

    CAS  Google Scholar 

  2. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H 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; 111: 5446–5456. [updated and corrected online version, December 8, 2008].

    CAS  Google Scholar 

  3. Craig FE, Foon KA . Flow cytometric immunophenotyping for hematologic neoplasms. Blood 2008; 111: 3941–3967.

    CAS  Google Scholar 

  4. Muller-Hermelink HK, Montserrat E, Catovsky D, Campo E, Harris NL, Stein H . Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon, 2008, 180–182.

    Google Scholar 

  5. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.

    CAS  Google Scholar 

  6. Palmer RG, Denman AM . Malignancies induced by chlorambucil. Cancer Treat Rev 1984; 11: 121–129.

    CAS  Google Scholar 

  7. 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.

    CAS  Google Scholar 

  8. Johnson S, Smith AG, Loffler 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.

    CAS  Google Scholar 

  9. 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.

    CAS  Google Scholar 

  10. Eichhorst BF, Busch R, Stauch M, Bergmann M, Ritgen M, Kranzhöfer N et al. No significant clinical benefit of first line therapy with fludarabine (F) in comparison to chlorambucil (Clb) in elderly patients (pts) with advanced chronic lymphocytic leukemia (CLL): Results of a Phase III study of the German CLL Study Group (GCLLSG). Blood 2007; 110: 11 (abstract 629).

    Google Scholar 

  11. 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.

    CAS  Google Scholar 

  12. Karlsson KA, Stromberg M, Jonsson V, Mulligan SP, Liliemark J, Juliusson G . Cladribine (CdA) gives longer response duration than fludarabine (F) and high-dose intermittent chlorambucil (Chl) as first-line treatment of symptomatic chronic lymphocytic leukemia (CLL). First results from the International Randomized Phase III Trial. Blood 2007; 110: 11 (abstract 630).

    Google Scholar 

  13. 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.

    CAS  Google Scholar 

  14. Knauf WU, Lissitchkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009; 27: 4378–4384.

    CAS  Google Scholar 

  15. Leoni LM, Bailey B, Reifert J, Bendall HH, Zeller RW, Corbeil J et al. Bendamustine (Treanda) displays a pattern of cytoxicity and unique mechanistic features compared with alkylating agents. Clin Cancer Res 2008; 14: 309–317.

    CAS  Google Scholar 

  16. Bellosillo B, Villamor N, Colomer D, Pons G, Montserrat E, Gil J . In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia. Blood 1999; 94: 2836–2843.

    CAS  Google Scholar 

  17. Pellacani A, Tosi P, Zinzani PL, Ottaviani E, Albertini P, Magagnoli M et al. Cytotoxic combination of loxoribine with fludarabine and mafosfamide on freshly isolated B-chronic lymphocytic leukemia cells. Leuk Lymphoma 1999; 33: 147–153.

    CAS  Google Scholar 

  18. O’Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ . Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 2001; 19: 1414–1420.

    Google Scholar 

  19. Flinn IW, Byrd JC, Morrison C, Jamison J, Diehl LF, Murphy T . Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood 2000; 96: 71–75.

    CAS  Google Scholar 

  20. Weiss MA, Maslak PG, Jurcic JG, Scheinberg DA, Aliff TB, Lamanna N et al. Pentostatin and cyclophosphamide: an effective new regimen in previously treated patients with chronic lymphocytic leukemia. J Clin Oncol 2003; 21: 1278–1284.

    CAS  Google Scholar 

  21. Robak T, Blonski JZ, Wawrzyniak E, Gora-Tybor J, Palacz A, Dmoszynska A et al. Activity of cladribine combined with cyclophosphamide in frontline therapy for chronic lymphocytic leukemia with 17p13.1/TP53 deletion: report from the Polish Adult Leukemia Group. Cancer 2009; 115: 94–100.

    CAS  Google Scholar 

  22. Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a Randomised Controlled Trial. Lancet 2007; 370: 230–239.

    CAS  Google Scholar 

  23. Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006; 107: 885–891.

    CAS  Google Scholar 

  24. Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM 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; 25: 793–798.

