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Immune defects in patients with chronic lymphocytic leukemia

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Abstract

Over the past decade, the introduction of nucleoside analogs and monoclonal antibodies into the treatment of patients with chronic lymphocytic leukemia (CLL) has resulted in higher rates and longer duration of response. This is a significant step towards achieving the ultimate goal of disease-eradication and improved survival. A continuing problem, however, is the susceptibility of these patients to infections. Profound dysregulation of the host immune system in patients with CLL and its impact on the clinical course of the disease are well established. A number of investigators have sought to identify the mechanisms underlying this innate immune dysfunction, which is further exacerbated by the actions of the potent therapeutic agents. The early recognition of infections as well as prophylactic administration of appropriate antibiotics has been the mainstay of managing infections in patients with CLL. Hopefully, increasing understanding of the molecular events underlying the neoplastic change in CLL will lead to more targeted and less immunosuppressive therapeutic modalities. Furthermore, the understanding of the mechanisms of immune dysfunction in CLL is of pivotal importance in the novel immune-based therapeutic strategies currently under development.

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References

  1. Molica S, Levato D, Levato L (1993) Infections in chronic lymphocytic leukemia. Analysis of incidence as a function of length of follow-up. Haematologica 78:374–377

    PubMed  CAS  Google Scholar 

  2. Morrison VA (1998) The infectious complications of chronic lymphocytic leukemia. Semin Oncol 25:98–106

    PubMed  CAS  Google Scholar 

  3. Tsiodras S, Samonis G, Keating MJ, Kontoyiannis DP (2000) Infection and immunity in chronic lymphocytic leukemia. Mayo Clin Proc 75:1039–1054

    PubMed  CAS  Google Scholar 

  4. Itala M, Helenius H, Nikoskelainen J, Remes K (1992) Infections and serum IgG levels in patients with chronic lymphocytic leukemia. Eur J Haematol 48:266–270

    PubMed  CAS  Google Scholar 

  5. Molica S (1994) Infections in chronic lymphocytic leukemia: risk factors, and impact on survival, and treatment. Leuk Lymphoma 13:203–214

    PubMed  CAS  Google Scholar 

  6. Rozman C, Montserrat E (1995) Chronic lymphocytic leukemia. N Engl J Med 333:1052–1057

    Article  PubMed  CAS  Google Scholar 

  7. Cheson BD (1995) Infectious and immunosuppressive complications of purine analog therapy. J Clin Oncol 13:2431–2448

    PubMed  CAS  Google Scholar 

  8. Frank DA, Mahajan S, Ritz J (1999) Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat Med 5:444–447

    PubMed  CAS  Google Scholar 

  9. Fairley GH, Scott RB (1961) Hypogammaglobulinemia in chronic lymphocytic leukemia. British Medical Journal 2:920

    PubMed  CAS  Google Scholar 

  10. Rozman C, Montserrat E, Vinolas N (1988) Serum immunoglobulins in B-chronic lymphocytic leukemia. Natural history and prognostic significance. Cancer 61:279–283

    PubMed  CAS  Google Scholar 

  11. Foa R, Catovsky D, Brozovic M et al (1979) Clinical staging and immunological findings in chronic lymphocytic leukemia. Cancer 44:483–487

    PubMed  CAS  Google Scholar 

  12. Fiddes P, Penny R, Wells JV, Rozenberg MC (1972) Clinical correlations with immunoglobulin levels in chronic lymphatic leukaemia. Aust N Z J Med 2:346–350

    PubMed  CAS  Google Scholar 

  13. Whelan CA, Willoughby R, McCann SR (1983) Relationship between immunoglobulin levels, lymphocyte subpopulations and Rai staging in patients with B-CLL. Acta Haematol 69:217–223

    PubMed  CAS  Google Scholar 

  14. Keating MJ (1990) Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Semin Oncol 17:49–62

    PubMed  CAS  Google Scholar 

  15. O’Brien S, Kantarjian H, Beran M et al (1993) Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment [see comments]. Blood 82:1695–1700

    PubMed  CAS  Google Scholar 

  16. Dighiero G (1988) An attempt to explain disordered immunity and hypogammaglobulinemia in B-CLL. Nouv Rev Fr Hematol 30:283–288

