Blood Reviews
Volume 23, Issue 5 , Pages 217-224 , September 2009

Emerging therapies for patients with advanced chronic lymphocytic leukaemia

References 

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96
  2. Ries LAG, Melbert D, Krapcho M et al. SEER Cancer statistics review, 1975–2005, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site; 2008.
  3. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–234
  4. Binet JL, Leporrier M, Dighiero G, et al. A clinical staging system for chronic lymphocytic leukemia: prognostic significance. Cancer. 1977;40:855–864
  5. 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;111:5446–5456
  6. Moreno C, Montserrat E. New prognostic markers in chronic lymphocytic leukemia. Blood Rev. 2008;22:211–219
  7. Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol. 2007;25:799–804
  8. 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;370:230–239
  9. Stilgenbauer S, Zenz T, Winkler D et al. Genomic aberrations, VH mutation status and outcome after fludarabine and cyclophosphamide (FC) or FC plus rituximab in the CLL8 Trial [abstract]. Blood (ASH Annual Meeting Abstracts) 2008;112: Abstract 781.
  10. Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent chronic lymphocytic leukemia. French cooperative group on chronic lymphocytic leukemia. N Engl J Med. 1998;338:1506–1514
  11. Nabhan C, Shanafelt TD, Kay NE. Controversies in the front-line management of chronic lymphocytic leukemia. Leukemia Res. 2008;32:679–688
  12. Eichhorst B, Goede V, Hallek M. Treatment of elderly patients with chronic lymphocytic leukemia. Leukemia Lymphoma. 2009;52:171–178
  13. Eichhorst BF, Busch R, Stauch M et al. No significant clinical benefit of first line therapy with fludarabine in comparison to chlorambucil in elderly patients with advanced chronic lymphocytic leukemia: Results of a phase III study of the German CLL Study Group [abstract]. Blood (ASH Annual Meeting Abstracts) 2007;110: Abstract 629.
  14. 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;25:793–798
  15. 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
  16. 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;105:49–53
  17. 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;112:975–980
  18. Bosch F, Abrisqueta P, Villamor N et al. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol, in press.
  19. Hallek M, Fingerle-Rowson G, Fink A-M et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab versus fludarabine and cyclophosphamide improves response rates and progression-free survival in previously untreated patients with advanced chronic lymphocytic leukaemia [abstract]. Blood (ASH Annual Meeting Abstracts) 2008;112: Abstract 325.
  20. Kay NE, Geyer SM, Call TG, 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
  21. Lamanna N, Jurcic JG, Noy A, 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
  22. 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;27:498–503
  23. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343:1750–1757
  24. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616–5623
  25. Bosch F, Ferrer A, Villamor N, et al. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008;14:155–161
  26. Wierda W, O’Brien S, Faderl S, et al. A retrospective comparison of three sequential groups of patients with recurrent/refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer. 2006;106:337–345
  27. Bosch F, Ferrer A, López-Guillermo A, et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002;119:976–984
  28. Robak T, Moiseev SI, Dmoszynska A et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression free survival in relapsed or refractory chronic lymphocytic leukaemia compared with FC alone: Final results from the International Randomized Phase III REACH Trial [abstract]. Blood (ASH Annual Meeting Abstracts) 2008;112: Abstract lba-1.
  29. Lamanna N, Kalaycio M, Maslak P, 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
  30. 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;23:7024–7031
  31. Weiss MA, Maslak PG, Jurcic JG, et al. Pentostatin and cyclophosphamide: an effective new regimen in previously treated patients with chronic lymphocytic leukemia. J Clin Oncol. 2003;21:1278–1284
  32. 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;97:114–120
  33. 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;23:2971–2979
  34. Karlsson C, Lundin J, Kimby E, et al. Phase II study of subcutaneous alemtuzumab without dose escalation in patients with advanced-stage, relapsed chronic lymphocytic leukaemia. Br J Haematol. 2009;144:78–85
