Current Oncology Reports

, Volume 9, Issue 5, pp 345–352

Chronic lymphocytic leukemia: Biology and current treatment

Article

Abstract

There has been considerable recent progress in understanding of the biology of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). These accomplishments have been accompanied by progressive improvement in the management of CLL and its complications. This review summarizes these changes and provides guidelines for a comprehensive approach to patient care.

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References and Recommended Reading

  1. 1.
    Zent CS, Kyasa MJ, Evans R, Schichman SA: Chronic lymphocytic leukemia incidence is substantially higher than estimated from tumor registry data. Cancer 2001, 92:1325–1330.PubMedCrossRefGoogle Scholar
  2. 2.
    Call TG, Phyliky RL, Noel P, et al.: Incidence of chronic lymphocytic leukemia in Olmsted County, Minnesota, 1935 through 1989, with emphasis on changes in initial stage at diagnosis. Mayo Clin Proc 1994, 69:323–328.PubMedGoogle Scholar
  3. 3.
    Muller-Hermelink HK, Catovsky D, Montserrat E, Harris NL: Chronic lymphocytic leukemia/small lymphocytic lymphoma. In Tumours of Haematopoietic and Lymphoid Tissues. Edited by Jaffe E, Harris N, Stein H, Vardiman J. Lyon: IARC Press, 2001:127–130.Google Scholar
  4. 4.
    Shanafelt TD, Byrd JC, Call TG, et al.: Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. Ann Intern Med 2006, 145:435–447.PubMedGoogle Scholar
  5. 5.
    Thorselius M, Krober A, Murray F, et al.: Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-utilizing chronic lymphocytic leukemia independent of geographical origin and mutational status. Blood 2006, 107:2889–2894.PubMedCrossRefGoogle Scholar
  6. 6.
    Rawstron AC, Green MJ, Kuzmicki A, et al.: Monoclonal B lymphocytes with the characteristics of “indolent” chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood 2002, 100:635–639.PubMedCrossRefGoogle Scholar
  7. 7.
    Marti GE, Carter P, Abbasi F, et al.: B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Cytometry B Clin Cytom 2003, 52:1–12.PubMedCrossRefGoogle Scholar
  8. 8.
    Nowakowski GS, Dewald GW, Hoyer JD, et al.: Interphase fluorescence in situ hybridization with an IGH probe is important in the evaluation of patients with a clinical diagnosis of chronic lymphocytic leukaemia. Br J Haematol 2005, 130:36–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Rai KR, Sawitsky A, Cronkite EP, et al.: Clinical staging of chronic lymphocytic leukemia. Blood 1975, 46:219–234.PubMedGoogle Scholar
  10. 10.
    Binet JL, Auquier A, Dighiero G, et al.: A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981, 48:198–205.PubMedCrossRefGoogle Scholar
  11. 11.
    Shanafelt TD, Geyer SM, Kay NE: Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL. Blood 2004, 103:1202–1210.PubMedCrossRefGoogle Scholar
  12. 12.
    Damle RN, Wasil T, Fais F, et al.: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999, 94:1840–1847.PubMedGoogle Scholar
  13. 13.
    Hamblin T, Davis Z, Gardiner A, et al.: Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999, 94:1848–1854.PubMedGoogle Scholar
  14. 14.
    Jelinek DF, Tschumper RC, Geyer SM, et al.: Analysis of clonal B-cell CD38 and immunoglobulin variable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukaemia. Br J Haematol 2001, 115:854–861.PubMedCrossRefGoogle Scholar
  15. 15.
    Oscier DG, Gardiner AC, Mould SJ, et al.: Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood 2002, 100:1177–1184.PubMedGoogle Scholar
  16. 16.
    Dohner H, Stilgenbauer S, Benner A, et al.: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000, 343:1910–1916.PubMedCrossRefGoogle Scholar
  17. 17.
    Dewald GW, Brockman SR, Paternoster SF, et al.: Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B-cell chronic lymphocytic leukaemia. Br J Haematol 2003, 121:287–295.PubMedCrossRefGoogle Scholar
  18. 18.
    Dohner H, Stilgenbauer S, James MR, et al.: 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 1997, 89:2516–2522.PubMedGoogle Scholar
  19. 19.
    Chen L, Widhopf G, Huynh L, et al.: Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2002, 100:4609–4614.PubMedCrossRefGoogle Scholar
  20. 20.
    Nolz JC, Tschumper RC, Pittner BT, et al.: ZAP-70 is expressed by a subset of normal human B-lymphocytes displaying an activated phenotype. Leukemia 2005, 19:1018–1024.PubMedCrossRefGoogle Scholar
  21. 21.
