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  • Review Article
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Prognostic factors in chronic lymphocytic leukemia—what do we need to know?

Nature Reviews Clinical Oncology volume 8, pages 38–47 (2011)Cite this article

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Abstract

Of all leukemias, chronic lymphocytic leukemia (CLL) shows the highest variability in its clinical presentation and course. CLL can present as an aggressive and life threatening leukemia or as an indolent form that will not require treatment over decades. The currently available clinical staging systems for CLL are simple and inexpensive but lack accuracy to predict disease progression and survival on an individual basis. The increased understanding of the key events of molecular pathogenesis has provided a plethora of novel molecular and biological factors that correlate with the outcome of CLL. This Review provides a concise discussion of the most important discoveries and gives guidance on how to implement novel prognostic tools in the clinical management of CLL by applying the criteria of evidence, relevance, and simplicity to the selection of prognostic markers.

Key Points

  • Tremendous progress in understanding the pathogenesis of chronic lymphocytic leukemia (CLL) has led to the development of many new biological markers that predict the prognosis of CLL patients

  • Oncologists are confronted with the challenge of integrating novel markers into daily practice, which requires a set of parameters based on evidence, potential relevance and simplicity

  • Applying these three criteria, we propose the following parameters to be used in clinical practice: clinical staging, lymphocyte doubling time, chromosomal aberrations, physical fitness (comorbidity) and response to therapy

  • We feel that other parameters need to be further investigated in clinical trials and are not currently recommended to guide treatment decisions in CLL

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Figure 1: Overall survival of patients with CLL according to Binet and Rai stages.
Figure 2: The impact of adverse cytogenetics on the probability of survival from the date of diagnosis among patients with CLL.
Figure 3: Proposal for the use of prognostic factors in clinical practice based on the three criteria evidence, simplicity and relevance.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Hallek, M. et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111, 5446–5456 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jemal, A. et al. Cancer statistics, 2007. CA Cancer J. Clin. 57, 43–66 (2007).

    Article  PubMed  Google Scholar 

  4. National Cancer Institute. SEER stat fact sheets: chronic lymphocytic leukemia [online], (2009).

  5. Molica, S. Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leuk. Lymphoma 47, 1477–1480 (2006).

    Article  PubMed  Google Scholar 

  6. Morton, L. M. et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood 107, 265–276 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Watson, L., Wyld, P. & Catovsky, D. Disease burden of chronic lymphocytic leukemia within the European Union. Eur. J. Haematol. 81, 253–258 (2008).

    Article  PubMed  Google Scholar 

  8. Mauro, F. R. et al. Clinical characteristics and outcome of young chronic lymphocytic patients: a single institution study of 204 cases. Blood 94, 448–454 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Binet, J. L. et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 107, 859–861 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Rai, K. R. in Chronic Lymphocytic Leukemia: Recent Progress and Future Directions. (eds Gale, R. P. & Rai, K. R.) 253–264 (Alan R. Liss, 1987).

    Google Scholar 

  11. Rai, K. R. et al. Clinical staging of chronic lymphocytic leukemia. Blood 46, 219–234 (1975).

    Article  CAS  PubMed  Google Scholar 

  12. Binet, J. L. et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48, 198–206 (1981).

    Article  CAS  PubMed  Google Scholar 

  13. Dighiero, G. et al. Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N. Engl. J. Med. 338, 1506–1514 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Vallespí, T., Montserrat, E. & Sanz, M. A. Chronic lymphocytic leukaemia: prognostic value of lymphocyte morphological subtypes. A multivariate survival analysis in 146 patients. Br. J. Haematol. 77, 478–485 (1991).

    Article  PubMed  Google Scholar 

  15. Oscier, D. G. et al. Atypical lymphocyte morphology: an adverse prognostic factor for disease progression in stage A CLL independent of trisomy 12. Br. J. Haematol. 98, 934–939 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Matutes, E. et al. Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br. J. Haematol. 92, 382–388 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Nowakowski, G. S. et al. Percentage of smudge cells on routine blood smear predicts survival in chronic lymphocytic leukemia. J. Clin. Oncol. 27, 1844–1849 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Molica, S., Levato, D., Cascavilla, N., Levato, L. & Musto, P. Clinico-prognostic implications of simultaneous increased serum levels of soluble CD23 and beta2-microglobulin in B-cell chronic lymphocytic leukemia. Eur. J. Haematol. 62, 117–122 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Rozman, C., Hernandez-Nieto, L., Montserrat, E. & Brugues, R. Prognostic significance of bone-marrow patterns in chronic lymphocytic leukemia. Br. J. Hematol. 47, 529–537 (1981).

