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Chronic Lymphocytic Leukemia

Strategies for Optimizing Therapy

  • Review Article
  • Published:
American Journal of Cancer

Abstract

In recent years, important progress has been made in understanding the pathophysiology, and in improving the diagnosis and treatment, of chronic lymphocytic leukemia (CLL). The characteristics of the B lymphocyte clone are now better defined and disclose great heterogeneity in the mechanisms involved in the development of lymphocytic tumours: both proliferative and apoptotic abnormalities are involved, and a single or recurrent triggering feature is not recognized. Accordingly, the course of the disease is highly variable. Although treatment abstention or deferral for a long period is convenient for many patients, others who present with, or progress to, active CLL will ultimately die from the disease.

Clinico-hematological staging systems have greatly clarified the prognostic factors of interest to clinicians, but they remain imprecise in a large category of patients. Recently, other characteristics such as cytogenetics, immunoglobulin gene sequencing, and serum levels of soluble CD23, thymidine kinase and lymphocyte p27 have been recognized as powerful prognostic factors and should now be evaluated in prospective clinical trials.

It remains unclear whether any of the available treatments, when indicated, could offer long-term survival benefits for patients. Chlorambucil, purine analogues (including fludarabine or cladribine) and anthracyclinecontaining regimens [i.e. cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)] have been evaluated in large prospective controlled trials, which demonstrated some differences according to response rates, but which failed to disclose any survival advantage, irrespective of the first-line drug treatment allocated. These disappointing results emphasize the need to develop other treatment strategies. Progress could be anticipated in two main ways. Firstly, new, effective and well tolerated treatments with greater specificity are now, or should soon be, available in the clinic: monoclonal antibodies, apoptotic inducers and vaccine systems. Preliminary data suggest that the best use of such treatments is as adjuvant therapy for patients with residual disease, thus complementing the results of chemotherapy. Secondly, intensive treatments with stem-cell rescue (autologous or allogenic) have provided evidence that clonal extinction is an obtainable goal in selected patients, some of whom remain free of any clonal molecular signal for many years. Whether such patients could be considered cured is still unresolved, and this point deserves longer follow-up. Controlled trials are currently exploring this important question.

Finally, optimum therapy also aims to improve quality of life, and clinical trials dealing with this important issue, especially in elderly patients, are needed.

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References

  1. Digheiro G, Binetc JL. When and how to treat chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1799–801

    Article  Google Scholar 

  2. Nishiyama H, Mokuno J, Inoue T. Relative frequency and mortality rate of various types of leukemia in Japan. Jpn J Cancer Res 1969; 60: 71–81

    CAS  Google Scholar 

  3. Caligaris Cappio F, Hamblin TJ. B-cell chronic lymphocytic leukemia: a bird of a different feather. J Clin Oncol 1999; 17: 399–408

    Google Scholar 

  4. Dameshek W. Chronic lymphocytic leukemia: an accumulative disease of immunologically incompetent lymphocytes. Blood 1967; 29: 566–84

    PubMed  Google Scholar 

  5. Panayiotidis P, Kotsi P. Genetics of small lymphocyte disorders. Semin Haematol 1999; 36: 171–7

    CAS  Google Scholar 

  6. Minot GB, Isaacs R. Lymphatic leukemia; age, incidence, duration, and benefit derived from irradiation. Boston Med Surg J 1924; 191: 1–9

    Article  Google Scholar 

  7. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46: 219–34

    PubMed  CAS  Google Scholar 

  8. 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: 198–206

    Article  PubMed  CAS  Google Scholar 

  9. French Cooperative Group on Chronic Lymphocytic Leukemia. Prognostic and therapeutic advances in CLL management: the experience of the French Cooperative Group. Semin Hematol 1987; 24: 275–90

    Google Scholar 

  10. Mandelli F, De Rossi G, Mancini P, et al. Prognosis in chronic lymphocytic leukemia: a retrospective multicentric study from the GIMEMA group. J Clin Oncol 1987; 5: 398–406

    PubMed  CAS  Google Scholar 

  11. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med 1995; 333: 1052–7

    Article  PubMed  CAS  Google Scholar 

  12. 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: 4990–7

    PubMed  CAS  Google Scholar 

  13. 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: 1506–14

    Article  PubMed  CAS  Google Scholar 

  14. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–6

    Article  PubMed  Google Scholar 

  15. Maloum K, Davi F, Merle-Beral H, et al. Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia. Blood 2000; 96: 377–9

    PubMed  CAS  Google Scholar 

  16. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–54

    PubMed  CAS  Google Scholar 

  17. Rajendra N, Damle RN, Wasil T, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–7

    Google Scholar 

  18. Del Poeta G, Maurillo L, Venditti A, et al. Clinical evidence of CD 38 expression in chronic lymphocytic leukemia. Blood 2001; 98: 2633–9

