Best Practice & Research Clinical Haematology
Volume 20, Issue 3 , Pages 455-468 , September 2007

Prognostic markers in chronic lympocytic leukaemia

  • Terry J. Hamblin, DM, FRCP, FRCPath, FmedSci (Professor of Immunohaematology)

      Affiliations

    • Corresponding Author InformationTel.: +44 1202 267154; Fax: +44 1202 300248.

References 

  1. Rai KR, Sawitsky A, Cronkite ER, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–234
  2. Binet J-L, Leporier M, Dighiero G, et al. A clinical staging system for chronic lymphocytic leukemia. Cancer. 1977;40:855–864
  3. CLL Trialists Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukaemia: a meta-analysis of the randomised trials. Journal of the National Cancer Institute. 1999;91:861–868
  4. 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
  5. Binet J-L, Caligaris-Cappio F, Catovsky D, et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood. 2006;107:859–861
  6. Marti GE, Rawstron AC, Ghia P, et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. British Journal of Haematology. 2005;130:325–332
  7. 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
  8. Rawstron AC, Yuille MR, Fuller J, et al. Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion. Blood. 2002;100:2289–2290
  9. 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. Part B, Clinical Cytometry. 2003;52:1–12
  10. Jaksic B, Vitale B. Total tumour mass score (TTM): a new parameter in chronic lymphocyte leukaemia. British Journal of Haematology. 1981;49:405–413
  11. Molica S, Levato D, Dell'Olio M, et al. Cellular expression and serum circulating levels of CD23 in B-cell chronic lymphocytic leukemia. Implications for prognosis. Haematologica. 1996;81:428–433
  12. Ferrajoli A, Keating MJ, Maushouri T, et al. The clinical significance of tunor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia. Blood. 2002;100:1215–1219
  13. Lai R, O'Brien S, Maushouri T, et al. Prognostic value of plasma interleukin-6 levels in patients with chronic lymphocytic leukemia. Cancer. 2002;96:1071–1075
  14. Wierda WG, Johnson MM, Do KA, et al. Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukemia. British Journal of Haematology. 2003;120:452–456
  15. Koller C, Bekele BN, Zhou X, et al. Plasma thrombpoietin compared with immunoglobulin heavy-chain mutation status as a predictor of survival in chronic lymphocytic leukemia. Blood. 2006;108:1001–1006
  16. Rozman C, Hernandez-Nieto L, Montserrat E, Brugues R. Prognostic significance of bone marrow patterns in chronic lymphocytic leukaemia. British Journal of Haematology. 1981;47:529–537
  17. Montserrat E, Sanchez-Bisono J, Vinolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. British Journal of Haematology. 1986;62:567–575
  18. Galton DAG. The natural history of chronic lymphocytic leukaemia. MD thesis. Cambridge University, Cambridge, 1963.
  19. Galton DAG. The pathogenesis of chronic lymphocytic leukaemia. Canadian Medical Association Journal. 1966;94:1005–1010
  20. Dameshek W. Chronic lymphocytic leukemia-an accumulative disease of immunologically incompetent lymphocytes. Blood. 1967;29:566–584
  21. Gan TE, Hallam L, Van der Weyden MB. Purine and pyrimidine activities in acute and chronic lymphocytic leukaemia: relation to cellular proliferative status. Leukemia Research. 1982;6:839–844
  22. Orfao A, Ciudad J, Gonzalez M, et al. Prognostic value of S-phase white blood cell count in B-cell chronic lymphocytic leukemia. Leukemia. 1992;6:47–51
  23. Drach J, Gattringer C, Glassl H, et al. Simultaneous flow cytometric analysis of surface markers and nuclear Ki-67 antigen in leukemia and lymphoma. Cytometry. 1989;10:743–749
  24. Del Giglio A, O'brien S, Ford RJ, et al. Proliferating cell nuclear antigen (PCNA) expression in chronic lymphocytic leukaemia (CLL). Leukemia & Lymphoma. 1993;10:265–271
  25. Damle RN, Batliwalla FM, Ghiotto F, et al. Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations. Blood. 2004;103:375–382
  26. Messmer BT, Messmer D, Allen S, et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. The Journal of Clinical Investigation. 2005;115:755–764
  27. Molica S, Alberti A. Prognostic value of lymphocyte doubling time in chronic lymphocytic leukemia. Cancer. 1987;60:2712–2716
  28. 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;93:1732–1737
  29. Magnac C, Porcher R, Davi F, et al. Predictive value of serum thymidine kinase level for Ig-V mutational status in B-CLL. Leukemia. 2003;17:133–137
  30. Montserrat E, Vinolas N, Reverter JC, Rozman C. Natural history of chronic lymphocytic leukemia: on the progression and progression and prognosis of early clinical stages. Nouvelle revue française d'hématologie. 1988;30:359–361
  31. French Cooperative Group on Chronic Lymphocytic Leukaemia . Natural history of stage A chronic lymphocytic leukaemia untreated patients. British Journal of Haematology. 1990;76:45–57
  32. Hamblin AD, Hamblin TJ. Functional and prognostic role of ZAP-70 in CLL. Expert Opinion on Therapeutic Targets. 2005;9:1165–1178