    CAS  Google Scholar 

  25. Stilgenbauer S, Eichhorst BF, Busch R, Zenz T, Winkler D, Bühler A 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. Blood 2008; 112: 11, (abstract 2089).

    Google Scholar 

  26. Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A 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; 108: 473–479.

    CAS  Google Scholar 

  27. Coiffier B, Feugier P, Mounier N, Franchi-Rezgui E, Van Den Neste M, Macro C et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol 2007; 25 (18 Suppl), (abstract 8009).

  28. Schulz H, Bohlius JF, Trelle S, Skoetz N, Reiser M, Kober T et al. Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst 2007; 99: 706–714.

    CAS  Google Scholar 

  29. Foran JM, Rohatiner AZ, Cunningham D, Popescu RA, Solal-Celigny P, Ghielmini M et al. European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 2000; 18: 317–324.

    CAS  Google Scholar 

  30. McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16: 2825–2833.

    Article  CAS  Google Scholar 

  31. Nguyen DT, Amess JA, Doughty H, Hendry L, Diamond LW . IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients. Eur J Haematol 1999; 62: 76–82.

    CAS  Google Scholar 

  32. Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A . Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999; 94: 2217–2224.

    CAS  Google Scholar 

  33. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2003; 21: 1746–1751.

    CAS  Google Scholar 

  34. Byrd JC, Murphy T, Howard RS, Lucas MS, Goodrich A, Park K 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.

    CAS  Google Scholar 

  35. O’Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001; 19: 2165–2170.

    Google Scholar 

  36. Williams ME, Densmore JJ, Pawluczkowycz AW, Beum PV, Kennedy AD, Lindorfer MA et al. Thrice-weekly low-dose rituximab decreases CD20 loss via shaving and promotes enhanced targeting in chronic lymphocytic leukemia. J Immunol 2006; 177: 7435–7443.

    CAS  Google Scholar 

  37. Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A 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; 23: 2971–2979.

    CAS  Google Scholar 

  38. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood 2002; 99: 3554–3561.

    CAS  Google Scholar 

  39. Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007; 25: 5616–5623.

    CAS  Google Scholar 

  40. Alas S, Bonavida B, Emmanouilides C . Potentiation of fludarabine cytotoxicity on non-Hodgkin's lymphoma by pentoxifylline and rituximab. Anticancer Res 2000; 20: 2961–2966.

    CAS  Google Scholar 

  41. Demidem A, Lam T, Alas S, Hariharan K, Hanna N, Bonavida B . Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm 1997; 12: 177–186.

    CAS  Google Scholar 

  42. Di Gaetano N, Xiao Y, Erba E, Bassan R, Rambaldi A, Golay J 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: 800–809.

    CAS  Google Scholar 

  43. Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 2000; 95: 3900–3908.

    CAS  Google Scholar 

  44. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–242.

    CAS  Google Scholar 

  45. Czuczman MS, Fallon A, Mohr A, Stewart C, Bernstein ZP, McCarthy P et al. Rituximab in combination with CHOP or fludarabine in low-grade lymphoma. Semin Oncol 2002; 29: 36–40.

    CAS  Google Scholar 

  46. Schulz H, Klein SK, Rehwald U, Reiser M, Hinke A, Knauf WU et al. Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia. Blood 2002; 100: 3115–3120.

    CAS  Google Scholar 

  47. Del Poeta G, Del Principe MI, Consalvo MA, Maurillo L, Buccisano F, Venditti A et al. The addition of rituximab to fludarabine improves clinical outcome in untreated patients with ZAP-70-negative chronic lymphocytic leukemia. Cancer 2005; 104: 2743–2752.

    CAS  Google Scholar 

  48. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E 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; 101: 6–14.

    CAS  Google Scholar 

  49. Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE 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; 105: 49–53.

    CAS  Google Scholar 

  50. Elter T, Borchmann P, Schulz H, Reiser M, Trelle S, Schnell R 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; 23: 7024–7031.

    CAS  Google Scholar 

  51. Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 4079–4088.

    CAS  Google Scholar 

  52. Tam CS, O’Brien S, Wierda W, Kantarjian H, Wen S, Do KA et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008; 112: 975–980.