    Article  Google Scholar 

  19. Jelinek DF, Tschumper RC, Geyer SM, et al. Analysis of clonal B-cell CD38 and immunoglobulin veriable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukemia. Br J Haematol 2001; 115: 854–61

    Article  PubMed  CAS  Google Scholar 

  20. Hamblin TJ, Orchard JA, Ibbotson R, et al. CD38 expression and immunoglobin 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: 1023–9

    Article  PubMed  CAS  Google Scholar 

  21. Hamblin TJ, Orchard JA, Gardiner A, et al. Immunoglobulin V genes and CD38 expression in CLL. Blood 2000; 95: 2455–7

    PubMed  CAS  Google Scholar 

  22. Thunberg U, Johnson A, Roos G, et al. CD38 expression is a poor predictor for VH gene mutational status and prognosis in chronic lymphocytic leukemia. Blood 2001; 97: 1892–4

    Article  PubMed  CAS  Google Scholar 

  23. Widhopf GF, Marathe CM, Rassenti LZ, et al. Lack of correlation between immunoglobulin somatic mutation and expression of CD38 in chronic lymphocytic leukemia [abstract]. Blood 2000; 96 Suppl. 1: 367a

    Google Scholar 

  24. Hanada M, Delia D, Aiello A, et al. Bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 1993; 82: 1820–8

    PubMed  CAS  Google Scholar 

  25. Vrhovac R, Delmer A, Tang R, et al. Prognostic significance of the cell cycle inhibitorp27 Kip1 in B-cell lymphocytic leukemia. Blood 1998; 91: 4694–700

    PubMed  CAS  Google Scholar 

  26. Fournier S, Rubio M, Delespesse G, et al. Role for low-affinity receptor for IgE (CD23) in normal and leukemic B-cell proliferation. Blood 1994; 84: 1881–6

    PubMed  CAS  Google Scholar 

  27. Fournier S, Yang LP, Delespesse G, et al. The two CD23 isoforms display differential regulation in chronic lymphocytic leukemia. Br J Haematol 1995; 89: 373–9

    Article  PubMed  CAS  Google Scholar 

  28. Reinisch W, Willheim M, Hilgarth M, et al. Soluble CD23 reliably reflects disease activity in B-cell chronic lymphocytic leukemia. J Clin Oncol 1994; 12: 2146–52

    PubMed  CAS  Google Scholar 

  29. Sarfati M, Chevret S, Chastang C, et al. Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia. Blood 1996; 88: 4259–64

    PubMed  CAS  Google Scholar 

  30. Källander CF, Simonsson B, Hagberg H, et al. Serum deoxythymidine kinase gives prognostic information in chronic lymphocytic leukemia. Cancer 1984; 54: 2450–5

    Article  PubMed  Google Scholar 

  31. Hallek M, Langenmayer I, Nerl C, et al. Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood 1999; 93: 1732–7

    PubMed  CAS  Google Scholar 

  32. CLL trialists’ collaborative group. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. J Natl Cancer Inst 1999; 91: 861–8

    Article  Google Scholar 

  33. Brugiatelli M, Jaksic B, Planinc-Peraica A, et al. Treatment of chronic lymphocytic leukemia in early and stable phase of the disease: long-term results of a randomized trial. Eur J Haematol 1995; 55: 158–63

    Article  PubMed  CAS  Google Scholar 

  34. Catovsky D, Richards S, Fooks J, et al. CLL trials in the United Kingdom. MRC trials 1, 2 and 3. Leuk Lymphoma 1991; Suppl. 4: 105–12

    Article  Google Scholar 

  35. French Cooperative Group on Chronic Lymphocytic Leukemia. Effects of chlorambucil and therapeutic decision in initial forms of chronic lymphocytic leukemia (stage A): results of a randomized clinical trial on 612 patients. Blood 1990; 75: 1414–21

    Google Scholar 

  36. Shustik C, Mick R, Silver R, et al. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol 1988; 6: 7–12

    Article  PubMed  CAS  Google Scholar 

  37. Spanish Cooperative Group Pethema. Treatment of chronic lymphocytic leukemia: a preliminary report of Spanish (Pethema) trials. Leuk Lymphoma 1991; Suppl. 4: 89–91

    Google Scholar 

  38. Jaksic B, Brugiatelli M. High dose continuous chlorambucil vs intermittent chlorambucil plus prednisone for treatment of B-CLL-IGCICLL-01 trial. Nouv Rev Fr Hematol 1988; 30: 437–42

    PubMed  CAS  Google Scholar 

  39. Sawitsky A, Rai KR, Glidewell O, et al. Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia. Blood 1977; 50: 1049–59

    PubMed  CAS  Google Scholar 

  40. French Cooperative Group on Chronic Lymphocytic Leukemia. A randomized clinical trial of chlorambucil versus COP in stage B chronic lymphocytic leukemia. Blood 1990; 75: 1422–5