    Article  CAS  Google Scholar 

  20. Rozman, C. et al. Bone marrow histologic pattern—the best single prognostic parameter in chronic lymphocytic leukemia: a multivariate survival analysis of 329 cases. Blood 64, 642–648 (1984).

    Article  CAS  PubMed  Google Scholar 

  21. Han, T. et al. Bone marrow infiltration pattern and their prognostic significance in chronic lymphocytic leukemia: correlations with clinical immunologic, phenotypic, and cytogenetic data. J. Clin. Oncol. 2, 562–570 (1984).

    Article  CAS  PubMed  Google Scholar 

  22. Wierda, W. G. et al. Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J. Clin. Oncol. 27, 1637–1643 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bergmann, M. A. et al. Prospective evaluation of prognostic parameters in early stage chronic lymphocytic leukemia (CLL): results of the CLL1-protocol of the German CLL Study Group (GCLLSG) [abstract]. Blood 110, a625 (2007).

    Article  Google Scholar 

  24. Molica, S. & Alberti, A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer 60, 2712–2716 (1987).

    Article  CAS  PubMed  Google Scholar 

  25. Viñolas, N., Reverter, J. C., Urbano-Ispizua, A., Montserrat, E. & Rozman, C. Lymphocyte doubling time in chronic lymphocytic leukemia: an update of its prognostic significance. Blood Cells 12, 457–470 (1987).

    PubMed  Google Scholar 

  26. Montserrat, E., Sanchez-Bisono, J., Viñolas, N. & Rozman, C. Lymphocyte doubling time in chronic lymphocytic leukemia: analysis of its prognostic significance. Br. J. Haematol. 62, 567–575 (1986).

    Article  CAS  PubMed  Google Scholar 

  27. Messmer, B. T. et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J. Clin. Invest. 115, 755–764 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gentile, M. et al. Predictive value of beta2-microglobulin (beta2-m) levels in chronic lymphocytic leukemia since Binet A stages. Haematologica 94, 887–888 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Simonsson, B., Wibell, L. & Nilsson, K. Beta 2-microglobulin in chronic lymphocytic leukemia. Scand. J. Haematol. 24, 174–180 (1980).

    Article  CAS  PubMed  Google Scholar 

  30. Hallek, M. et al. Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma. Leuk. Lymphoma 22, 439–447 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Delgado, J. et al. Beta2-microglobulin is a better predictor of treatment-free survival in patients with chronic lymphocytic leukemia if adjusted to glomerular filtration rate. Br. J. Haematol. 145, 801–805 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Di Giovanni, S., Valentini, G., Carducci, P. & Giallonardo, P. Beta-2-microglobulin is a reliable tumor marker in chronic lymphocytic leukemia. Acta Haematol. 81, 181–185 (1989).

    Article  CAS  PubMed  Google Scholar 

  33. Späti, B., Child, J. A., Kerruish, S. M. & Cooper, E. H. Behaviour of serum beta 2-microglobulin and acute phase reactant proteins in chronic lymphocytic leukaemia. A multicentre study. Acta Haematol. 64, 79–86 (1980).

    Article  PubMed  Google Scholar 

  34. Koller, C. et al. Plasma thrombopoietin compared with immunoglobulin heavy-chain mutation status as a predictor of survival in chronic lymphocytic leukemia. Blood 108, 1001–1006 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Schroers, R. et al. Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia. Leukemia 19, 750–758 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Heintel, D. et al. Association of CD38 antigen expression with other prognostic parameters in early stages of chronic lymphocytic leukemia. Leuk. Lymphoma 42, 1315–1321 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Hallek, M. et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine and cyclophosphamide (FC) improves response rates and progression-free survival (PFS) of previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL) [abstract]. Blood 112, a325 (2008).

