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Staging and prognosis of chronic lymphocytic leukemia


Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). According to the WHO classification, B cell chronic lymphocytic leukemia is considered to be identical (ie, one disease at different stages) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma [1-3]. It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin.

The staging and prognosis of CLL will be reviewed here. The pathophysiology, clinical manifestations, diagnosis, and treatment of B cell CLL, including hematopoietic cell transplantation, are discussed separately on the appropriate topic reviews. (See "Pathologic features, diagnosis, and differential diagnosis of chronic lymphocytic leukemia" and "Clinical manifestations, pathologic features, and diagnosis of small lymphocytic lymphoma" and "Overview of the treatment of chronic lymphocytic leukemia" and "Overview of the complications of chronic lymphocytic leukemia".)


There had been a general belief that chronic lymphocytic leukemia (CLL) is an indolent disease associated with a prolonged (ie, 10 to 20 years) clinical course, and that the eventual cause of death may be unrelated to CLL. However, this observation is true for less than 30 percent of all CLL cases. Some patients die rapidly, within two to three years from diagnosis, from complications or causes directly related to CLL. Other patients live for 5 to 10 years with an initial course that is relatively benign followed by a terminal phase lasting one to two years. During this terminal phase there is considerable morbidity, both from the disease itself and from complications of therapy. The biologic reasons behind this clinical variability are under intense study, and are discussed below. (See 'Clinical staging and prognosis' below.)

During the initial asymptomatic phase, patients are able to maintain their usual lifestyles, but during the terminal phase the performance status is poor, with recurring need for hospitalization. The most frequent causes of death are severe systemic infection (especially pneumonia and septicemia), bleeding, and inanition with cachexia. Spontaneous clinical regression has been reported, but is rare [4].


As noted above, the natural history of chronic lymphocytic leukemia (CLL) is extremely variable, with survival times from initial diagnosis that range from 2 to 20 years, and a median survival of approximately 10 years. Until the mid 1970s, there were no reliable clinically applicable criteria that would allow the prospective separation of patients with a poor outlook for survival from those with an excellent prognosis. This difficulty forced physicians to make decisions concerning the need for, and timing of, therapeutic intervention in their patients with CLL, almost exclusively on an empiric basis.


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Literature review current through: Mar 2014. | This topic last updated: Apr 16, 2014.
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  1. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17:3835.
  2. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  3. Tsimberidou AM, Wen S, O'Brien S, et al. Assessment of chronic lymphocytic leukemia and small lymphocytic lymphoma by absolute lymphocyte counts in 2,126 patients: 20 years of experience at the University of Texas M.D. Anderson Cancer Center. J Clin Oncol 2007; 25:4648.
  4. Thomas R, Ribeiro I, Shepherd P, et al. Spontaneous clinical regression in chronic lymphocytic leukaemia. Br J Haematol 2002; 116:341.
  5. Boggs DR, Sofferman SA, Wintrobe MM, Cartwright GE. Factors influencing the duration of survival of patients with chronic lymphocytic leukemia. Am J Med 1966; 40:243.
  6. Galton DA. The pathogenesis of chronic lymphocytic leukemia. Can Med Assoc J 1966; 94:1005.
  7. Hansen MM. Chronic lymphocytic leukaemia. Clinical studies based on 189 cases followed for a long time. Scand J Haematol Suppl 1973; 18:3.
  8. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood 1975; 46:219.
  9. Sawitsky A, Rai KR, Glidewell O, Silver RT. Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia. Blood 1977; 50:1049.
  10. Shustik C, Mick R, Silver R, et al. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol 1988; 6:7.
  11. 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.
  12. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann Intern Med 1989; 110:236.
  13. Epstein AL, Marder RJ, Winter JN, et al. Two new monoclonal antibodies, Lym-1 and Lym-2, reactive with human B-lymphocytes and derived tumors, with immunodiagnostic and immunotherapeutic potential. Cancer Res 1987; 47:830.