    Google Scholar 

  41. Montserrat E, Alcala A, Parody R, et al. Treatment of chronic lymphocytic leukemia in advanced stages. A randomized trial comparing chlorambucil plus prednisone versus cyclophosphamide, vincristine, and prednisone. Cancer 1985; 56: 2369–75

    Article  PubMed  CAS  Google Scholar 

  42. Raphael B, Andersen JW, Silber R, et al. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol 1991; 9: 770–6

    PubMed  CAS  Google Scholar 

  43. French Cooperative Group on Chronic Lymphocytic leukemia. Effectiveness of ‘CHOP’ regimen in advanced untreated chronic lymphocytic leukemia. Lancet 1986; 1: 1346–9

    Google Scholar 

  44. French Cooperative Group on CLL. Is the CHOP regimen a good treatment for advanced CLL? Results from two randomized clinical trials. French Cooperative Group on Chronic Lymphocytic Leukemia. Leuk Lymphoma 1994; 13: 449–56

    Article  Google Scholar 

  45. Hansen MM, Andersen E, Birgens H, et al. CHOP versus chlorambucil plus prednisolone in chronic lymphocytic leukemia. Leuk Lymphoma 1991; Suppl. 4: 97–100

    Google Scholar 

  46. Kimby E, Mellstedt H. Chlorambucil/prednisolone versus CHOP in symptomatic chronic lymphocytic leukemia of B-cell type. Leuk Lymphoma 1991; Suppl. 4: 93–6

    Google Scholar 

  47. Jaksic B, Brugiatelli M, Krc I, et al. High dose chlorambucil versus Binet’s modified cyclophosphamide, doxorubicin, vincristine, and prednisone regimen in the treatment of patients with advanced B-cell chronic lymphocytic leukemia. Cancer 1997; 79: 2107–14

    Article  PubMed  CAS  Google Scholar 

  48. Jacobs P, King HS. A randomized prospective comparison of chemotherapy to total body irradiation as initial treatment for the indolent lymphoproliferative diseases. Blood 1987; 69: 1642–6

    PubMed  CAS  Google Scholar 

  49. 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: 1750–7

    Article  PubMed  CAS  Google Scholar 

  50. French Cooperative Group on CLL, Johnson S, Smith AG, et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukemia. Lancet 1996; 347: 1432–8

    PubMed  CAS  Google Scholar 

  51. Leporrier M, Chevret S, Cazin 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(8): 2319–25

    Article  PubMed  CAS  Google Scholar 

  52. Patapanian H, Graham S, Sambrook PN, et al. The oncogenicity of chlorambucil in rheumatoid arthritis. Br J Rheumatol 1988; 27: 44–7

    Article  PubMed  CAS  Google Scholar 

  53. Robak T, Blonski JZ, Kasznicki M, 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: 2723–9

    PubMed  CAS  Google Scholar 

  54. Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Eng J Med 1981; 304: 441–7

    Article  CAS  Google Scholar 

  55. Palmer RG, Denman AM. Malignancies induced by chlorambucil. Cancer Treat Rev 1984; 11: 121–9

    Article  PubMed  CAS  Google Scholar 

  56. Dedrick RL, Morrison PF. Carcinogenic potency of alkylating agents in rodents and humans. Cancer Res 1992; 52: 2464–7

    PubMed  CAS  Google Scholar 

  57. Kauppi MJ, Savolainen HA, Anttila VJ, et al. Increased risk of leukemia in patients with juvenile chronic arthritis treated with chlorambucil. Acta Paediatr 1996; 85: 248–50

    Article  PubMed  CAS  Google Scholar 

  58. Keating MJ, Hester JP, McCredie KB, et al. Long term results of CAP therapy in chronic lymphocytic leukemia. Leuk Lymphoma 1990; 2: 391–7

    Article  Google Scholar 

  59. Keating MJ, Scouros M, Murphy S, et al. Multiple agent chemotherapy (POACH) in previously treated and untreated patients with chronic lymphocytic leukemia. Leukemia 1988; 2: 157–64

    PubMed  CAS  Google Scholar 

  60. French Cooperative Group on Chronic Lymphocytic leukemia. Long-term results of the CHOP regimen in stage C chronic lymphocytic leukemia [see comments]. Br J Haematol 1989; 73: 334–40

    Article  Google Scholar 

  61. Leporrier M, Chevret S, Cazin B, et al. Randomized clinical trial comparing two anthracycline-containing regimens (CHOP and CAP) and fludarabine (fdr) in advanced chronic lymphocytic leukemia (CLL) [abstract]. French Cooperative Group on CLL. Blood 1999; 94 Suppl. 1: 603a