    PubMed  CAS  Google Scholar 

  17. Dighiero G (1993) Hypogammaglobulinemia and disordered immunity in CLL. In: Cheson DB (ed) Chronic lymphocytic leukemia:Scientific advances and clinical developments. Marcel Dekker Inc., New York, pp 147–166

    Google Scholar 

  18. Kneitz C, Goller M, Wilhelm M et al (1999) Inhibition of T cell/B cell interaction by B-CLL cells. Leukemia 13:98–104

    Article  PubMed  CAS  Google Scholar 

  19. Noelle RJ, Ledbetter JA, Aruffo A (1992) CD40 and its ligand, an essential ligand-receptor pair for thymus-dependent B-cell activation. Immunol Today 13:431–433

    Article  PubMed  CAS  Google Scholar 

  20. Lotz M, Ranheim E, Kipps TJ (1994) Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells. J Exp Med 179:999–1004

    Article  PubMed  CAS  Google Scholar 

  21. Semenzato G, Foa R, Agostini C et al (1987) High serum levels of soluble interleukin 2 receptor in patients with B chronic lymphocytic leukemia. Blood 70:396–400

    PubMed  CAS  Google Scholar 

  22. Monserrat-Costa E, Matutes E, Rozman C (1977) Infecciones en la leukemia linfoide cronica. Sangre 22:968–975

    PubMed  Google Scholar 

  23. Foa R (1993) Pathogenesis of immunodeficiency in chronic lymphocytic leukemia. In: Cheson BD (ed) Chronic lymphocytic leukemia: Scientific advances and clinical developments. Marcel Dekker Inc., New York, pp 147–166

    Google Scholar 

  24. Griffiths H, Lea J, Bunch C, Lee M, Chapel H (1992) Predictors of infection in chronic lymphocytic leukaemia (CLL). Clin Exp Immunol 89:374–377

    Article  PubMed  CAS  Google Scholar 

  25. Rai KR, Montserrat E (1987) Prognostic factors in chronic lymphocytic leukemia. Semin Hematol 24:252–256

    PubMed  CAS  Google Scholar 

  26. Morrison VA, Hibbs JR, Janoff EN (1996) Systemic and mucosal immunoglobulin levels and risk of infection in patients with chronic lymphocytic leukemia. Blood 88:240a

    Google Scholar 

  27. Aittoniemi J, Miettinen A, Laine S et al (1999) Opsonising immunoglobulins and mannan-binding lectin in chronic lymphocytic leukemia. Leuk Lymphoma 34:381–385

    PubMed  CAS  Google Scholar 

  28. Copson ER, Ellis BA, Westwood NB, Majumdar G (1994) IgG subclass levels in patients with B cell chronic lymphocytic leukaemia. Leuk Lymphoma 14:471–473

    PubMed  CAS  Google Scholar 

  29. Apostolopoulos A, Symeonidis A, Zoumbos N (1990) Prognostic significance of immune function parameters in patients with chronic lymphocytic leukaemia. Eur J Haematol 44:39–44

    PubMed  CAS  Google Scholar 

  30. Matutes E, Wechsler A, Gomez R, Cherchi M, Catovsky D (1981) Unusual T-cell phenotype in advanced B-chronic lymphocytic leukaemia. Br J Haematol 49:635–642

    PubMed  CAS  Google Scholar 

  31. Rossi E, Matutes E, Morilla R, Owusu-Ankomah K, Heffernan AM, Catovsky D (1996) Zeta chain and CD28 are poorly expressed on T lymphocytes from chronic lymphocytic leukemia. Leukemia 10:494–497

    PubMed  CAS  Google Scholar 

  32. Kunicka JE, Platsoucas CD (1988) Defective helper function of purified T4 cells and excessive suppressor activity of purified T8 cells in patients with B-cell chronic lymphocytic leukemia. T4 suppressor effector cells are present in certain patients. Blood 71:1551–1560

    PubMed  CAS  Google Scholar 

  33. Prieto A, Garcia-Suarez J, Reyes E, Lapena P, Hernandez M, Alvarez-Mon M (1993) Diminished DNA synthesis in T cells from B chronic lymphocytic leukemia after phytohemagglutinin, anti-CD3, and phorbol myristate acetate mitogenic signals. Exp Hematol 21:1563–1569