  35. 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;23:4070–4078
  36. Gribben JG. Stem cell transplantation in chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2009;15(Suppl. 1):53–58
  37. Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia. 2007;21:12–17
  38. Dreger P, Brand R, Milligan D, et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia. 2005;19:1029–1033
  39. Sorror ML, Storer BE, Maloney DG, Sandmaier BM, Martin PJ, Storb R. Outcomes after allogeneic hematopoietic cell transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of lymphoma and chronic lymphocytic leukemia. Blood. 2008;111:446–452
  40. Hoogendoorn M, Jedema I, Barge RM, et al. Characterization of graft-versus-leukemia responses in patients treated for advanced chronic lymphocytic leukemia with donor lymphocyte infusions after in vitro T-cell depleted allogeneic stem cell transplantation following reduced-intensity conditioning. Leukemia. 2007;21:2569–2574
  41. Delgado J, Thomson K, Russell N, et al. Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British society of blood and marrow transplantation study. Blood. 2006;107:1724–1730
  42. Ritgen M, Böttcher S, Stilgenbauer S, et al. Quantitative MRD monitoring identifies distinct GVL response patterns after allogeneic stem cell transplantation for chronic lymphocytic leukemia: results from the GCLLSG CLL3X trial. Leukemia. 2008;22:1377–1386
  43. Sorror ML, Storer BE, Sandmaier BM, et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008;26:4912–4920
  44. Delgado J, Pillai S, Benjamin R, et al. The effect of in vivo T cell depletion with alemtuzumab on reduced-intensity allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2008;14:1288–1297
  45. Caballero D, Garcia-Marco JA, Martino R, et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukaemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-). Clin Cancer Res. 2005;11:7757–7763
  46. Schetelig J, van Biezen A, Brand R, et al. Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European group for blood and marrow transplantation analysis. J Clin Oncol. 2008;26:5094–5100
  47. Keating MJ, Kantarjian H, O’Brien S, et al. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol. 1991;9:44–49
  48. 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. Lancet. 1996;347:1432–1438
  49. Keating MJ, O’Brien SO, Kontoyiannis D, et al. Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia. Leukemia Lymphoma. 2002;34:1755–1762
  50. Perkins JG, Flynn JM, Howard RS, Byrd JC. Frequency and type of serious infections in fludarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma. Implications for clinical trials in this patient population. Cancer. 2002;94:2033–2039
  51. Döhner H, Fischer K, Bentz M, et al. P53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995;85:1580–1589
  52. Gribben JG, Hallek M. Rediscovering alemtuzumab: current and emerging therapeutic roles. Br J Haematol. 2009;144:818–831
  53. 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;99:3554–3561
  54. 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;doi:10.1200/JCO.2008.21.1128.
  55. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103:3278–3281
  56. Tam CS, O’Brien S, Lerner S, et al. The natural history of fludarabine-refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy. Leukemia Lymphoma. 2007;48:1931–1939
  57. Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001;98:1326–1331
  58. Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004;104:1793–1800
  59. Coiffier B, Lepretre S, Pedersen LM, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study. Blood. 2008;111:1094–1100
  60. Osterborg A, Kipps T, Mayer J 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 [abstract]. Blood (ASH Annual Meeting Abstract) 2008;112: Abstract 328.
  61. Fries T, Gerdes C, Nopora A et al. GA101, a novel humanized type II CD20 antibody with glycoengineered Fc and enhanced cell death induction, mediates superior efficacy in a variety of NHL xenograft models in comparison to rituximab [abstract]. Blood (ASH Annual Meeting Abstracts) 2007;110: Abstract 2338.
  62. 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;13:4448–4455
  63. 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 [abstract]. Blood (ASH Annual Meeting Abstracts) 2006;108: Abstract 32.
  64. Tsimberidou AM, Wierda WG, Plunkett W, et al. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter’s syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008;26:196–203