  14. Rai KR. A critical analysis of staging in CLL. In: Chronic Lymphocytic Leukemia: Recent Progress and future Direction. 1987 UCLA Symposia on Molecular and Cellular Biology, New Series, Vol. 59. Gale RP, Rai KR (Eds). Alan R Liss, New York 1987. p.253.
  15. 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.
  16. Binet JL, Lepoprier M, Dighiero G, et al. A clinical staging system for chronic lymphocytic leukemia: prognostic significance. Cancer 1977; 40:855.
  17. Blum KA, Young D, Broering S, et al. Computed tomography scans do not improve the predictive power of 1996 national cancer institute sponsored working group chronic lymphocytic leukemia response criteria. J Clin Oncol 2007; 25:5624.
  18. Zent CS, Ding W, Schwager SM, et al. The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma. Br J Haematol 2008; 141:615.
  19. Moreno C, Hodgson K, Ferrer G, et al. Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood 2010; 116:4771.
  20. Shanafelt TD, Geyer SM, Kay NE. Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL. Blood 2004; 103:1202.
  21. Shanafelt TD, Byrd JC, Call TG, et al. Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. Ann Intern Med 2006; 145:435.
  22. Giles FJ, O'Brien SM, Keating MJ. Chronic lymphocytic leukemia in (Richter's) transformation. Semin Oncol 1998; 25:117.
  23. Kjeldsberg CR, Marty J. Prolymphocytic transformation of chronic lymphocytic leukemia. Cancer 1981; 48:2447.
  24. Melo JV, Catovsky D, Galton DA. The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. II. Patterns of evolution of 'prolymphocytoid' transformation. Br J Haematol 1986; 64:77.
  25. Ohno T, Smir BN, Weisenburger DD, et al. Origin of the Hodgkin/Reed-Sternberg cells in chronic lymphocytic leukemia with "Hodgkin's transformation". Blood 1998; 91:1757.
  26. Fong D, Kaiser A, Spizzo G, et al. Hodgkin's disease variant of Richter's syndrome in chronic lymphocytic leukaemia patients previously treated with fludarabine. Br J Haematol 2005; 129:199.
  27. Kanzler H, Küppers R, Helmes S, et al. Hodgkin and Reed-Sternberg-like cells in B-cell chronic lymphocytic leukemia represent the outgrowth of single germinal-center B-cell-derived clones: potential precursors of Hodgkin and Reed-Sternberg cells in Hodgkin's disease. Blood 2000; 95:1023.
  28. Tsimberidou AM, O'Brien S, Kantarjian HM, et al. Hodgkin transformation of chronic lymphocytic leukemia: the M. D. Anderson Cancer Center experience. Cancer 2006; 107:1294.
  29. Molica S, Alberti A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer 1987; 60:2712.
  30. Montserrat E, Sanchez-Bisono J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol 1986; 62:567.
  31. Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 2013; 121:1403.
  32. Schnaiter A, Paschka P, Rossi M, et al. NOTCH1, SF3B1, and TP53 mutations in fludarabine-refractory CLL patients treated with alemtuzumab: results from the CLL2H trial of the GCLLSG. Blood 2013; 122:1266.
  33. Lipshutz MD, Mir R, Rai KR, Sawitsky A. Bone marrow biopsy and clinical staging in chronic lymphocytic leukemia. Cancer 1980; 46:1422.
  34. Pangalis GA, Boussiotis VA, Kittas C. B-chronic lymphocytic leukemia. Disease progression in 150 untreated stage A and B patients as predicted by bone marrow pattern. Nouv Rev Fr Hematol 1988; 30:373.
  35. Rozman C, Montserrat E, Rodríguez-Fernández JM, et al. Bone marrow histologic pattern--the best single prognostic parameter in chronic lymphocytic leukemia: a multivariate survival analysis of 329 cases. Blood 1984; 64:642.
  36. Rozman C, Hernandez-Nieto L, Montserrat E, Brugues R. Prognostic significance of bone-marrow patterns in chronic lymphocytic leukaemia. Br J Haematol 1981; 47:529.