    PubMed  CAS  Google Scholar 

  34. Dianzani U, Omede P, Marmont F et al (1994) Expansion of T cells expressing low CD4 or CD8 levels in B-cell chronic lymphocytic leukemia: correlation with disease status and neoplastic phenotype. Blood 83:2198–2205

    PubMed  CAS  Google Scholar 

  35. Semenzato G, Pezzutto A, Foa R, Lauria F, Raimondi R (1983) T lymphocytes in B-cell chronic lymphocytic leukemia: characterization by monoclonal antibodies and correlation with Fc receptors. Clin Immunol Immunopathol 26:155–161

    Article  PubMed  CAS  Google Scholar 

  36. Serrano D, Monteiro J, Allen SL et al (1997) Clonal expansion within the CD4+CD57+ and CD8+CD57+ T cell subsets in chronic lymphocytic leukemia. J Immunol 158:1482–1489

    PubMed  CAS  Google Scholar 

  37. Platsoucas CD, Galinski M, Kempin S, Reich L, Clarkson B, Good RA (1982) Abnormal T lymphocyte subpopulations in patients with B cell chronic lymphocytic leukemia: an analysis by monoclonal antibodies. J Immunol 129:2305–2312

    PubMed  CAS  Google Scholar 

  38. Kay NE (1981) Abnormal T-cell subpopulation function in CLL: excessive suppressor (T gamma) and deficient helper (T mu) activity with respect to B-cell proliferation. Blood 57:418–420

    PubMed  CAS  Google Scholar 

  39. Totterman TH, Carlsson M, Simonsson B, Bengtsson M, Nilsson K (1989) T-cell activation and subset patterns are altered in B-CLL and correlate with the stage of the disease. Blood 74:786–792

    PubMed  CAS  Google Scholar 

  40. Peller S, Kaufman S (1991) Decreased CD45RA T cells in B-cell chronic lymphatic leukemia patients: correlation with disease stage. Blood 78:1569–1573

    PubMed  CAS  Google Scholar 

  41. Vuillier F, Tortevoye P, Binet JL, Dighiero G (1988) CD4, CD8 and NK subsets in B-CLL. Nouv Rev Fr Hematol 30:331–334

    PubMed  CAS  Google Scholar 

  42. Reyes E, Prieto A, Carrion F, Garcia-Suarez J, Esquivel F, Alvarez-Mon M (1997) Morphological variants of leukemic cells in B chronic lymphocytic leukemia are associated with different T cell and NK cell abnormalities. Am J Hematol 55:175–182

    Article  PubMed  CAS  Google Scholar 

  43. Lundin J, Porwit-MacDonald A, Rossmann ED et al (2004) Cellular immune reconstitution after subcutaneous alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH-1H) treatment as first-line therapy for B-cell chronic lymphocytic leukaemia. Leukemia 18:484–490

    Article  PubMed  CAS  Google Scholar 

  44. Tinhofer I, Marschitz I, Kos M et al (1998) Differential sensitivity of CD4+ and CD8+ T lymphocytes to the killing efficacy of Fas (Apo-1/CD95) ligand+ tumor cells in B chronic lymphocytic leukemia. Blood 91:4273–4281

    PubMed  CAS  Google Scholar 

  45. Han T, Ozer H, Henderson ES, Dadey B, Nussbaum-Blumenson A, Barcos M (1981) Defective immunoregulatory T-cell function in chronic lymphocytic leukemia. Blood 58:1182–1189

    PubMed  CAS  Google Scholar 

  46. Lauria F, Foa R, Mantovani V, Fierro MT, Catovsky D, Tura S (1983) T-cell functional abnormality in B-chronic lymphocytic leukaemia: evidence of a defect of the T-helper subset. Br J Haematol 54:277–283

    PubMed  CAS  Google Scholar 

  47. Briggs PG, Kraft N, Atkins RC (1991) T-lymphocyte response to cytokines in B-chronic lymphocytic leukemia. Leuk Res 15:859–865

    Article  PubMed  CAS  Google Scholar 

  48. Burton JD, Weitz CH, Kay NE (1989) Malignant chronic lymphocytic leukemia B cells elaborate soluble factors that down-regulate T cell and NK function. Am J Hematol 30:61–67