  33. Caligaris-Cappio fb: Chronic lymphocytic leukemia: a malignancy of anti-self B cells. Blood. 1996;87:2615–2620
  34. Kipps TJ, Tomhave E, Pratt LF, et al. Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America. 1989;86:5913–5917
  35. Deane M, Norton JD. Preferential rearrangement of developmentally regulated immunoglobulin VH1 genes in human B-lineage leukaemias. Leukemia. 1991;5:646–650
  36. Schroeder HW, Dighiero G. The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunology Today. 1994;15:288–294
  37. Fais F, Ghiotto F, Hashimoto S, et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. The Journal of Clinical Investigation. 1998;102:1515–1525
  38. Oscier DG, Thompsett A, Zhu D, Stevenson FK. Differential rates of somatic hypermutation in VH genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood. 1997;89:4153–4160
  39. Juliusson G, Oscier DG, Fitchett M, et al. Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. The New England Journal of Medicine. 1990;323:720–724
  40. Hamblin TJ, Davies Z, Oscier DG, Stevenson FK. In chronic lymphocytic leukemias germline configuration of immunoglobulin heavy chain genes is associated with a more aggressive form of the disease. Blood. 1998;92(supplement 1):515a
  41. 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
  42. Hamblin TJ, 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
  43. 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;95:377–378
  44. 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. British Journal of Haematology. 2001;115:854–861
  45. Stilgenbauer S, Bullinger L, Lichter P, Dohner H, German CLL Study Group (GCLLSG) . Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. Leukemia. 2002;16:993–1007
  46. Ritgen M, Lange A, Stilgenbauer S, et al. The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status. Blood. 2004;103:2850–2858
  47. Hamblin TJ. Chronic lymphocytic leukaemia: one disease or two?. Annals of Hematology. 2002;81:299–303
  48. Tobin G, Thunberg U, Johnson A, et al. Somatically mutated IgVH3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood. 2002;99:2262–2264
  49. Tobin G, Thunberg U, Johnson A, et al. Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted V lambda 2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope. Blood. 2003;101:4952–4957
  50. Messmer BT, Albesiano E, Efremov DG, et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. The Journal of Experimental Medicine. 2004;200:519–525
  51. Hamblin TJ, Orchard JA, Gardiner A, et al. Immunoglobulin V genes and CD38 expression in CLL. Blood. 2000;95:2455–2457
  52. 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
  53. Deaglio S, Vaisitti T, Aydin S, et al. In-tandem insight from basic science combined with clinical research: CD38 as both marker and key component of the pathogenetic network underlying chronic lymphocytic leukemia. Blood. 2006;108:1135–1144
  54. Krober A, Seiler T, Benner A, et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100:1410–1416
  55. Thornton PD, Gustolisi G, Morilla R, et al. CD38 as a prognostic indicator in B-CLL. Leukemia & Lymphoma. 2001;42(supplement 1):35–36
  56. Ghia P, Guida G, Stella S, et al. The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression. Blood. 2003;101:1262–1269
  57. Pepper C, Brennan P, Alghazal S, et al. CD38+ chronic lymphocytic leukaemia cells co-express high levels of ZAP-70 and are functionally distinct from their CD38- counter-parts. Leukemia. 2006;20:743–747
  58. Klein U, Tu Y, Stolovitzky GA, et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. The Journal of Experimental Medicine. 2001;194:1625–1638
  59. Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. The Journal of Experimental Medicine. 2001;194:1639
  60. 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
  61. Lanham S, Hamblin T, Oscier D, et al. Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. Blood. 2003;101:1087–1093
  62. Cragg MS, Chan HTC, Fox MD, et al. The alternative transcript of CD79b is overexpressed in B-CLL and inhibits signalling for apoptosis. Blood. 2002;100:3068–3076
  63. Chen L, Apgar J, Huynh L, et al. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood. 2005;105:2036–2041
  64. Gobessi S, Laurenti L, Longo PG, et al. ZAP-70 enhances B-cell receptor signaling in spite of absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B-cells. Blood. 2007;109:2032–2039
  65. 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;106:2606–2612
  66. Wiestner A, Rosenwald A, Barry T, 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
  67. Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. The New England Journal of Medicine. 2003;348:1764–1775
  68. Orchard JA, Ibbotson RE, Davis Z, et al. ZAP-70 expression by flow cytometry is a good prognostic marker in CLL and a potential surrogate for immunoglobulin VH gene mutations. Lancet. 2004;363:105–111