    Google Scholar 

  62. Grever MR, Kopecky KJ, Coltman CA, et al. Fludarabine monophosphate: a potentially useful agent in chronic lymphocytic leukemia. Nouv Rev Fr Hematol 1988; 30: 457–9

    PubMed  CAS  Google Scholar 

  63. Keating MJ, Kantarjian H, Talpaz M, et al. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood 1989; 74: 19–25

    PubMed  CAS  Google Scholar 

  64. O’Brien S, Kantarjian H, Beran M, et al. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 1993; 82: 1695–700

    PubMed  Google Scholar 

  65. Keating MJ, O’Brien S, Lerner S, et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 1998; 92: 1165–71

    PubMed  CAS  Google Scholar 

  66. Cheson BD, Bennett JM, Rai KR, et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the national cancer institute-sponsored working group. Am J Hematol 1988; 29: 152–63

    Article  PubMed  CAS  Google Scholar 

  67. Yee C, Browman G, Wong S, et al. Fludarabine in intermediate and high-risk chronic lymphocytic leukemia. Cancer Care Practice Guideline Initiative CPG 6-1 [online]. Available from URL: http://hiru.mcmaster.ca/ccopgi/guidelines/hem/cpg6_lf.html [Accessed 2001 Jan 03]

  68. Cheson BD, Frame JN, Vena D, et al. Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia. J Clin Oncol 1998; 16: 2313–20

    PubMed  CAS  Google Scholar 

  69. Byrd JC, Hargis JB, Kester KE, et al. Opportunistic pulmonary infections with fludarabine in previously treated patients with low grade lymphoid malignancies: a role for pneumocystis carinii pneumonia prophylaxis. Am J Hematol 1995; 49: 135–42

    Article  PubMed  CAS  Google Scholar 

  70. Anaissie EJ, Kotoyiannis DP, O’Brien S, et al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med 1998; 129: 559–66

    PubMed  CAS  Google Scholar 

  71. Mauro FR, Foa R, Cerretti R, et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000; 95: 2786–92

    PubMed  CAS  Google Scholar 

  72. Di Raimondo F, Giustolisi R, Cacciola E, et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia patients treated with fludarabine. Leuk Lymphoma l993; 11: 63–8

    Article  PubMed  Google Scholar 

  73. Myint H, Copplestone JA, Orchard J, et al. Fludarabine-related autoimmune hemolytic anaemia in patients with chronic lymphocytic leukemia. Br J Hematol 1995; 91: 342–4

    Article  Google Scholar 

  74. Weiss RB, Freiman J, Kweder S, et al. Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol 1998; 16: 1885–9

    PubMed  CAS  Google Scholar 

  75. Hamblin T, Orchard JA, Myint H, et al. Fludarabine and hemolytic anemia in chronic lymphocytic leukemia. J Clin Oncol 1998; 16: 3209–10

    PubMed  CAS  Google Scholar 

  76. Leporrier M, Reman O, Troussard X. Pure red cell aplasia with fludarabine for chronic lymphocytic leukemia. Lancet 1993; 342: 555

    Article  PubMed  CAS  Google Scholar 

  77. Bay JO, Fouassier M, Beal D, et al. Autoimmune thrombocytopenia after six cycles of fludarabine phosphate in a patient with chronic lymphocytic leukemia. Hematol Cell Ther 1997; 39: 209–12

    Article  PubMed  CAS  Google Scholar 

  78. Leach M, Parsons RM, Reilly JT, et al. Autoimmune thrombocytopenia: a complication of fludarabine therapy in lymphoproliferative disorders. Clin Lab Haematol 2000; 22: 175–8

    Article  PubMed  CAS  Google Scholar 

  79. Cheson BD, Vena DA, Barrett J, et al. Second malignancies as a consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol 1999; 17: 2454–60

    PubMed  CAS  Google Scholar 

  80. Piro LD, Carrera CJ, Beutler E, et al. 2-chlorodeoxyadenosine: an effective new agent for the treatment of chronic lymphocytic leukemia. Blood 1989; 72: 1069–73

    Google Scholar 

  81. Saven A, Lemon RH, Kosty M, et al. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol 1995; 13: 570–4

    PubMed  CAS  Google Scholar 

  82. Delannoy A, Martiat P, Gala JL, et al. 2-Chlorodeoxyadenosine (CdA) for patients with previously untreated chronic lymphocytic leukemia (CLL). Leukemia 1995; 9: 1130–5

    PubMed  CAS  Google Scholar 

  83. Saven A, Piro LD. 2-Chlorodeoxyadenosine: a potent antimetabolite with major activity in the treatment of indolent lymphoproliferative disorders. Hematol Cell Ther 1996; 38: S93–101

    PubMed  CAS  Google Scholar 

  84. O’Brien S, Kantarjian H, Estey E, et al. Lack of effect of 2-chlorodeoxyadenosine therapy in patients with chronic lymphocytic leukemia refractory to fludarabine therapy. N Engl J Med 1994; 330: 319–22