    PubMed  CAS  Google Scholar 

  49. Decker T, Flohr T, Trautmann P et al (1995) Role of accessory cells in cytokine production by T cells in chronic B- cell lymphocytic leukemia. Blood 86:1115–1123

    PubMed  CAS  Google Scholar 

  50. Cantwell M, Hua T, Pappas J, Kipps TJ (1997) Acquired CD40-ligand deficiency in chronic lymphocytic leukemia. Nat Med 3:984–9

    Article  PubMed  CAS  Google Scholar 

  51. Miller D, Lizardo JG, Snyderman RK (1961) Homologous and heterologous skin transplantation in patients with lymphomatous disease. J Natl Cancer Inst 26:569–579

    PubMed  CAS  Google Scholar 

  52. Miller D, Karnofsky DA (1961) Immunologic factors and resistance to infection in chronic lymphocytic leukemia. Am J Med 31:748–757

    Article  PubMed  CAS  Google Scholar 

  53. Chapel HM, Bunch C (1987) Mechanisms of infection in chronic lymphocytic leukemia. Semin Hematol 24:291–296

    PubMed  CAS  Google Scholar 

  54. Foa R, Lauria F, Lusso P et al (1984) Discrepancy between phenotypic and functional features of natural killer T-lymphocytes in B-cell chronic lymphocytic leukaemia. Br J Haematol 58:509–516

    PubMed  CAS  Google Scholar 

  55. Foa R, Fierro MT, Raspadori D et al (1990) Lymphokine-activated killer (LAK) cell activity in B and T chronic lymphoid leukemia: defective LAK generation and reduced susceptibility of the leukemic cells to allogeneic and autologous LAK effectors. Blood 76:1349–1354

    PubMed  CAS  Google Scholar 

  56. Foa R, Fierro MT, Lusso P et al (1986) Reduced natural killer T-cells in B-cell chronic lymphocytic leukaemia identified by three monoclonal antibodies: Leu-11, A10, AB8.28. Br J Haematol 62:151–154

    PubMed  CAS  Google Scholar 

  57. Orsini E, Guarini A, Chiaretti S, Mauro FR, Foa R (2003) The circulating dendritic cell compartment in patients with chronic lymphocytic leukemia is severely defective and unable to stimulate an effective T-cell response. Cancer Res 63:4497–4506

    PubMed  CAS  Google Scholar 

  58. Orsini E, Pasquale A, Maggio R et al (2004) Phenotypic and functional characterization of monocyte-derived dendritic cells in chronic lymphocytic leukaemia patients: influence of neoplastic CD19 cells in vivo and in vitro. Br J Haematol 125:720–728

    Article  PubMed  Google Scholar 

  59. Rezvany MR, Jeddi-Tehrani M, Biberfeld P et al (2001) Dendritic cells in patients with non-progressive B-chronic lymphocytic leukaemia have a normal functional capability but abnormal cytokine pattern. Br J Haematol 115:263–271

    Article  PubMed  CAS  Google Scholar 

  60. Vuillier F, Maloum K, Thomas EK, Jouanne C, Dighiero G, Scott-Algara D (2001) Functional monocyte-derived dendritic cells can be generated in chronic lymphocytic leukaemia. Br J Haematol 115:831–844

    Article  PubMed  CAS  Google Scholar 

  61. Rozman C, Montserrat E, Rodriguez-Fernandez JM et al (1984) Bone marrow histologic pattern–the best single prognostic parameter in chronic lymphocytic leukemia: a multivariate survival analysis of 329 cases. Blood 64:642–648

    PubMed  CAS  Google Scholar 

  62. Broxmeyer HE, Pahwa R, Jacobsen N et al (1980) Specific inhibitory activity against granulocyte-progenitor cells produced by non-T lymphocytes from patients with neutropenia. Exp Hematol 8:278–297

    PubMed  CAS  Google Scholar 

  63. Zeya HI, Keku E, Richards F II, Spurr CL (1979) Monocyte and granulocyte defect in chronic lymphocytic leukemia. Am J Pathol 95:43–53

    PubMed  CAS  Google Scholar 

  64. Itala M, Vainio O, Remes K (1996) Functional abnormalities in granulocytes predict susceptibility to bacterial infections in chronic lymphocytic leukaemia. Eur J Haematol 57:46–53