  37. Wierda WG, O'Brien S, Wang X, et al. Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol 2009; 27:1637.
  38. Fayad L, Keating MJ, Reuben JM, et al. Interleukin-6 and interleukin-10 levels in chronic lymphocytic leukemia: correlation with phenotypic characteristics and outcome. Blood 2001; 97:256.
  39. Moreno A, Villar ML, Cámara C, et al. Interleukin-6 dimers produced by endothelial cells inhibit apoptosis of B-chronic lymphocytic leukemia cells. Blood 2001; 97:242.
  40. Delgado J, Pratt G, Phillips N, et al. Beta2-microglobulin is a better predictor of treatment-free survival in patients with chronic lymphocytic leukaemia if adjusted according to glomerular filtration rate. Br J Haematol 2009; 145:801.
  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.
  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.
  43. Fais F, Ghiotto F, Hashimoto S, et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 1998; 102:1515.
  44. Ritgen M, Lange A, Stilgenbauer S, et al. Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood 2003; 101:2049.
  45. Kröber 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.
  46. Tobin G, Thunberg U, Johnson A, et al. Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 2002; 99:2262.
  47. Hamblin TJ, Davis ZA, Oscier DG. Determination of how many immunoglobulin variable region heavy chain mutations are allowable in unmutated chronic lymphocytic leukaemia - long-term follow up of patients with different percentages of mutations. Br J Haematol 2008; 140:320.
  48. Lin KI, Tam CS, Keating MJ, et al. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood 2009; 113:3168.
  49. Chevallier P, Penther D, Avet-Loiseau H, et al. CD38 expression and secondary 17p deletion are important prognostic factors in chronic lymphocytic leukaemia. Br J Haematol 2002; 116:142.
  50. Ibrahim S, Keating M, Do KA, et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 2001; 98:181.
  51. 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.
  52. Mainou-Fowler T, Dignum H, Taylor PR, et al. Quantification improves the prognostic value of CD38 expression in B-cell chronic lymphocytic leukaemia. Br J Haematol 2002; 118:755.
  53. Dürig J, Naschar M, Schmücker U, et al. CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. Leukemia 2002; 16:30.
  54. D'Arena G, Musto P, Cascavilla N, et al. CD38 expression correlates with adverse biological features and predicts poor clinical outcome in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 2001; 42:109.
  55. Joshi AD, Hegde GV, Dickinson JD, et al. ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressing B-cell chronic lymphocytic leukemia. Clin Cancer Res 2007; 13:5295.
  56. Dürig J, Nückel H, Cremer M, et al. ZAP-70 expression is a prognostic factor in chronic lymphocytic leukemia. Leukemia 2003; 17:2426.
  57. Rassenti LZ, Jain S, Keating MJ, et al. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood 2008; 112:1923.
  58. 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.
  59. Shanafelt TD, Drake MT, Maurer MJ, et al. Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood 2011; 117:1492.
  60. Wierda WG, Johnson MM, Do KA, et al. Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukaemia. Br J Haematol 2003; 120:452.
  61. Manshouri T, Do KA, Wang X, et al. Circulating CD20 is detectable in the plasma of patients with chronic lymphocytic leukemia and is of prognostic significance. Blood 2003; 101:2507.
  62. Bulian P, Shanafelt TD, Fegan C, et al. CD49d Is the Strongest Flow Cytometry-Based Predictor of Overall Survival in Chronic Lymphocytic Leukemia. J Clin Oncol 2014; 32:897.
  63. Brachtl G, Piñón Hofbauer J, Greil R, Hartmann TN. The pathogenic relevance of the prognostic markers CD38 and CD49d in chronic lymphocytic leukemia. Ann Hematol 2014; 93:361.
  64. Zucchetto A, Caldana C, Benedetti D, et al. CD49d is overexpressed by trisomy 12 chronic lymphocytic leukemia cells: evidence for a methylation-dependent regulation mechanism. Blood 2013; 122:3317.
  65. Majid A, Lin TT, Best G, et al. CD49d is an independent prognostic marker that is associated with CXCR4 expression in CLL. Leuk Res 2011; 35:750.
