Best Practice & Research Clinical Haematology
Volume 23, Issue 1 , Pages 47-59 , March 2010

Autoimmune Complications in Chronic Lymphocytic Leukaemia (CLL)

  • Clive S. Zent, MD (Consultant physician and Associate Professor of Medicine)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +1 507 266 1154; Fax: +1 507 266 4972.
    • ,
  • Neil E. Kay, MD (Consultant physician and Professor of Medicine)

      Affiliations

    • Tel.: +1 507 285 1961; Fax: +1 507 266 4972.

References 

  1. Hamblin TJ. Non-hemic autoimmunity in CLL. Leuk Res. 2009;33:366–367
  2. Dameshek W. Chronic lymphocytic leukemia–an accumulative disease of immunolgically incompetent lymphocytes. Blood. 1967;29:566–584Suppl
  3. Landgren O, Engels EA, Caporaso NE, et al. Patterns of autoimmunity and subsequent chronic lymphocytic leukemia in Nordic countries. Blood. 2006;108:292–296
  4. Barcellini W, Capalbo S, Agostinelli RM, et al. Relationship between autoimmune phenomena and disease stage and therapy in B-cell chronic lymphocytic leukemia. Haematologica. 2006;91:1689–1692
  5. Hamblin TJ. Just exactly how common is CLL?. Leuk Res. 2009;33:1452–1453
  6. Zent CS, Kyasa MJ, Evans R, et al. Chronic lymphocytic leukemia incidence is substantially higher than estimated from tumor registry data. Cancer. 2001;92:1325–1330
  7. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107:265–276
  8. Wasserman LR, Stats D, Schwartz L, et al. Symptomatic and hemopathic hemolytic anemia. Am J Med. 1955;18:961–989
  9. Hamblin T. Autoimmune disease and its management in chronic lymphocytic leukemia. In:  Cheson B editors. Chronic lymphocytic leukemias. 2 ed.. New York: Marcel Dekker; 2001;p. 435–458
  10. Zent CS, Ding W, Schwager SM, et al. The prognostic significance of cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Br J Haematol. 2008;141:615–621
  11. 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
  12. Kyasa MJ, Parrish RS, Schichman SA, et al. Autoimmune cytopenia does not predict poor prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Hematol. 2003;74:1–8
  13. Gehrs B, Friedberg R. Autoimmune hemolytic anemia. Am J Hematol. 2002;69:258–271
  14. Sallah S, Wan JY, Hanrahan LR. Future development of lymphoproliferative disorders in patients with autoimmune hemolytic anemia. Clin Cancer Res. 2001;7:791–794
  15. 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
  16. Mittal S, Blaylock MG, Culligan DJ, et al. A high rate of CLL phenotype lymphocytes in autoimmune hemolytic anemia and immune thrombocytopenic purpura. Haematologica. 2008;93:151–152
  17. Visco C, Ruggeri M, Laura Evangelista M, et al. Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukemia. Blood. 2008;111:1110–1116
  18. Hamblin T, Oscier D, Young B. Autoimmunity in chronic lymphocytic leukaemia. J Clin Pathol. 1986;39:713–716
  19. Warner MN, Moore JC, Warkentin TE, et al. A prospective study of protein-specific assays used to investigate idiopathic thrombocytopenic purpura. Br J Haematol. 1999;104:442–447
  20. Tomer A, Koziol J, McMillan R. Autoimmune thrombocytopenia: flow cytometric determination of platelet-associated autoantibodies against platelet-specific receptors. J Thromb Haemost. 2005;3:74–78
  21. Yoo D, Pierce L, Lessin L. Acquired pure red cell aplasia associated with chronic lymphocytic leukemia. Cancer. 1983;51:844–850
  22. Kipps TJ, Carson DA. Autoantibodies in chronic lymphocytic leukemia and related systemic autoimmune diseases. Blood. 1993;81:2475–2487
  23. Beaume A, Brizard A, Dreyfus B, et al. High incidence of serum monoclonal Igs detected by a sensitive immunoblotting technique in B-cell chronic lymphocytic leukemia. Blood. 1994;84:1216–1219
  24. Broker BM, Klajman A, Youinou P, et al. Chronic lymphocytic leukemic (CLL) cells secrete multispecific autoantibodies. J Autoimmun. 1988;1:469–481
  25. Stevenson FK, Hamblin TJ, Stevenson GT, et al. Extracellular idiotypic immunoglobulin arising from human leukemic B lymphocytes. J Exp Med. 1980;152:1484–1496
  26. Diehl L, Ketchum L. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia. Semin Oncol. 1998;25:80–97
  27. Oliveira GG, Hutchings PR, Roitt IM, et al. Production of erythrocyte autoantibodies in NZB mice is inhibited by CD4 antibodies. Clin Exp Immunol. 1994;96:297–302
  28. Barker RN, Hall AM, Standen GR, et al. Identification of T-cell epitopes on the Rhesus polypeptides in autoimmune hemolytic anemia. Blood. 1997;90:2701–2715