    PubMed  CAS  Google Scholar 

  65. De Rossi G, Mauro FR, Ialongo P, Coluzzi S, Pizzo F (1991) Monocytopenia and infections in chronic lymphocytic leukemia (CLL). Eur J Haematol 46:119

    PubMed  Google Scholar 

  66. Schlesinger M, Broman I, Lugassy G (1996) The complement system is defective in chronic lymphatic leukemia patients and in their healthy relatives [see comments]. Leukemia 10:1509–1513

    PubMed  CAS  Google Scholar 

  67. Praz F, Karsenty G, Binet JL, Lesavre P (1984) Complement alternative pathway activation by chronic lymphocytic leukemia cells: its role in their hepatosplenic localization. Blood 63:463–467

    PubMed  CAS  Google Scholar 

  68. Heath ME, Cheson BD (1985) Defective complement activity in chronic lymphocytic leukemia. Am J Hematol 19:63–73

    PubMed  CAS  Google Scholar 

  69. Fust G, Czink E, Minh D, Miszlay Z, Varga L, Hollan SR (1985) Depressed classical complement pathway activities in chronic lymphocytic leukaemia. Clin Exp Immunol 60:489–495

    PubMed  CAS  Google Scholar 

  70. Miszlai Z, Czink E, Varga L et al (1986) Repressed classical complement pathway activities and clinical correlations in chronic lymphocytic leukaemia. Acta Med Hung 43:389–395

    PubMed  CAS  Google Scholar 

  71. Varga L, Czink E, Miszlai Z et al (1995) Low activity of the classical complement pathway predicts short survival of patients with chronic lymphocytic leukaemia. Clin Exp Immunol 99:112–116

    Article  PubMed  CAS  Google Scholar 

  72. Sgambati MT, Linet MS, Devesa SS (2001) Chronic lymphocytic leukemia: epidemiological, familial, and genetic aspects. In: Cheson BD (ed) Chronic lymphoid leukemias. Marcel Dekker, New York, pp 33–62

    Google Scholar 

  73. McGlauchlen KS, Vogel LA (2003) Ineffective humoral immunity in the elderly. Microbes Infect 5:1279–1284

    Article  PubMed  CAS  Google Scholar 

  74. Ginaldi L, Loreto MF, Corsi MP, Modesti M, De Martinis M (2001) Immunosenescence and infectious diseases. Microbes Infect 3:851–857

    Article  PubMed  CAS  Google Scholar 

  75. Ferrajoli A, O’Brien SM (2004) Treatment of chronic lymphocytic leukemia. Semin Oncol 31:60–65

    Article  PubMed  Google Scholar 

  76. Anaissie E, Kontoyiannis DP, Kantarjian H, Elting L, Robertson LE, Keating M (1992) Listeriosis in patients with chronic lymphocytic leukemia who were treated with fludarabine and prednisone. Ann Intern Med 117:466–469

    PubMed  CAS  Google Scholar 

  77. Anaissie EJ, Kontoyiannis DP, O’Brien S et al (1998) Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med 129:559–566

    PubMed  CAS  Google Scholar 

  78. Girmenia C, Mauro FR, Rahimi S (1994) Late listeriosis after fludarabine plus prednisone treatment. Br J Haematol 87:407–408

    PubMed  CAS  Google Scholar 

  79. Sanders C, Perez EA, Lawrence HJ (1992) Opportunistic infections in patients with chronic lymphocytic leukemia following treatment with fludarabine [letter]. Am J Hematol 39:314–315

    PubMed  CAS  Google Scholar 

  80. Byrd JC, Hargis JB, Kester KE, Hospenthal DR, Knutson SW, Diehl LF (1995) Opportunistic pulmonary infections with fludarabine in previously treated patients with low-grade lymphoid malignancies: a role for Pneumocystis carinii pneumonia prophylaxis. Am J Hematol 49:135–142

    PubMed  CAS  Google Scholar 

  81. Wijermans PW, Gerrits WB, Haak HL (1993) Severe immunodeficiency in patients treated with fludarabine monophosphate. Eur J Haematol 50:292–296