  66. Walsby E, Buggins A, Devereux S, et al. Development and characterization of a physiologically relevant model of lymphocyte migration in chronic lymphocytic leukemia. Blood 2014.
  67. Maurer MJ, Cerhan JR, Katzmann JA, et al. Monoclonal and polyclonal serum free light chains and clinical outcome in chronic lymphocytic leukemia. Blood 2011; 118:2821.
  68. Morabito F, De Filippi R, Laurenti L, et al. The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia. Blood 2011; 118:6353.
  69. Koller C, Bekele BN, Zhou X, et al. Plasma thrombopoietin compared with immunoglobulin heavy-chain mutation status as a predictor of survival in chronic lymphocytic leukemia. Blood 2006; 108:1001.
  70. Stamatopoulos B, Meuleman N, Haibe-Kains B, et al. microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification. Blood 2009; 113:5237.
  71. Visone R, Rassenti LZ, Veronese A, et al. Karyotype-specific microRNA signature in chronic lymphocytic leukemia. Blood 2009; 114:3872.
  72. Vasconcelos Y, Davi F, Levy V, et al. Binet's staging system and VH genes are independent but complementary prognostic indicators in chronic lymphocytic leukemia. J Clin Oncol 2003; 21:3928.
  73. Montserrat E, Vinolas N, Reverter JC, et al. Chronic lymphocytic leukemia in early stage "smoldering" and "active" forms in chronic lymphocytic leukemia: Scientifc advances and clinical developments. Cheston BD (Ed). Marcel Dekker, New York 1993. p.281.
  74. Matutes E, Owusu-Ankomah K, Morilla R, et al. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 1994; 8:1640.
  75. Effects of chlorambucil and therapeutic decision in initial forms of chronic lymphocytic leukemia (stage A): results of a randomized clinical trial on 612 patients. The French Cooperative Group on Chronic Lymphocytic Leukemia. Blood 1990; 75:1414.
  76. Montserrat E, Rozman C. Chronic lymphocytic leukaemia: prognostic factors and natural history. Baillieres Clin Haematol 1993; 6:849.
  77. Muntañola A, Bosch F, Arguis P, et al. Abdominal computed tomography predicts progression in patients with Rai stage 0 chronic lymphocytic leukemia. J Clin Oncol 2007; 25:1576.
  78. French Cooperative Group on Chronic Lymphocytic Leukaemia. Natural history of stage A chronic lymphocytic leukaemia untreated patients. Br J Haematol 1990; 76:45.
  79. Molica S, Vitelli G, Levato D, et al. Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia. Br J Haematol 1999; 107:605.
  80. Chen H, Treweeke AT, West DC, et al. In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells. Blood 2000; 96:3181.
  81. 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.
  82. Thornton PD, Fernandez C, Giustolisi GM, et al. CD38 expression as a prognostic indicator in chronic lymphocytic leukaemia. Hematol J 2004; 5:145.
  83. Gentile M, Mauro FR, Calabrese E, et al. The prognostic value of CD38 expression in chronic lymphocytic leukaemia patients studied prospectively at diagnosis: a single institute experience. Br J Haematol 2005; 130:549.
  84. Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001; 194:1639.
  85. 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. J Exp Med 2001; 194:1625.
  86. Damle RN, Ghiotto F, Valetto A, et al. B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. Blood 2002; 99:4087.
  87. Dürig J, Nückel H, Hüttmann A, et al. Expression of ribosomal and translation-associated genes is correlated with a favorable clinical course in chronic lymphocytic leukemia. Blood 2003; 101:2748.
  88. Rai KR, Chiorazzi N. Determining the clinical course and outcome in chronic lymphocytic leukemia. N Engl J Med 2003; 348:1797.
  89. Guarini A, Gaidano G, Mauro FR, et al. Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features. Blood 2003; 102:1035.