  29. Leddy JP, Falany JL, Kissel GE, et al. Erythrocyte membrane proteins reactive with human (warm-reacting) anti-red cell autoantibodies. J Clin Invest. 1993;91:1672–1680
  30. Hall AM, Vickers MA, McLeod E, et al. Rh autoantigen presentation to helper T cells in chronic lymphocytic leukemia by malignant B cells. Blood. 2005;105:2007–2015
  31. Galletti J, Canones C, Morande P, et al. Chronic lymphocytic leukemia cells bind and present the erythrocyte protein band 3: possible role as initiators of autoimmune hemolytic anemia. J Immunol. 2008;181:3674–3683
  32. Bluestone JA, Tang Q. How do CD4+CD25+ regulatory T cells control autoimmunity?. Curr Opin Immunol. 2005;17:638–642
  33. Ward FJ, Hall AM, Cairns LS, et al. Clonal regulatory T cells specific for a red blood cell autoantigen in human autoimmune hemolytic anemia. Blood. 2008;111:680–687
  34. Yu J, Heck S, Patel V, et al. Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura. Blood. 2008;112:1325–1328
  35. Beyer M, Kochanek M, Darabi K, et al. Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood. 2005;106:2018–2025
  36. Dearden C, Wade R, Else M, et al. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood. 2008;111:1820–1826
  37. Psaila B, Bussel JB. Refractory immune thrombocytopenic purpura: current strategies for investigation and management. Br J Haematol. 2008;143:16–26
  38. Lewis FB, Schwartz RS, Dameshek W. X-radiation and alkylating agents as possible “trigger” mechanisms in the autoimmune complications of malignant lymphophroliferative disease. Clin Exp Immunol. 1966;1:3–11
  39. Montillo M, Tedeschi A, Leoni P. Recurrence of autoimmune thrombocytopenia after treatment with fludarabine in a patient with chronic lymphocytic leukemia. Leuk Lymphoma. 1994;15:187–188
  40. Leporrier M, Reman O, Troussard X. Pure red-cell aplasia with fludarabine for chronic lymphocytic leukaemia. Lancet. 1993;342:555
  41. Weiss RB, Freiman J, Kweder SL, et al. Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol. 1998;16:1885–1889
  42. Otton SH, Turner DL, Frewin R, et al. Autoimmune thrombocytopenia after treatment with Campath 1H in a patient with chronic lymphocytic leukaemia. Br J Haematol. 1999;106:261–262
  43. Byrd JC, Hertler AA, Weiss RB, et al. Fatal recurrence of autoimmune hemolytic anemia following pentostatin therapy in a patient with a history of fludarabine-associated hemolytic anemia. Ann Oncol. 1995;6:300–301
  44. Robak T, Blasinska-Morawiec M, Krykowski E, et al. Autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia treated with 2-chlorodeoxyadenosine (cladribine). Eur J Haematol. 1997;58:109–113
  45. Stern SC, Shah S, Costello C. Probable autoimmune neutropenia induced by fludarabine treatment for chronic lymphocytic leukaemia. Br J Haematol. 1999;106:836–837
  46. Myint H, Copplestone J, Orchard J, et al. Fludarabine-related autoimmune hemolytic anaemia in patients with chronic lymphocytic leukaemia. Br J Haematol. 1995;91:341–344
  47. Hamblin TJ. Autoimmune complications of chronic lymphocytic leukemia. Semin Oncol. 2006;33:230–239
  48. Majumdar G, Brown S, Slater G, et al. Clinical spectrum of autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Leuk Lymphoma. 1993;9:149–151
  49. Zent CS, Ding W, Reinalda MS, et al. Autoimmune cytopenia in chronic lymphocytic leukemia/small lymphocytic lymphoma: changes in clinical presentation and prognosis. Leuk Lymphoma. 2009;50:1261–1268
  50. Efremov D, Ivanovski M, Siljanovski N, et al. Restricted immunoglobulin VH region repertoire in chronic lymphocytic leukemia patients with autoimmune hemolytic leukemia. Blood. 1996;87:3869–3876
  51. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–234
  52. 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
  53. Mouthon L, Guillevin L, Tellier Z. Intravenous immunoglobulins in autoimmune- or parvovirus B19-mediated pure red-cell aplasia. Autoimmun Rev. 2005;4:264–269
  54. Zent CS, Shanafelt T. Management of autoimmune cytopenia complicating chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50:863–864
  55. 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 (IWCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 guidelines. Blood. 2008;111:5446–5456
  56. Dameshek W, Komninos ZD. The present status of treatment of autoimmune hemolytic anemia with ACTH and cortisone. Blood. 1956;11:648–664