    PubMed  CAS  Google Scholar 

  82. Bergmann L, Fenchel K, Jahn B, Mitrou PS, Hoelzer D (1993) Immunosuppressive effects and clinical response of fludarabine in refractory chronic lymphocytic leukemia. Ann Oncol 4:371–375

    PubMed  CAS  Google Scholar 

  83. Juliusson G, Liliemark J (1993) High complete remission rate from 2-chloro-2’-deoxyadenosine in previously treated patients with B-cell chronic lymphocytic leukemia: response predicted by rapid decrease of blood lymphocyte count. J Clin Oncol 11:679–689

    PubMed  CAS  Google Scholar 

  84. Rai KR, Peterson BL, Appelbaum FR et al (2000) Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750–1757

    Article  PubMed  CAS  Google Scholar 

  85. Johnson S, Smith AG, Loffler H et al (1996) 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 347:1432–1438

    PubMed  CAS  Google Scholar 

  86. Leporrier M, Chevret S, Cazin B et al (2001) Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 98:2319–2325

    PubMed  CAS  Google Scholar 

  87. Morrison VA, Rai KR, Peterson BL et al (2001) Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011. J Clin Oncol 19:3611–3621

    PubMed  CAS  Google Scholar 

  88. O’Brien SM, Kantarjian HM, Cortes J et al (2001) Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 19:1414–1420

    PubMed  CAS  Google Scholar 

  89. Wierda W, O’Brien S, Faderl S et al (2003) Improved survival in patients with relapsed refractory Chronic Lymphocytic Leukemia (CLL) treated with Fludarabine, Cyclophosphamide, and Rituximab (FCR) combination. Blood 102

  90. Robak T, Blonski JZ, Kasznicki M et al (2000) Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood 96:2723–2729

    PubMed  CAS  Google Scholar 

  91. Robak T, Blonski JZ, Kasznicki M et al (2001) Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia. Leukemia 15:1510–1516

    Article  PubMed  CAS  Google Scholar 

  92. Weiss MA, Maslak PG, Jurcic JG et al (2003) Pentostatin and cyclophosphamide: an effective new regimen in previously treated patients with chronic lymphocytic leukemia. J Clin Oncol 21:1278–1284

    Article  PubMed  CAS  Google Scholar 

  93. Van Den Neste E, Delannoy A, Vandercam B et al (1996) Infectious complications after 2-chlorodeoxyadenosine therapy. Eur J Haematol 56:235–240

    Article  PubMed  Google Scholar 

  94. Johnson SA, Catovsky D, Child JA, Newland AC, Milligan DW, Janmohamed R (1998) Phase I/II evaluation of pentostatin (2’-deoxycoformycin) in a five day schedule for the treatment of relapsed/refractory B-cell chronic lymphocytic leukaemia. Invest New Drugs 16:155–160

    Article  PubMed  CAS  Google Scholar 

  95. Mavromatis B, Cheson BD (2003) Monoclonal antibody therapy of chronic lymphocytic leukemia. J Clin Oncol 21:1874–1881

    Article  PubMed  CAS  Google Scholar 

  96. Onrust SV, Lamb HM, Balfour JA (1999) Rituximab. Drugs 58:79–88; discussion 89–90

    Google Scholar 

  97. Maloney DG, Grillo-Lopez AJ, White CA et al (1997) IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90:2188–2195

    PubMed  CAS  Google Scholar 

  98. McLaughlin P, Grillo-Lopez AJ, Link BK et al (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825–2833

    PubMed  CAS  Google Scholar 

  99. Voog E, Morschhauser F, Solal-Celigny P (2003) Neutropenia in patients treated with rituximab. N Engl J Med 348:2691–2694; discussion 2691–2694

    Google Scholar 

  100. O’Brien SM, Kantarjian H, Thomas DA et al (2001) Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 19:2165–2170

    PubMed  CAS  Google Scholar 

  101. Byrd JC, Murphy T, Howard RS et al (2001) 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 19:2153–2164

    PubMed  CAS  Google Scholar 

  102. Byrd JC, Peterson BL, Morrison VA et al (2003) 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 101:6–14

    Article  PubMed  CAS  Google Scholar 

  103. Schulz H, Klein SK, Rehwald U et al (2002) Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia. Blood 100:3115–3120