    Article  PubMed  Google Scholar 

  85. Chasty RC, Myint H, Oscier DG, et al. Autoimmune haemolysis in patients with B-CLL treated with chlorodeoxyadenosine (CDA). Leuk Lymphoma 1998; 29: 391–8

    Article  PubMed  CAS  Google Scholar 

  86. Robak T, Kasznicki M, Blonski JZ, et al. Pure red cell aplasia in patients with chronic lymphocytic leukemia treated with cladribine. Br J Haematol 2001; 112: 1083–5

    Article  PubMed  CAS  Google Scholar 

  87. Hale G, Bright S, Chumbley G, et al. Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood 1983; 62: 873–82

    PubMed  CAS  Google Scholar 

  88. Hale G, Xia MQ, Tighe HP, et al. The Campath-1H antigen (CDw52). Tissue Antigens 1990; 35: 118–27

    Article  PubMed  CAS  Google Scholar 

  89. Hale G, Rye PD, Warford A, et al. The glycophosphatidylinositol-anchored lymphocyte antigen cdw52 is associated with the epididymal maturation of human spermatozoa. J Reprod Immunol 1993; 23: 189–205

    Article  PubMed  CAS  Google Scholar 

  90. Greenwood J, Gorman SD, Routledge EG, et al. Engineering multiple-domain forms of the therapeutic antibody Campath-1H: effects on complement lysis. Ther Immunol 1994; 1: 247–55

    PubMed  CAS  Google Scholar 

  91. Riechmann L, Clark M, Waldmann H, et al. Reshaping human antibodies for therapy. Nature 1988; 332: 323–7

    Article  PubMed  CAS  Google Scholar 

  92. Österborg A, Fassas AS, Anagnostopoulos A, et al. Humanized CD52 monoclonal antibody Campath-1H as first-line treatment in chronic lymphocytic leukemia. Br J Haematol 1996; 93: 151–3

    Article  PubMed  Google Scholar 

  93. Pawson R, Dyer MJS, Barge R. Treatment of T-cell prolymphocytic leukemia with human CD52 antibody. J Clin Oncol 1997; 15: 2667–72

    PubMed  CAS  Google Scholar 

  94. Keating MJ, Cazin B, Coutre S, et al. Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed. J Clin Oncol 2002; 20: 205–13

    Article  PubMed  CAS  Google Scholar 

  95. Bowen AL, Zomas A, Emmett E, et al. Subcutaneous Campath-1H in fludarabineresistant/relapsed chronic lymphocytic leukemia. Br J Haematol 1997; 96: 617–9

    Article  PubMed  CAS  Google Scholar 

  96. Österborg A, Dyer MJS, Bunjes D, et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. J Clin Oncol 1997; 15: 1567–74

    PubMed  Google Scholar 

  97. Rawstron AC, Davies FE, Evans P, et al. Campath-1H therapy for patients with refractory chronic lymphocytic leukemia [abstract]. Blood 1997; 90 Suppl. 1: 529a

    Google Scholar 

  98. Keating MJ, Byrd J, Rai K, et al. Multicenter study of Campath-1H in patients with chronic lymphocytic leukemia (B-CLL) refractory to fludarabine [abstract]. Blood 1999; 94 Suppl. 1: 705a

    Google Scholar 

  99. Rawstron AC, Kennedy B, Evans PA, et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 2001; 98: 29–35

    Article  PubMed  CAS  Google Scholar 

  100. Dyer MJS, Kelsey SM, Mackay HJ, et al. In vivo ‘purging’ of residual disease in CLL with Campath-1H. Br J Haematol 1997; 97: 669–72

    Article  PubMed  CAS  Google Scholar 

  101. Gilleece MH, Dexter TM. Effect of campath-1H antibody on human hematopoietic progenitors in vitro. Blood 1993; 82: 807–12

    PubMed  CAS  Google Scholar 

  102. McLaughlin P, Grillo-López A, Link B, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a 4-dose treatment program. J Clin Oncol 1998; 16: 2825–33

    PubMed  CAS  Google Scholar 

  103. O’Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001; 19: 2165–70

    PubMed  Google Scholar 

  104. Byrd JC, Waselenko JK, Maneatis TJ, et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 1999; 17: 791–5

    PubMed  CAS  Google Scholar 

  105. Jensen M, Winkler U, Manzke O, et al. Rapid tumor lysis in a patient with B-cell chronic lymphocytic leukemia and lymphocytosis treated with an anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab). Ann Hematol 1998; 77: 89–91

    Article  PubMed  CAS  Google Scholar 

  106. Lim LC, Koh LP, Tan P. Fatal cytokine release syndrome with chimeric anti-CD20 monoclonal antibody rituximab in a 71-year-old patient with chronic lymphocytic leukemia. J Clin Oncol 1999; 17: 1962–3