    Castro JE, Prada CE, Loria O, et al.: ZAP-70 is a novel conditional heat shock protein 90 (Hsp90)-client protein: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis and impaired signaling in chronic lymphocytic leukemia. Blood 2005, 106:2506–2512.PubMedCrossRefGoogle Scholar
  22. 22.
    Crespo M, Bosch F, Villamor N, et al.: ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003, 348:1764–1775.PubMedCrossRefGoogle Scholar
  23. 23.
    Wiestner A, Rosenwald A, Barry TS, et al.: ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003, 101:4944–4951.PubMedCrossRefGoogle Scholar
  24. 24.
    Rassenti LZ, Huynh L, Toy TL, et al.: ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 2004, 351:893–901.PubMedCrossRefGoogle Scholar
  25. 25.
    Orchard JA, Ibbotson RE, Davis Z, et al.: ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 2004, 363:105–111.PubMedCrossRefGoogle Scholar
  26. 26.
    Oscier DG, Richards S, Orchard J, et al.: Prognostic factors in the UK LRF CLL4 trial [abstract]. Blood 2005, 106:2099.CrossRefGoogle Scholar
  27. 27.
    Letestu R, Le Garff-Tavernier M, Vaur D, et al.: Analysis of B-CLL with discordant ZAP-70 expression and IgVH mutational status [abstract]. Blood 2005, 106:1194.Google Scholar
  28. 28.
    Del Principe MI, Del Poeta G, Buccisano F, et al.: Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood 2006, 108:853–861.PubMedCrossRefGoogle Scholar
  29. 29.
    Deaglio S, Capobianco A, Bergui L, et al.: CD38 is a signaling molecule in B-cell chronic lymphocytic leukemia cells. Blood. 2003, 102:2146–2155.PubMedCrossRefGoogle Scholar
  30. 30.
    Ibrahim S, Keating M, Do KA, et al.: CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 2001, 98:181–186.PubMedCrossRefGoogle Scholar
  31. 31.
    Guarini A, Gaidano G, Mauro FR, et al.: Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features. Blood 2003, 102:1035–1041.PubMedCrossRefGoogle Scholar
  32. 32.
    Damle R, Wasil T, Fais F, et al.: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999, 94:1840–1847.PubMedGoogle Scholar
  33. 33.
    Hamblin TJ, Orchard JA, Ibbotson RE, et al.: CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002, 99:1023–1029.PubMedCrossRefGoogle Scholar
  34. 34.
    Zent CS, Slager SL, Ding W, et al.: Autoimmune cytopenias in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL): The clinical implications of earlier diagnosis and longer follow up [abstract]. Blood 2006, 108:790a.Google Scholar
  35. 35.
    Kyasa MJ, Parrish RS, Schichman SA, Zent CS: Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol 2003, 74:1–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Mauro F, Foa R, Cerretti R, et al.: Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000, 95:2786–2792.PubMedGoogle Scholar
  37. 37.
    Cheson BD, Bennett JM, Grever M, et al.: National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 1996, 87:4990–4997.PubMedGoogle Scholar
  38. 38.
    Lee YK, Bone ND, Strege AK, et al.: VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia. Blood 2004, 104:788–794.PubMedCrossRefGoogle Scholar
  39. 39.
    Shanafelt TD, Lee YK, Call TG, et al.: Clinical effects of oral green tea extracts in four patients with low grade B-cell malignancies. Leuk Res 2006, 30:707–712.PubMedCrossRefGoogle Scholar
  40. 40.
    Zent CS, Bone ND, Call TG, et al.: Alemtuzumab and rituximab for therapy of patents with early stage high risk CLL: report of a planned Interim Analysis. Blood 2006, 108:800a–801a.Google Scholar
  41. 41.
    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.PubMedCrossRefGoogle Scholar
  42. 42.
    Bellosillo B, N V, Colomer D, et al.: In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia. Blood 1999, 94:2836–2843.PubMedGoogle Scholar
  43. 43.
    Yamauchi T, Nowak BJ, Keating MJ, Plunkett W: DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine. Clin Cancer Res 2001, 7:3580–3589.PubMedGoogle Scholar
  44. 44.
    O’Brien SM, Kantarjian HM, Cortes J, et al.: Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 2001, 19:1414–1420.PubMedGoogle Scholar
  45. 45.
    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.PubMedCrossRefGoogle Scholar
  46. 46.
    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, 25:1–6.CrossRefGoogle Scholar
  47. 47.
    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.PubMedCrossRefGoogle Scholar
  48. 48.
    Keating MJ, O’Brien S, Albitar M, 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.PubMedCrossRefGoogle Scholar
  49. 49.