  69. 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. The New England Journal of Medicine. 2004;351:893–901
  70. Krober A, Bloehdorn J, Hafner S, et al. Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia. Journal of Clinical Oncology. 2006;24:969–975
  71. Marti G, Orfao A, Goolsby C. ZAP-70 in CLL: towards standardization of a biomarker for patient management: history of clinical cytometry special issue. Cytometry. Part B, Clinical Cytometry. 2006;70B:197–200
  72. Shankey TV, Forman M, Scibelli P, et al. An optimized whole blood method for flow cytometric measurement of ZAP-70 protein expression un chronic lymphocytic leukemia. Cytometry. Part B, Clinical Cytometry. 2006;70B:259–269
  73. Best OG, Ibbotson RE, Parker AE, et al. ZAP-70 by flow cytometry: a comparison of different antibodies, anticoagulants, and methods of analysis. Cytometry. Part B, Clinical Cytometry. 2006;70B:235–241
  74. Letestu R, Rawstron A, Ghia P, et al. Evaluation ofZAP-70 expression by flow cytometry in chronic lymphocytic leukemia: A multicentric international harmonization process. Cytometry. Part B, Clinical Cytometry. 2006;70B:309–314
  75. Zucchetto A, Bomben R, Dal Bo M, et al. ZAP-70 expression in B-cell chronic lymphocytic leukemia: evaluation by external (isotypic) or internal (T/NK cells) controls and correlation with IgVH mutations. Cytometry. Part B, Clinical Cytometry. 2006;70B:284–292
  76. Shults KE, Miller DT, Davis BH, et al. A standardized ZAP-70 assay – lessons learned from the trenches. Cytometry. Part B, Clinical Cytometry. 2006;70B:276–283
  77. Sheridan R, Mounajjed T, Ehrmann DE, et al. Comparison of bone marrow and peripheral blood ZAP-70 status examined by flow cytometric immunophenotyping in patients with chronic lymphocytic leukemia. Cytometry. Part B, Clinical Cytometry. 2006;70B:320–321
  78. Villamor N, Crespo M, Bosch F, et al. ZAP-70 expression remains stable during the course of chronic lymphocytic leukemia. Leukemia & Lymphoma. 2005;46:S43
  79. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. The New England Journal of Medicine. 2000;343:1910–1916
  80. Fitchett M, Griffiths MJ, Oscier DG, et al. Chromosome abnormalities involving band 13q14 in hematologic malignancies. Cancer Genetics and Cytogenetics. 1987;24:143–150
  81. Calin GA, Liu CG, Shimizu M, et al. MicroRNA profiling reveals distinct signatures in B-cell chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America. 2004;101:11755–11760
  82. Cimmino A, Callin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:13944–13949
  83. Oscier DG, Matutes E, Copplestone A, et al. Prognostic factors in stage A chronic lymphocytic leukaemia; the importance of atypical lymphocyte morphology and abnormal karyotype for disease progression in stage A CLL. British Journal of Haematology. 1997;98:934–939
  84. Dohner H, Stilgenbauer S, James M, et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterised by extensive nodal involvement and inferior prognosis. Blood. 1997;89:2516–2522
  85. Lin K, Sherrington PD, Dennis M, et al. Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia. Blood. 2002;100:1404–1409
  86. Austen B, Powell JE, Alvi A, et al. Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood. 2005;106:3175–3182
  87. Dohner H, Fischer K, Bentz M, et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995;85:1580–1589
  88. 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
  89. Krober A, Seller T, Benner A, et al. VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100:1410–1416
  90. Shanafelt TD, Witzig TE, Fink SR, et al. Prospective evolution during long-term follow-up of patients with untreated early stage chronic lymphocytic leukemia. Journal of Clinical Oncology. 2006;24:4634–4641
  91. Cuneo A, Rigolin GM, Bigoni R, et al. Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis. Leukemia. 2004;18:476–483
  92. Byrd JC, Gribben JG, Peterson BL, et al. Select high risk features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. Journal of Clinical Oncology. 2006;24:437–443
  93. Del Poeta G, Del Principe MI, Consalvo MA, et al. The addition of rituximab improves clinical outcome in untreated patients with ZAP-70 negative chronic lymphocytic leukemia. Cancer. 2005;104:2743–2752
  94. Stilgenbauer S, Krober A, Busch R, et al. 17p deletion predicts for overall survival after fludarabine-based first line therapy in chronic lymphocytic leukemia: first analysis of genetics in the CLL4 trial of the GCLLSG. Blood. 2005;106:212a;(abstract 715)
  95. 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
  96. Oscier DG, Richards S, Orchard J, et al. Prognostic factors in the UK LRF CLL4 trial. Blood. 2005;106:594a;(abstract 2099)
  97. Hamblin TJ, Gardiner AC, Mould SJ, et al. Can we predict which patients with early stage CLL will progress and require treatment?. Leukemia & Lymphoma. 2005;46:S46

PII: S1521-6926(07)00017-5

doi: 10.1016/j.beha.2007.02.001

Best Practice & Research Clinical Haematology
Volume 20, Issue 3 , Pages 455-468 , September 2007