    CAS  Google Scholar 

  53. Wierda W, O’Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 4070–4078.

    CAS  Google Scholar 

  54. Lamanna N, Jurcic JG, Noy A, Maslak P, Gencarelli AN, Panageas KS et al. Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: molecular remissions predict for durable complete responses. J Clin Oncol 2009; 27: 491–497.

    CAS  Google Scholar 

  55. Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L 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; 27: 498–503.

    CAS  Google Scholar 

  56. Hallek M, Fingerle-Rowson G, Fink A, Busch R, Mayer J, Hensel 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). Blood 2008; 112: 11, (abstract 325).

    Google Scholar 

  57. Robak T, Moiseev SI, Dmoszynska A, Solal-Céligny P, Warzocha K, Loscertales J 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. Blood LBA-1 2008; 112: 11, (abstract 157420).

    Google Scholar 

  58. Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol 2009; 27: 4578–4584.

    CAS  Google Scholar 

  59. Faderl S, Wierda W, O’Brien S, Ferrajoli A, Lerner S, Keating MJ . Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL <70 Years. Leuk Res 2009. (e-pub ahead of print).

  60. Wierda WG, O’Brien SM, Faderl SH, Ferrajoli A, Koller C, Estrov Z et al. CFAR, an active frontline regimen for high-risk patients with CLL, including those with del 17p. Blood 2008; 112: 11, (abstract 2095).

    Google Scholar 

  61. Lamanna N, Kalaycio M, Maslak P, Jurcic JG, Heaney M, Brentjens R et al. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol 2006; 24: 1575–1581.

    CAS  Google Scholar 

  62. Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2007; 109: 405–411.

    CAS  Google Scholar 

  63. Kay NE, Wu W, Byrd JC, Kabat B, Jelinek DF, Zent CS et al. Cyclophosphamide remains an important component of treatment in CLL patients receiving pentostatin and rituximab based chemoimmunotherapy. Blood 2008; 112: 11, (abstract 43).

    Google Scholar 

  64. Reynolds C, Di Bella N, Lyons RM, Hyman WJ, Lee GL, Richards DA et al. Phase III trial of fludarabine, cyclophosphamide, and rituximab vs pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia. Blood 2008; 112: 11, (abstract 327).

    Google Scholar 

  65. Robak T, Smolewski P, Cebula B, Grzybowska-Izydorczyk O, Błoñski JZ . Rituximab plus cladribine with or without cyclophosphamide in patients with relapsed or refractory chronic lymphocytic leukemia. Eur J Haematol 2007; 79: 107–113.

    CAS  Google Scholar 

  66. Frankfurt O, Hamilton E, Duffey S, Acharya S, Raji A, Ma S et al. Alemtuzumab and rituximab combination therapy for patients with untreated CLL—a Phase II Trial. Blood 2008; 112: 11, (abstract 2098).

    Google Scholar 

  67. Fischer K, Stilgenbauer S, Schweighofer CD, Busch R, Renschler J, Kiehl M 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). Blood 2008; 112: 11, (abstract 330)TBD.

    Google Scholar 

  68. James AF, Castro JE, Sandoval-Sus JD, Jain S, Bole J, Rassenti L et al. Rituximab and high-dose methylprednisolone for the initial treatment of chronic lymphocytic leukemia is associated with promising clinical activity and minimal hematologic toxicity. Blood 2008; 112: 11, (abstract 47).

    Google Scholar 

  69. Rai JR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS . Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46: 219–234.

    CAS  Google Scholar 

  70. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981; 48: 198–204.

    CAS  Google Scholar 

  71. Zent CS, Ding W, Schwager SM, Reinalda MS, Hoyer JD, Jelinek DF et al. The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma. Br J Haematol 2008; 141: 615–621.

    Google Scholar 

  72. Abrisqueta P, Pereira A, Rozman C, Aymerich M, Giné E, Moreno C et al. Improving survival in patients with chronic lymphocytic leukemia (1980–2008): the Hospital Clinic of Barcelona experience. Blood 2009; 114: 2044–2050.

    CAS  Google Scholar 

  73. Brenner H, Gondos A, Pulte D . Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980 s to the early 21st century. Blood 2008; 111: 4916–4921.