    Article  PubMed  CAS  Google Scholar 

  104. Weiss MA, Nicole L, Jurcic JG et al (2003) Pentostatin, Cyclophosphamide, and Rituximab (PCR therapy): a new active regimen for previously treated patients with Chronic Lymphocytic Leukemia (CLL). Blood 102

  105. Hale G, Xia MQ, Tighe HP, Dyer MJ, Waldmann H (1990) The CAMPATH-1 antigen (CDw52). Tissue Antigens 35:118–127

    Article  PubMed  CAS  Google Scholar 

  106. Osterborg A, Werner A, Halapi E et al (1997) Clonal CD8+ and CD52- T cells are induced in responding B cell lymphoma patients treated with Campath-1H (anti-CD52). Eur J Haematol 58:5–13

    PubMed  CAS  Google Scholar 

  107. Osterborg A, Dyer MJ, Bunjes D et al (1997) 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 15:1567–1574

    PubMed  CAS  Google Scholar 

  108. Lundin J, Osterborg A, Brittinger G et al (1998) CAMPATH-1H monoclonal antibody in therapy for previously treated low- grade non-Hodgkin’s lymphomas: a phase II multicenter study. European Study Group of CAMPATH-1H Treatment in Low-Grade Non-Hodgkin’s Lymphoma. J Clin Oncol 16:3257–3263

    PubMed  CAS  Google Scholar 

  109. Keating MJ, Flinn I, Jain V et al (2002) Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 99:3554–3561

    Article  PubMed  CAS  Google Scholar 

  110. Rai KR, Freter CE, Mercier RJ et al (2002) Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol 20:3891–3897

    Article  PubMed  CAS  Google Scholar 

  111. Lundin J, Kimby E, Bjorkholm M et al (2002) Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B- cell chronic lymphocytic leukemia (B-CLL). Blood 100:768–773

    Article  PubMed  CAS  Google Scholar 

  112. Wendtner CM, Ritgen M, Schweighofer CD et al (2004) 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 18:1093–1101

    Article  PubMed  CAS  Google Scholar 

  113. O’Brien SM, Kantarjian HM, Thomas DA et al (2003) Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer 98:2657–2663

    Article  PubMed  CAS  Google Scholar 

  114. Rai K, Byrd J, Peterson BL, Larson RA (2002) A phase II trial of fludarabine followed by alemtuzumab (Campath-1H) in previously untreated chronic lymphocytic leukemia (CLL) patients with active disease: Cancer and Leukamia Group B (CALGB) study 19901. Blood 100:205a

    Google Scholar 

  115. van Besien K, Keralavarma B, Devine S, Stock W (2001) Allogeneic and autologous transplantation for chronic lymphocytic leukemia. Leukemia 15:1317–1325

    Article  PubMed  CAS  Google Scholar 

  116. Khouri IF, Keating MJ, Vriesendorp HM et al (1994) Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. J Clin Oncol 12:748–758

    PubMed  CAS  Google Scholar 

  117. Dreger P, Schmitz N (1997) The role of stem cell transplantation in the treatment of chronic lymphocytic leukemia. Leukemia 11:S42–S45

    Article  PubMed  CAS  Google Scholar 

  118. Milligan DW, Fernandes S, Dasgupta R et al (2005) Autografting for younger patients with chronic lymphocytic leukaemia is safe and achieves a high percentage of molecular responses. Results of the MRC pilot study. Blood 105(1):397–404

    Article  PubMed  CAS  Google Scholar 

  119. Rabinowe SN, Soiffer RJ, Gribben JG et al (1993) Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia. Blood 82:1366–1376

    PubMed  CAS  Google Scholar 

  120. Brigden ML, Pattullo AL (1999) Prevention and management of overwhelming postsplenectomy infection—an update. Crit Care Med 27:836–842

    Article  PubMed  CAS  Google Scholar 

  121. Lynch AM, Kapila R (1996) Overwhelming postsplenectomy infection. Infect Dis Clin North Am 10:693–707

    Article  PubMed  CAS  Google Scholar 

  122. O’Brien S, Kantarjian H, Beran M et al (1997) Fludarabine and granulocyte colony-stimulating factor (G-CSF) in patients with chronic lymphocytic leukemia. Leukemia 11:1631–1635