    Article  Google Scholar 

  38. Gronowitz, J. S., Hagberg, H., Källander, C. F. & Simonsson, B. The use of serum deoxythymidine kinase as a prognostic marker, and in the monitoring of patients with non-Hodgkin's lymphoma. Br. J. Cancer 47, 487–495 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Källander, C. F., Simonsson, B., Hagberg, H. & Gronowitz, J. S. Serum deoxythymidine kinase gives prognostic information in chronic lymphocytic leukemia. Cancer 54, 2450–2455 (1984).

    Article  PubMed  Google Scholar 

  40. Magnac, C. et al. Predictive value of serum thymidine kinase level for Ig-V mutational status in B-CLL. Leukemia 17, 133–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Matthews, C. et al. Serum TK levels in CLL identify Binet stage A patients within biologically defined prognostic subgroups most likely to undergo disease progression. Eur. J. Haematol. 77, 309–317 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Hallek, M. et al. Elevated serum thymidine kinase levels identify a subgroup at high risk of disease-progression in early, nonsmoldering chronic lymphocytic leukemia. Blood 93, 1732–1737 (1999).

    CAS  PubMed  Google Scholar 

  43. Callea, V. et al. Clinical significance of sIL2R, sCD23, sICAM-1, IL6 and sCD14 serum levels in chronic lymphocytic leukemia. Haematologica 81, 310–315 (1996).

    CAS  PubMed  Google Scholar 

  44. Knauf, W. U. et al. Serum levels of soluble CD23, but not soluble CD25, predict disease progression in early stage B-cell chronic lymphocytic leukemia. Leuk. Lymphoma 27, 523–532 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Leotard, S. et al. Prognostic relevance of a scoring system based on clinical and biological parameters in early chronic lymphocytic leukemia. Hematol. J. 1, 301–306 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Saka, B. et al. Prognostic importance of soluble CD23 in B-cell chronic lymphocytic leukemia. Clin. Lab. Haematol. 28, 30–35 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Schwarzmeier, J. D. et al. The role of soluble CD23 in distinguishing stable and progressive forms of B-chronic lymphocytic leukemia. Leuk. Lymphoma 43, 549–554 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Sarfati, M. et al. Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia. Blood 88, 4259–4264 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Reinisch, W. et al. Soluble CD23 reliably reflects disease activity in B-cell chronic lymphocytic leukemia. J. Clin. Oncol. 12, 2146–2152 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Meuleman, N. et al. Doubling time of soluble CD23: a powerful prognostic factor for newly diagnosed and untreated stage A chronic lymphocytic leukemia patients. Leukemia 22, 1882–1890 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Hallek, M., Wanders, L., Strohmeyer, S. & Emmerich, B. Thymidine kinase: a tumor marker with prognostic value for non-Hodgkin's lymphoma and a broad range of potential clinical applications. Ann. Hematol. 1, 1–5 (1992).

    Article  Google Scholar 

  52. Döhner, H. et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 89, 2516–2522 (1997).

    Article  PubMed  Google Scholar 

  53. Döhner, H. et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N. Engl. J. Med. 343, 1910–1916 (2000).

    Article  PubMed  Google Scholar 

  54. Kröber, A. et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100, 1410–1416 (2002).

    Article  PubMed  Google Scholar 

  55. Dewald, G. W. et al. Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B-cell chronic lymphocytic leukaemia. Br. J. Haematol. 121, 287–295 (2003).

    Article  PubMed  Google Scholar 

  56. Shanafelt, T. D. et al. Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early stage chronic lymphocytic leukemia. J. Clin. Oncol. 24, 4634–4641 (2006).

    Article  PubMed  Google Scholar 

  57. Stilgenbauer, S. et al. Incidence and clinical significance of 6q deletions in B cell chronic lymphocytic leukemia. Leukemia 13, 1331–1334 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Stilgenbauer, S. et al. Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberrations associated with unmutated VH, resistance to therapy, and short survival. Haematologica 92, 1242–1245 (2007).

    Article  PubMed  Google Scholar 

  59. Oscier, D. G. 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 100, 1177–1184 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Zenz, T. et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood 112, 3322–3329 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Rosenwald, A. et al. Fludarabine treatment of patients with chronic lymphocytic leukemia induces a p53-dependent gene expression response. Blood 104, 1428–1434 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Byrd, J. C. 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. 24, 437–443 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Kröber, A. 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. 24, 969–975 (2006).