  65. Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008;22:2048–2053
  66. Dungarwalla M, Evans SO, Riley U, Catovsky D, Dearden CE, Matutes E. High dose methylprednisolone and rituximab is an effective therapy in advanced refractory chronic lymphocytic leukemia resistant to fludarabine therapy. Haematologica. 2008;93:475–476
  67. Wierda W, O’Brien S, Faderl S et al. Combined cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR), an active regimen for heavily treated patients with CLL [abstract]. Blood (ASH Annual Meeting Abstracts) 2006;108: Abstract 31.
  68. Wierda W, O’Brien S, Faderl S et al. CFAR, an active frontline regimen for high-risk patients with CLL, including those with del17p [abstract]. Blood (ASH Annual Meeting Abstracts) 2008;112: Abstract 2095.
  69. Fischer K, Stilgenbauer S, Schweighofer CD et al. Bendamustine in combination with rituximab for patients with relapsed chronic lymphocytic leukemia: a multicentre phase II trial of the German CLL Study Group [abstract]. Blood (ASH Annual Meeting Abstracts) 2008;112: Abstract 330.
  70. Chanan-Khan A, Miller KC, Takeshita K, et al. Results of a phase I clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia. Blood. 2005;106:3348–3352
  71. Chanan-Khan A, Miller KC, Musial L, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2006;24:5343–5349
  72. Andritsos LA, Johnson AJ, Lozanski G, 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
  73. Ferrajoli A, Lee BN, Schlette EJ, et al. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008;111:5291–5297
  74. Ferrajoli A, Keating M, Wierda W et al. Lenalidomide is active in patients with relapsed/refractory chronic lymphocytic leukemia carrying unfavorable chromosomal abnormalities [abstract]. Blood (ASH Annual Meeting Abstracts) 2007;110: Abstract 754.
  75. Chanan-Khan A, Czuczman M, Padmanabhan S et al. Clinical efficacy of lenalidomide in fludarabine-refractory chronic lymphocytic leukemia patients [abstract]. Blood (ASH Annual Meeting Abstracts) 2007;110: Abstract 3108.
  76. Byrd JC, Shinn C, Waselenko JK, 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
  77. Flinn IW, Byrd JC, Bartlett N, et al. Flavopiridol administered as a 24-h continuous infusion in chronic lymphocytic leukemia lacks clinical activity. Leukemia Res. 2005;29:1253–1257
  78. Byrd JC, Peterson BL, Gabrilove J, et al. Treatment of relapsed chronic lymphocytic leukemia by 72-h continuous infusion or 1-h bolus infusion of flavopiridol: results from cancer and leukemia group B study 19,805. Clin Cancer Res. 2005;11:4176–4181
  79. 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;109:399–404
  80. Phelps MA, Lin TS, Johnson AJ, et al. Clinical response and pharmacokinetics from a phase I study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood. 2009;113:2637–2645
  81. Chen R, Wierda WG, Chubb S, et al. Mechanism of action of SNS-032, a novel cyclin dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009;113:4637–4645
  82. Pepper C, Lin TT, Pratt G, et al. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood. 2008;112:3807–3817
  83. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324–1337
  84. O’Brien SM, Claxton DF, Crump M, et al. Phase I study of obatoclax mesylate (GX15–070), a small molecule pan–Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009;113:299–305
  85. Wilson WH, Czuczman MS, LaCasce AS et al. A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of ABT-263 in subjects with refractory or relapsed lymphoid malignancies [abstract]. J Clin Oncol (ASCO Annual Meeting Abstracts) 2008;28: Abstract 8511.
  86. Roberts AW, Brown J, Seymour JF et al. An ongoing phase 1 study of ABT-263; pharmacokinetics, safety and anti-tumor activity in patients with relapsed or refractory chronic lymphocytic leukaemia [abstract]. Blood (ASH Annual Meeting Abstracts) 2008;112: Abstract 3177.
  87. Raval A, Byrd JC, Plass C. Epigenetics in chronic lymphocytic leukemia. Semin Oncol. 2006;33:157–166
  88. Delgado J. Novel epigenetic targets in lymphoproliferative disorders. Curr Cancer Drug Targets. 2008;8:378–391
  89. Byrd JC, Marcucci G, Parthun MR, et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood. 2005;105:959–967
  90. Inoue S, Walewska R, Dyer MJ, Cohen GM. Downregulation of Mcl-1 potentiates HDACi-mediated apoptosis in leukemic cells. Leukemia. 2008;22:819–825

PII: S0268-960X(09)00039-3

doi: 10.1016/j.blre.2009.07.001

Blood Reviews
Volume 23, Issue 5 , Pages 217-224 , September 2009

Article Tools