    PubMed  CAS  Google Scholar 

  107. Yang H, Rosove MH, Figlin RA. Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: high-grade non-Hodg-kin’s lymphoma and chronic lymphocytic leukemia. Am J Hematol 1999; 62: 247–50

    Article  PubMed  CAS  Google Scholar 

  108. Winkler U, Jensen M, Manzke O, et al. 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: 2217–24

    PubMed  CAS  Google Scholar 

  109. Berkahn LC, Simpson DR, Raptis A, et al. Rituxan in vivo purging of stem cells for autologous transplantation in chronic lymphocytic leukemia (CLL) [abstract]. Blood 2000; 96 Suppl. 1: 186a

    Google Scholar 

  110. Keating MJ, O’Brien S, Albitar M, et al. Emerging information on the use of rituximab in chronic lymphocytic leukemia. Semin Oncol 2002; 29 Suppl. 2: 70–4

    Article  CAS  Google Scholar 

  111. Kaminski MS, Estes J, Zasadny KR, et al. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 2000; 96: 1259–66

    PubMed  CAS  Google Scholar 

  112. Frewin R, Turner D, Tighe M, et al. Combination therapy with fludarabine and cyclophosphamide as salvage treatment in lymphoproliferative disorders. Br J Haematol 1999; 104: 612–3

    Article  PubMed  CAS  Google Scholar 

  113. 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: 1414–20

    PubMed  Google Scholar 

  114. Flinn IW, Byrd JC, Morrison C, et al. Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood 2000; 96: 71–5

    PubMed  CAS  Google Scholar 

  115. Cazin B, Maloum K, Divine M, et al. for the French Cooperative Group for CLL. Oral fludarabine and cyclophosphamide in previously untreated chronic lymphocytic leukemia (CLL): preliminary data [abstract]. Blood 2001; 98 Suppl. 1: 772a

    Google Scholar 

  116. Weiss MA, Glenn M, Maslak P, et al. Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy. Leukemia 2000; 14: 1577–82

    Article  PubMed  CAS  Google Scholar 

  117. Laurencet FM, Zulian GB, Guetty-Alberto M, et al. Cladribine with cyclophosphamide and prednisone in the management of low-grade lymphoproliferative malignancies. Br J Cancer 1999; 79: 1215–9

    Article  PubMed  CAS  Google Scholar 

  118. Van Den Neste E, Louviaux I, Michaux JL, et al. Phase I/II study of 2-chloro-2′-deoxyadenosine with cyclophosphamide in patients with pretreated B cell chronic lymphocytic leukemia and indolent non-Hodgkin’s lymphoma. Leukemia 2000; 14: 1136–42

    Article  CAS  Google Scholar 

  119. Byrd JC, Shinn C, Ravi R, et al. Depsipeptide (FR901228): a novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemia cells. Blood 1999; 94: 1401–8

    PubMed  CAS  Google Scholar 

  120. Senderowicz AM. Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies. Leukemia 2001; 15: 1–9

    Article  PubMed  CAS  Google Scholar 

  121. Gledhill RM. Differential sensitivities of normal and chronic lymphocytic leukemia lymphocytes to 1-methyl, 3-isobutylxanthine and N6-2′-O-dibutyril adenosine-3′, 5′-cyclic monophosphate. J Med 1978; 9: 291–311

    PubMed  CAS  Google Scholar 

  122. Mentz F, Merle-Beral H, Ouaaz F, et al. Theophylline, a new inducer of apoptosis in B-CLL: role of cyclic nucleotides. Br J Haematol 1995; 90: 957–9

    Article  PubMed  CAS  Google Scholar 

  123. Mentz F, Mossalayi MD, Ouaaz F, et al. Theophylline synergizes with chlorambucil in inducing apoptosis of B-chronic lymphocytic leukemia cells. Blood 1996; 88: 2172–82

    PubMed  CAS  Google Scholar 

  124. Binet JL, Mentz F, Leblond V, et al. Synergistic action of alkylating agents and methylxanthine derivatives in the treatment of chronic lymphocytic leukemia. Leukemia 1995; 9: 2159–61

    PubMed  CAS  Google Scholar 

  125. Kipps TJ. Future strategies toward the cure of indolent B-cell malignancies. Molecular genetic approaches. Semin Hematol 1999; 36: 3–8

    PubMed  CAS  Google Scholar 

  126. King CA, Spellerberg MB, Zhu D, et al. DNA vaccines with single-chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma. Nat Med 1998; 4: 1281–6

    Article  PubMed  CAS  Google Scholar 

  127. Sutton L, Azar N, Cazin B. Intravenous infusion of activated autologous macrophages armed with anti-CD2-monoclonal antibodies can yield sustained molecular remission in CLL. Blood 2001; 98 Suppl. 1: 808a