    CAS  Google Scholar 

  74. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin's Lymphoma 2009; v.1: 1–155.

    Google Scholar 

  75. Tam CS, Wierda WG, O’Brien S, Lerner S, Khouri IF, Kantarjian HM et al. Life after fludarabine, cyclophosphamide, & rituximab (FCR)—the clinical outcome of patients with chronic lymphocytic leukemia who receive salvage treatment after frontline FCR. Blood 2008; 112: 11, (abstract 2090).

    Google Scholar 

  76. Lin TS, Donohue KA, Lucas MS, Byrd JC, Bengtson EM, Peterson BL et al. Consolidation therapy with subcutaneous (SC) alemtuzumab results in severe infectious toxicity in previously untreated CLL patients who achieve a complete response (CR) after fludarabine and rituximab (FR) induction therapy: Interim safety analysis of the CALGB study 10101. Blood 2007; 110: 11, (abstract 755).

    Google Scholar 

  77. Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jäger G 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; 18: 1093–1101.

    CAS  Google Scholar 

  78. Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004; 103: 3278–3281.

    CAS  Google Scholar 

  79. Zent CS, Call TG, Shanafelt TD, Jelinek DF, Tschumper RC, Secreto CR et al. Alemtuzumab and rituximab for initial treatment of high risk, early stage chronic lymphocytic leukemia (CLL). Blood 2007; 110: 611a, (abstract 2050).

    Google Scholar 

  80. Dreger P, Corradini P, Kimby E, Michallet M, Milligan D, Schetelig J et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21: 12–17.

    CAS  Google Scholar 

  81. Boyiadzis M, Foon KA, Pavletic S . Hematopoietic stem cell transplantation for chronic lymphocytic leukemia: potential cure for an incurable disease. Expert Opin Biol Ther 2007; 7: 1789–1797.

    CAS  Google Scholar 

  82. Delgado J, Milligan DW, Dreger P . Hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time? Blood 2009; 114: 2581–2588.

    CAS  Google Scholar 

  83. Byrd JC, O’Brien S, Flinn IW, Kipps TJ, Weiss M, Rai K 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; 13: 4448–4455.

    CAS  Google Scholar 

  84. Osterborg A, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmen A et al. Ofatumumab (HuMax-CD20), a novel CD20 monoclonal antibody, is an active treatment for patients with CLL refractory to both fludarabine and alemtuzumab or bulky fludarabine-refractory disease: Results from the planned interim analysis of an international pivotal trial. Blood 2008; 112: 11, (abstract 328).

    Google Scholar 

  85. Andritsos LA, Johnson AJ, Lozanski G, Blum W, Kefauver C, Awan F et al. Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol 2008; 26: 2519–2525.

    CAS  Google Scholar 

  86. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K 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; 24: 5343–5349.

    CAS  Google Scholar 

  87. Chen C, Paul H, Xu W, Kukreti V, Trudel S, Wei E et al. A Phase II study of lenalidomide in previously untreated, symptomatic chronic lymphocytic leukemia (CLL). Blood 2008; 112: 11, (abstract 44).

    Google Scholar 

  88. Ferrajoli A, Lee BN, Schlette EJ, O’Brien SM, Gao H, Wen S et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008; 111: 5291–5297.

    CAS  Google Scholar 

  89. Ferrajoli A, O’Brien S, Wierda W, Faderl S, Kornblau S, Yerrow K et al. Lenalidomide as initial treatment of elderly patients with chronic lymphocytic leukemia (CLL). Blood 2008; 112: 11, (abstract 45).

    Google Scholar 

  90. Chao SH, Price DH . Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 2001; 276: 31793–31799.

    CAS  Google Scholar 

  91. de Azevedo Jr W, Canduri F, da Silveira NJ . Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol. Biochem Biophys Res Commun 2002; 293: 566–571.

    Google Scholar 

  92. 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.

    CAS  Google Scholar 

  93. 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.

    CAS  Google Scholar 

  94. Lin TS, Heerema NA, Lozanski G, Fischer B, Blum KA, Andritsos LA et al. Flavopiridol (Alvocidib) induces durable responses in relapsed chronic lymphocytic leukemia (CLL) patients with high-risk cytogenetic abnormalities. Blood 2008; 112: 11, (abstract 46).