  90. Wierda WG, O'Brien S, Wang X, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol 2011; 29:4088.
  91. Degan M, Bomben R, Bo MD, et al. Analysis of IgV gene mutations in B cell chronic lymphocytic leukaemia according to antigen-driven selection identifies subgroups with different prognosis and usage of the canonical somatic hypermutation machinery. Br J Haematol 2004; 126:29.
  92. Haslinger C, Schweifer N, Stilgenbauer S, et al. Microarray gene expression profiling of B-cell chronic lymphocytic leukemia subgroups defined by genomic aberrations and VH mutation status. J Clin Oncol 2004; 22:3937.
  93. Dickinson JD, Smith LM, Sanger WG, et al. Unique gene expression and clinical characteristics are associated with the 11q23 deletion in chronic lymphocytic leukaemia. Br J Haematol 2005; 128:460.
  94. Kienle DL, Korz C, Hosch B, et al. Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes. J Clin Oncol 2005; 23:3780.
  95. Grabowski P, Hultdin M, Karlsson K, et al. Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status. Blood 2005; 105:4807.
  96. Oppezzo P, Vasconcelos Y, Settegrana C, et al. The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia. Blood 2005; 106:650.
  97. Calin GA, Ferracin M, Cimmino A, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353:1793.
  98. Byrd JC, Gribben JG, Peterson BL, et al. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol 2006; 24:437.
  99. Kröber 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. J Clin Oncol 2006; 24:969.
  100. 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.
  101. Dicker F, Schnittger S, Haferlach T, et al. Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: A study of 132 CLL cases with correlation to FISH, IgVH status, and CD38 expression. Blood 2006; 108:3152.
  102. Tinhofer I, Rubenzer G, Holler C, et al. Expression levels of CD38 in T cells predict course of disease in male patients with B-chronic lymphocytic leukemia. Blood 2006; 108:2950.
  103. Del Poeta G, Maurillo L, Venditti A, et al. Clinical significance of CD38 expression in chronic lymphocytic leukemia. Blood 2001; 98:2633.
  104. Friedman DR, Weinberg JB, Barry WT, et al. A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia. Clin Cancer Res 2009; 15:6947.
  105. 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.
  106. Dreger P, Stilgenbauer S, Benner A, 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.
  107. Ritgen M, Stilgenbauer S, von Neuhoff N, et al. Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 2004; 104:2600.
  108. Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348:1764.
  109. Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003; 101:4944.
  110. Orchard JA, Ibbotson RE, Davis Z, et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 2004; 363:105.
  111. Schwaenen C, Nessling M, Wessendorf S, et al. Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations. Proc Natl Acad Sci U S A 2004; 101:1039.
  112. Del Principe MI, Del Poeta G, Buccisano F, et al. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood 2006; 108:853.
  113. Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 2004; 351:893.
  114. Khouri IF, Saliba RM, Admirand J, et al. Graft-versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J Haematol 2007; 137:355.
  115. Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol 2007; 25:799.
  116. Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007; 109:399.
  117. Lin TS, Fischer B, Moran ME, et al. Flavopiridol, fludarabine and rituximab (FFR) is an active regimen in indolent B-cell lymphoproliferative disorders and mantle cell lymphoma (MCL) (abstract). J Clin Oncol 2006; 24:446s.
  118. Wierda WG. Current and investigational therapies for patients with CLL. Hematology Am Soc Hematol Educ Program 2006; :285.
  119. Gribben JG. How I treat CLL up front. Blood 2010; 115:187.
  120. Schöllkopf C, Rosendahl D, Rostgaard K, et al. Risk of second cancer after chronic lymphocytic leukemia. Int J Cancer 2007; 121:151.
  121. Maddocks-Christianson K, Slager SL, Zent CS, et al. Risk factors for development of a second lymphoid malignancy in patients with chronic lymphocytic leukaemia. Br J Haematol 2007; 139:398.
  122. Solh M, Rai KR, Peterson BL, et al. The impact of initial fludarabine therapy on transformation to Richter syndrome or prolymphocytic leukemia in patients with chronic lymphocytic leukemia: analysis of an intergroup trial (CALGB 9011). Leuk Lymphoma 2013; 54:252.