    Article  PubMed  CAS  Google Scholar 

  123. Flinn IW, Byrd JC, Morrison C et al (2000) Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood 96:71–75

    PubMed  CAS  Google Scholar 

  124. Besa EC (1984) Use of intravenous immunoglobulin in chronic lymphocytic leukemia. Am J Med 76:209–218

    Article  PubMed  CAS  Google Scholar 

  125. Griffiths H, Brennan V, Lea J, Bunch C, Lee M, Chapel H (1989) Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood 73:366–368

    PubMed  CAS  Google Scholar 

  126. Anon (1988) Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. New Eng J Med 6:902–907

    Google Scholar 

  127. Wierda WG, O’Brien S (2001) Immunotherapy of chronic lymphocytic leukemia. Expert Rev Anticancer Ther 1:73–83

    Article  PubMed  CAS  Google Scholar 

  128. Bruserud O, Ulvestad E (2003) Human acute lymphoblastic leukemia (ALL) blasts as accessory cells during T-cell activation: differences between patients in costimulatory capacity affect proliferative responsiveness and cytokine release by activated T cells. Cancer Immunol Immunother 52:215–225

    PubMed  CAS  Google Scholar 

  129. Kato K, Cantwell MJ, Sharma S, Kipps TJ (1998) Gene transfer of CD40-ligand induces autologous immune recognition of chronic lymphocytic leukemia B cells. J Clin Invest 101:1133–1141

    PubMed  CAS  Google Scholar 

  130. Fenchel K, Bergmann L, Wijermans P et al (1995) Clinical experience with fludarabine and its immunosuppressive effects in pretreated chronic lymphocytic leukemias and low-grade lymphomas. Leuk Lymphoma 18:485–492

    PubMed  CAS  Google Scholar 

  131. Zinzani PL, Lauria F, Rondelli D et al (1993) Fludarabine in patients with advanced and/or resistant B-chronic lymphocytic leukemia. Eur J Haematol 51:93–97

    Article  PubMed  CAS  Google Scholar 

  132. Keating MJ, Kantarjian H, O’Brien S et al (1991) Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol 9:44–49

    PubMed  CAS  Google Scholar 

  133. Dillman RO, Mick R, McIntyre OR (1989) Pentostatin in chronic lymphocytic leukemia: a phase II trial of Cancer and Leukemia group B. J Clin Oncol 7:433–438

    PubMed  CAS  Google Scholar 

  134. Ho AD, Thaler J, Stryckmans P et al (1990) Pentostatin in refractory chronic lymphocytic leukemia: a phase II trial of the European Organization for Research and Treatment of Cancer. J Natl Cancer Inst 82:1416–1420

    PubMed  CAS  Google Scholar 

  135. Tallman MS, Hakimian D, Zanzig C et al (1995) Cladribine in the treatment of relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 13:983–988

    PubMed  CAS  Google Scholar 

  136. Saven A (1996) The Scripps clinic experience with cladribine (2-CdA) in the treatment of chronic lymphocytic leukemia. Semin Hematol 33:28–33

    PubMed  CAS  Google Scholar 

  137. Robak T, Blonski JZ, Urbanska-Rys H, Blasinska-Morawiec M, Skotnicki AB (1999) 2-Chlorodeoxyadenosine (Cladribine) in the treatment of patients with chronic lymphocytic leukemia 55 years old and younger. Leukemia 13:518–523

    Article  PubMed  CAS  Google Scholar 

  138. Robak T, Blasinska-Morawiec M, Blonski JZ, Dmoszynska A (1999) 2-Chlorodeoxyadenosine (cladribine) in the treatment of elderly patients with B-cell chronic lymphocytic leukemia. Leuk Lymphoma 34:151–157

    PubMed  CAS  Google Scholar 

  139. Juliusson G, Liliemark J (1996) Long-term survival following cladribine (2-chlorodeoxyadenosine) therapy in previously treated patients with chronic lymphocytic leukemia. Ann Oncol 7:373–379

    PubMed  CAS  Google Scholar 

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Correspondence to Farhad Ravandi.

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This article forms part of the Symposium in Writing “Immunotherapy in chronic lymphocytic leukemia”, edited by Øystein Bruserud.

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Ravandi, F., O’Brien, S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunol Immunother 55, 197–209 (2006). https://doi.org/10.1007/s00262-005-0015-8

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