    Google Scholar 

  128. Muirhead MJ, Isakson PC, Krolick KA, et al. BCL1, a murine model of prolymphocytic leukemia. I. Effect of splenectomy on growth kinetics and organ distribution. Am J Pathol 1981; 105: 295–305

    PubMed  CAS  Google Scholar 

  129. Muirhead MJ, Holbert JM, Uhr JW, et al. BCL1, a murine model of prolymphocytic leukemia. II. Morphology and ultrastructure. Am J Pathol 1981; 105: 306–15

    PubMed  CAS  Google Scholar 

  130. Slavin S, Weiss L, Morecki S, et al. Ultrastructural, cell membrane, and cytogenetic characteristics of Bcl 1 leukemia, a murine model of chronic lymphocytic leukemia. Cancer Res 1981; 41: 4162–6

    PubMed  CAS  Google Scholar 

  131. Fabian I, Kletter Y, Slavin S. Therapeutic potential of recombinant granulocyte-macrophage colony-stimulating factor and interleukin-3 in murine B-cell leukemia. Blood 1988; 72: 913–8

    PubMed  CAS  Google Scholar 

  132. Michallet M, Corront B, Hollard D, et al. Allogeneic bone marrow transplantation in chronic lymphocytic leukemia: 17 cases. Report from the EBMTG. Bone Marrow Transplant 1991; 7: 275–9

    PubMed  CAS  Google Scholar 

  133. Rabinowe SN, Soiffer RJ, Gribben JG, et al. Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia. Blood 1993; 82: 1366–76

    PubMed  CAS  Google Scholar 

  134. Khouri IF, Keating MJ, Vriesendorp HM. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. J Clin Oncol 1994; 12: 748–58

    PubMed  CAS  Google Scholar 

  135. Dreger P, van Biezen A, Brand R, et al. Prognostic factors for survival after autologous stem cell transplantation for chronic lymphocytic leukemia (CLL): the EBMT experience. Chronic Leukemia Working Party, European Blood and Marrow Transplant Group (EBMT) [abstract]. Blood 2000; 96 Suppl. 1: 482a

    Google Scholar 

  136. Michallet M, Brand R, Dreger P, et al. Allogeneic hematopoietic stem cell transplantation (HSCT) for chronic lymphocytic leukemia (CLL): results and prognostic factors for survival after transplantation. Analysis from EBMT registry. Chronic Leukemia Working Party, EBMT [abstract]. Blood 2000; 96 Suppl. 1: 205a

    Google Scholar 

  137. Dreger P, von Neuhoff N, Kuse R, et al. Early stem cell transplantation for chronic lymphocytic leukemia: a chance for cure? Br J Cancer 1998; 77: 2291–7

    Article  PubMed  CAS  Google Scholar 

  138. Provan D, Bartlett-Pandite L, Zwicky C, et al. Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood 1996; 88: 2228–35

    PubMed  CAS  Google Scholar 

  139. Sutton L, Maloum K, Gonzalez H, et al. Autologous hematopoietic stem cell transplantation as salvage treatment for advanced B cell chronic lymphocytic leukemia. Leukemia 1998; 12: 1699–707

    Article  PubMed  CAS  Google Scholar 

  140. Schey SA, Ahsan G, Jones R. Dose intensification and molecular responses in patients with chronic lymphocytic leukemia: a phase II single centre study. Bone Marrow Transplant 1999; 24: 989–93

    Article  PubMed  CAS  Google Scholar 

  141. Meloni G, Proia A, Mauro F, et al. Unmanipulated peripheral blood stem cell autograft in chronic lymphocytic leukemia: clinical findings and biological monitoring. Haematologica 2000; 85(9): 952–60

    PubMed  CAS  Google Scholar 

  142. Dreger P, von Neuhoff N, Sonnen R, et al. Efficacy and prognostic implications of early autologous stem cell transplantation for poor-risk chronic lymphocytic leukemia (CLL) [abstract]. Blood 2000; 96 Suppl. 1: 483a

    Google Scholar 

  143. Esteve J, Villamor N, Colomer D, et al. Stem cell transplantation for chronic lymphocytic leukemia: different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status. Leukemia 2001; 15: 445–51

    Article  PubMed  CAS  Google Scholar 

  144. Forsyth PD, Milligan DW, Davies FE, et al. High-dose chemoradiotherapy with autologous stem cell rescue for patients with CLL is an effective and safe means of inducing molecular responses: an MRC pilot study. Blood 2000; 96 Suppl. 1: 843a

    Google Scholar 

  145. Gribben JG, Neuberg RJ, Soiffier DC, et al. Autologous versus allogenic bone marrow transplantation for patients with poor prognosis CLL [abstract]. Blood 1998; 92 Suppl. 1: 322a