    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.PubMedCrossRefGoogle Scholar
  50. 50.
    Rawstron AC, Villamor N, Ritgen M, et al.: International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia 2007, 21:956–964.PubMedGoogle Scholar
  51. 51.
    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.PubMedCrossRefGoogle Scholar
  52. 52.
    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.PubMedCrossRefGoogle Scholar
  53. 53.
    Gribben JG: Salvage therapy for CLL and the role of stem cell transplantation. Hematology 2005:292–298.Google Scholar
  54. 54.
    Faderl S, Thomas DA, O’Brien S, et al.: Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood 2003, 101:3413–3415.PubMedCrossRefGoogle Scholar
  55. 55.
    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.PubMedCrossRefGoogle Scholar
  56. 56.
    Chanan-Khan A, Miller KC, DiMiceli L, et al.: Antileukemic effects of lenalidomide (Revlimid) in patients with relapsed or refractory chronic lymphocytic leukemia: results of a pilot phase II study. Leuk Lymphoma 2005, 46(Suppl 1):S96–S97.Google Scholar
  57. 57.
    Coffier B, Tilly H, Pedersen LM, et al.: A novel, fully human, anti-CD20 monoclonal antibody. First results from an ongoing phase I/II trial in patients with chronic lymphocytic leukemia. Leuk Lymphoma 2005, 46(suppl 1):S96–S97.Google Scholar
  58. 58.
    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 leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q-and 17p-). Clin Cancer Res 2005, 11:7757–7763.PubMedCrossRefGoogle Scholar
  59. 59.
    Ritgen M, Stilgenbauer S, Von Neuhoff N, et al.: Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leuekmia with unmutated immunoglobulin variable heavy chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 2004, 104:2600–2602.PubMedCrossRefGoogle Scholar
  60. 60.
    Paneesha S, Milligan DW: Stem cell transplantation for chronic lymphocytic leukaemia. Br J Haematol 2005, 128:145–152.PubMedCrossRefGoogle Scholar
  61. 61.
    Sorror ML, Maris MB, Sandmaier BM, et al.: Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 2005, 23:3819–3829.PubMedCrossRefGoogle Scholar
  62. 62.
    Montserrat E, Moreno C, Esteve J, et al.: How we treat refractory chronic lymphocytic leukemia. Blood 2006, 107:1276–1283.PubMedCrossRefGoogle Scholar
  63. 63.
    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.PubMedCrossRefGoogle Scholar
  64. 64.
    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.PubMedCrossRefGoogle Scholar
  65. 65.
    Milligan DW, Fernandes S, Dasgupta R, et al.: Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood 2005, 105:397–404.PubMedCrossRefGoogle Scholar
  66. 66.
    Gribben JG, Zahrieh D, Stephans K, et al.: Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood 2005, 106:4389–4396.PubMedCrossRefGoogle Scholar
  67. 67.
    Morrison V: The infectious complications of chronic lymphocytic leukemia. Semin Oncol 1998, 25:98–106.PubMedGoogle Scholar
  68. 68.
    Sinisalo M, Aittoniemi J, Kayhty H, Vilpo J: Vaccination against infections in chronic lymphocytic leukemia. Leuk Lymphoma 2003, 44:649–652.PubMedCrossRefGoogle Scholar
  69. 69.
    Ljungman P, Nahi H, Linde A: Vaccination of patients with haematological malignancies with one or two doses of influenza vaccine: a randomised study. Br J Haematol 2005, 130:96–98.PubMedCrossRefGoogle Scholar
  70. 70.
    Morrison VA: Infections in patients with chronic lymphocytic leukemia. In Chronic Lymphocytic Leukemias, end 2, Edited by Cheson BD. New York: Marcel Dekker; 2001:505–523.Google Scholar
  71. 71.
    Diehl L, Ketchum L: Autoimmune disease and chronic lymphocytic leukemia: Autoimmune hemolyticanemia, pure red cell aplasia, and autoimmune thrombocytopenia. Semin Oncol 1998, 25:80–97.PubMedGoogle Scholar
  72. 72.
    Giles F, O’Brien S, Keating M: Chronic lymphocytic leukemia in (Richter’s) transformation. Semin Oncol 1998, 25:117–125.PubMedGoogle Scholar
  73. 73.
    Kyasa MJ, Hazlett L, Parrish RS, et al.: Veterans with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have a markedly increased rate of second malignancy, which is the most common cause of death. Leuk Lymphoma 2004, 45:507–513.PubMedCrossRefGoogle Scholar
  74. 74.
    Hisada M, Biggar R, Greene M, et al.: Solid tumors after chronic lymphocytic leukemia. Blood 2001, 98:1979–1981.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  1. 1.Division of HematologyMayo Clinic College of MedicineRochesterUSA

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