    Google Scholar 

  95. Byrd JC, Lin TS, Dalton JT, Wu D, Phelps MA, Fischer B 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; 109: 399–404.

    CAS  Google Scholar 

  96. Schena M, Larsson LG, Gottardi D, Gaidano G, Carlsson M, Nilsson K et al. Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells. Blood 1992; 79: 2981–2989.

    CAS  Google Scholar 

  97. Klasa RJ, Gillum AM, Klem RE, Frankel SR . Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 2002; 12: 193–213.

    CAS  Google Scholar 

  98. Auer RL, Corbo M, Fegan C, Frankel SR, Cotter FE . Bcl-2 antisense (Genasense) induces apoptosis and potentiates activity of both cytotoxic chemotherapy and rituximab in primary CLL cells. Blood 2001; 98: 11, (abstract 3358).

    Google Scholar 

  99. Cotter FE, Auer RL, Corbo M, McElwaine S, Frankel SR . Oblimersen sodium (G3139) sensitizes malignant B-cells to alemtuzumab (Ab) induced apoptosis. Proc Am Soc Clin Oncol 2003; 22: 1, (abstract 910).

    Google Scholar 

  100. O’Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B 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; 25: 1114–1120.

    Google Scholar 

  101. O’Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki AB, Koziner B et al. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol 2009; 27: 5208–5212.

    Google Scholar 

  102. Hus I, Schmitt M, Tabarkiewicz J, Radej S, Wojas K, Bojarska-Junak A et al. Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response. Leukemia 2008; 22: 1007–1017.

    CAS  Google Scholar 

  103. Biagi E, Rousseau R, Yvon E, Schwartz M, Dotti G, Foster A et al. Responses to human CD40 ligand/human interleukin-2 autologous cell vaccine in patients with B-cell chronic lymphocytic leukemia. Clin Cancer Res 2005; 11: 6916–6923.

    CAS  Google Scholar 

  104. Castro J, Sandoval JD, Melo-Cardenas J, Darrah D, Urquiza M, Prussak C et al. A Phase I study of immune gene therapy for patients with CLL using intranodal injection of ISF35, a membrane-stable CD40 binding protein. Blood 2008; 112: 11, (abstract 2100).

    Google Scholar 

  105. Takahashi S, Yotnda P, Rousseau RF, Mei Z, Smith S, Rill D et al. Transgenic expression of CD40 L and interleukin-2 induces an autologous antitumor immune response in patients with non-Hodgkin's lymphoma. Cancer Gene Ther 2001; 8: 378–387.

    CAS  Google Scholar 

  106. Provan D, Bartlett-Pandite L, Zwicky C, Neuberg D, Maddocks A, Corradini P et al. Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood 1996; 88: 2228–2235.

    CAS  Google Scholar 

  107. Bosch F, Ferrer A, Lopez-Guillermo A, Giné E, Bellosillo B, Villamor N et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol 2002; 119: 976–984.

    CAS  Google Scholar 

  108. Del Poeta G, Del Principe MI, Buccisano F, Maurillo L, Capelli G, Luciano F et al. Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia. Cancer 2008; 112: 119–128.

    CAS  Google Scholar 

  109. Montillo M, Tedeschi A, Miqueleiz S, Veronese S, Cairoli R, Intropido L et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol 2006; 24: 2337–2342.

    CAS  Google Scholar 

  110. O’Brien SM, Kantarjian HM, Thomas DA, Cortes J, Giles FJ, Wierda WG et al. Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer 2003; 98: 2657–2663.

    Google Scholar 

  111. Schweighofer CD, Ritgen M, Eichhorst BF, Busch R, Abenhardt W, Kneba M 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 2008; 144: 95–98.

    Google Scholar 

  112. Boettcher S, Fischer K, Stilgenbauer S, Busch R, Fingerle-Rowson G, Fink AM 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. Blood 2008; 112: 11, (abstract 326).

    Google Scholar 

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Foon, K., Hallek, M. Changing paradigms in the treatment of chronic lymphocytic leukemia. Leukemia 24, 500–511 (2010). https://doi.org/10.1038/leu.2009.266

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