    Google Scholar 

  146. Khouri IF, Przepiorka D, van Besien K, et al. Allogeneic blood or marrow transplantation for chronic lymphocytic leukemia: timing of transplantation and potential effect of fludarabine on acute graft-versus-host disease. Br J Haematol 1997; 97: 466–73

    Article  PubMed  CAS  Google Scholar 

  147. Mattsson J, Uzunel M, Remberger M, et al. Minimal residual disease is common after allogeneic stem cell transplantation in patients with B cell chronic lymphocytic leukemia and may be controlled by graft-versus-host disease. Leukemia 2000; 14: 247–54

    Article  PubMed  CAS  Google Scholar 

  148. Michallet M, Thiebaut A, Dreger P, et al. Peripheral blood stem cell (PBSC) mobilisation and transplantation after fludarabine therapy in chronic lymphocytic leukemia (CLL): a report of the European Blood and Marrow Transplantation (EBMT) CLL subcommittee on behalf of the EBMT Chronic leukemias working party (CLWP). Br J Haematol 2000; 108: 595–601

    Article  PubMed  CAS  Google Scholar 

  149. Pavletic ZS, Arrowsmith ER, Bierman PJ, et al. Outcome of allogenic transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant 2000; 25: 717–22

    Article  PubMed  CAS  Google Scholar 

  150. Michallet M, Archimbaud E, Bandini G, et al. HLA-identical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia. European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry. Ann Intern Med 1996; 124: 311–5

    PubMed  CAS  Google Scholar 

  151. Giralt S, Estey E, Albitar M, et al. Engraftment of allogenic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft versus leukemia without myeloablative therapy. Blood 1997; 89: 4531–6

    PubMed  CAS  Google Scholar 

  152. Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and non malignant hematologic diseases. Blood 1998; 91: 756–63

    PubMed  CAS  Google Scholar 

  153. Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817–24

    PubMed  CAS  Google Scholar 

  154. Lawrence JH, Low-Beer BVA, Carpenter WJ. Chronic lymphocytic leukemia: study of 100 patients with radioactive phosphorus. JAMA 1949; 140: 585–8

    Article  CAS  Google Scholar 

  155. Comby E, André I, Troussard X, et al. I. In vitro evaluation of B-CLL cells apoptotic responses to irradiation. Leuk Lymphoma 1999; 34: 159–66

    PubMed  CAS  Google Scholar 

  156. Parmentier C, Schlienger M, Hayat M, et al. Splenic irradiation in decompensated chronic lymphocytic leukemia. J Radiol Electrol Med Nucl 1968; 49: 187–98

    PubMed  CAS  Google Scholar 

  157. Schiffer LM, Chanana AD, Cronkite EP, et al. Lymphocyte kinetics in chronic lymphocytic leukemia (CLL) studied by ECIB. Br J Haematol 1969; 17: 408

    PubMed  CAS  Google Scholar 

  158. Chanana AD, Cronkite EP, Rai KR. The role of extracorporeal irradiation of blood in treatment of leukemia. Int J Radiat Oncol Biol Phys 1976; l: 539–48

    Article  Google Scholar 

  159. Johnson RE. Total body irradiation of chronic lymphocytic leukemia. Relationship between therapeutic response and prognosis. Cancer 1976; 37: 2691–6

    Article  PubMed  CAS  Google Scholar 

  160. Leporrier M, Reman O, Troussard X, et al. Double hemibody irradiation with GM-CSF as salvage therapy for refractory chronic lymphocytic leukemia. Leuk Lymphoma 1994; 1: 121–4

    Article  Google Scholar 

  161. Aabo K, Walbom-Jorgensen S. Spleen irradiation in chronic lymphocytic leukemia (CLL): palliation in patients unfit for splenectomy. Am J Hematol 1985; 19: 177–80

    Article  PubMed  CAS  Google Scholar 

  162. Guiney MJ, Liew KH, Quong GG, et al. A study of splenic irradiation in chronic lymphocytic leukemia. Int J Radiat Oncol Biol Phys 1989; 16: 225–9

    Article  PubMed  CAS  Google Scholar 

  163. Cooperative group for the study of immunoglobulin in chronic lymphocytic leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled trial. N Engl J Med 1988; 319: 902–7

    Article  Google Scholar 

  164. Diehl LF, Ketchum LH. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombo-cytopenia. Semin Oncol 1998; 25: 80–97

    PubMed  CAS  Google Scholar 

  165. Levy V, Porcher R, Delabarre F, et al. Evaluating treatment strategies in chronic lymphocytic leukemia: use of quality-adjusted survival analysis. J Clin Epidemiol 2001; 54: 747–54

    Article  PubMed  CAS  Google Scholar 

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    Stephane Cheze & Michel Leporrier

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Cheze, S., Leporrier, M. Chronic Lymphocytic Leukemia. Am J Cancer 1, 127–143 (2002). https://doi.org/10.2165/00024669-200201020-00006

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