  57. Packman CH. Hemolytic anemia due to warm autoantibodies. Blood Rev. 2008;22:17–31
  58. Cortes J, O'Brien S, Loscertales J, et al. Cyclosporin A for the treatment of cytopenia associated with chronic lymphocytic leukemia. Cancer. 2001;92:2016–2022
  59. Ruess-Borst MA, Waller HD, Muller CA. Successful treatment of steroid-resistant hemolysis in chronic lymphocytic leukemia with cyclosporine A. Am J Hematol. 1994;46:375–376
  60. Zaja F, Vianelli N, Sperotto A, et al. Anti-CD20 therapy for chronic lymphocytic leukemia-associated autoimmune diseases. Leuk Lymphoma. 2003;44:1951–1955
  61. Gupta N, Kavuru S, Patel D, et al. Rituximab-based chemotherapy for steroid-refractory autoimmune hemolytic anemia of chronic lymphocytic leukemia. Leukemia. 2002;16:2092–2095
  62. D'Arena G, Laurenti L, Capalbo S, et al. Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia. Am J Hematol. 2006;81:598–602
  63. Neal TF, Tefferi A, Witzig TE, et al. Splenectomy in advanced chronic lymphocytic leukemia: a single institution experience with 50 patients. Am J Med. 1992;93:435–440
  64. Akpek G, McAneny D, Weintraub L. Comparative response to splenectomy in Coombs-positive autoimmune hemolytic anemia with or without associated disease. Am J Hematol. 1999;61:98–102
  65. Kaufman M, Limaye S, Driscoll N, et al. A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50:892–899
  66. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417–1423
  67. Karlsson C, Hansson L, Celsing F, et al. Treatment of severe refractory autoimmune hemolytic anemia in B-cell chronic lymphocytic leukemia with alemtuzumab (humanized CD52 monoclonal antibody). Leukemia. 2007;21:511–514
  68. Okamoto M, Nakano S, Namura K, et al. CD5-negative chronic lymphocytic leukemia with indolent clinical course and autoimmune thrombocytopenia, successfully treated with rituximab. Am J Hematol. 2004;77:413–415
  69. Shanafelt TD, Madueme HL, Wolf RC, et al. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome. Mayo Clin Proc. 2003;78:1340–1346
  70. Anderson JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med. 1994;330:1560–1564
  71. Chikkappa G, Pasquale D, Zarrabi MH, et al. Cyclosporine and prednisone therapy for pure red cell aplasia in patients with chronic lymphocytic leukemia. Am J Hematol. 1992;41:5–12
  72. Ghazal H. Successful treatment of pure red cell aplasia with rituximab in patients with chronic lymphocytic leukemia. Blood. 2002;99:1092–1094
  73. Marotta G, Lenoci M, Fabbri A, et al. Efficacy of rituximab in the treatment of refractory chronic lymphocytic leukemia patient with bone marrow aplasia. Hematol J. 2002;3:299–301
  74. Pantelidou D, Tsatalas C, Margaritis D, et al. Anti-CD20 monoclonal antibody rituximab for the treatment of B-cell chronic lymphocytic leukemia-associated pure red cell aplasia. Hematol J. 2004;5:546–547
  75. Narra K, Borghaei H, Al-Saleem T, et al. Pure red cell aplasia in B-cell lymphoproliferative disorder treated with rituximab: report of two cases and review of the literature. Leuk Res. 2006;30:109–114
  76. Ru X, Liebman HA. Successful treatment of refractory pure red cell aplasia associated with lymphoproliferative disorders with the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). Br J Haematol. 2003;123:278–281
  77. Rodon P, Breton P, Courouble G. Treatment of pure red cell aplasia and autoimmune haemolytic anaemia in chronic lymphocytic leukaemia with Campath-1H. Eur J Haematol. 2003;70:319–321
  78. Borthakur G, O'Brien S, Wierda WG, et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab–incidence and predictors. Br J Haematol. 2007;136:800–805
  79. 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
  80. Bowen DA, Call TG, Jenkins GD, et al. Methylprednisolone-rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Leuk Lymphoma. 2007;48:2412–2417
  81. 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
  82. 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
  83. Podolanczuk A, Lazarus AH, Crow AR, et al. Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood. 2009;113:3154–3160
  84. Buchner M, Fuchs S, Prinz G, et al. Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Cancer Res. 2009;69:5424–5432

PII: S1521-6926(10)00005-8

doi: 10.1016/j.beha.2010.01.004

Best Practice & Research Clinical Haematology
Volume 23, Issue 1 , Pages 47-59 , March 2010

Article Tools