    Article  PubMed  CAS  Google Scholar 

  64. Stilgenbauer, S. et al. Molecular cytogenetic delineation of a novel critical genomic region in chromosome bands 11q22.3–9231 in lymphoproliferative disorders. Proc. Natl Acad. Sci. USA 93, 11837–11841 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Thomas, A., Pepper, C., Hoy, T. & Bentley, P. Bcl-2 and bax expression and chlorambucil-induced apoptosis in the T-cells and leukaemic B-cells of untreated B-cell chronic lymphocytic leukaemia patients. Leuk. Res. 24, 813–821 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Malcikova, J. et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood 114, 5307–5314 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Austen, B. 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 106, 3175–3182 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Austen, B. et al. Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. J. Clin. Oncol. 25, 5448–5457 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Zenz, T., Benner, A., Döhner, H. & Stilgenbauer, S. Chronic lymphocytic leukemia and treatment resistance in cancer: the role of the p53 pathway. Cell Cycle 7, 3810–3814 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Oscier, D., Fitchett, M., Herbert, T. & Lambert, R. Karyotypic evolution in B-cell chronic lymphocytic leukaemia. Genes Chromosomes Cancer 3, 16–20 (1991).

    Article  CAS  PubMed  Google Scholar 

  71. Finn, W. G., Kay, N. E., Kroft, S. H., Church, S. & Peterson, L. C. Secondary abnormalities of chromosome 6q in B-cell chronic lymphocytic leukemia: a sequential study of karyotypic instability in 51 patients. Am. J. Hematol. 59, 223–229 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Chevallier, P. et al. CD38 expression and secondary 17p deletion are important prognostic factors in chronic lymphocytic leukaemia. Br. J. Haematol. 116, 142–150 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Dyer, M. J. & Oscier, D. G. The configuration of the immunoglobulin genes in B cell chronic lymphocytic leukemia. Leukemia 16, 973–984 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Hayat, A. et al. CD38 expression level and pattern of expression remains a reliable and robust marker of progressive disease in chronic lymphocytic leukemia. Leuk. Lymphoma 47, 2371–2379 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Jelinek, D. F. et al. Analysis of clonal B-cell CD38 and immunoglobulin variable region sequence status in relation to clinical outcome for B-chronic lymphocytic leukaemia. Br. J. Haematol. 115, 854–861 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Hamblin, T. J. 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 99, 1023–1029 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Hamblin, T. J., Davis, Z., Gardiner, A., Oscier, D. G. & Stevenson, F. K. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94, 1848–1854 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Tobin, G. et al. Somatically mutated Ig V(H)3–21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 99, 2262–2264 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Tobin, G. et al. Chronic lymphocytic leukemias utilizing the VH3–21 gene display highly restricted Vlambda2–14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope. Blood 101, 4952–4957 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Thorsélius, M. et al. Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status. Blood 107, 2889–2894 (2006).

    Article  PubMed  CAS  Google Scholar 

  81. Montserrat, E. New prognostic markers in CLL. Hematology Am. Soc. Hematol. Educ. Program 279–284 (2006).

    Article  Google Scholar 

  82. Damle, R. N. et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94, 1840–1847 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Orchard, J. A. et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363, 105–111 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Patten, P. E. et al. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood 111, 5173–5181 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Deaglio, S., Vaisitti, T., Aydin, S., Ferrero, E. & Malavasi, F. 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 108, 1135–1144 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Domingo-Domènech, E. et al. CD38 expression in B-chronic lymphocytic leukemia: association with clinical presentation and outcome in 155 patients. Haematologica 87, 1021–1027 (2002).

    PubMed  Google Scholar 

  87. Dürig, J. et al. CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. Leukemia 16, 30–35 (2002).

    Article  PubMed  Google Scholar 

  88. Del Poeta, G. et al. Clinical significance of CD38 expression in chronic lymphocytic leukemia. Blood 98, 2633–2639 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Ibrahim, S. et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 98, 181–186 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Morabito, F. et al. Peripheral blood CD38 expression predicts survival in B-cell chronic lymphocytic leukemia. Leuk. Res. 25, 927–932 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. D'Arena, G. et al. CD38 expression correlates with adverse biological features and predicts poor clinical outcome in B-cell chronic lymphocytic leukemia. Leuk. Lymphoma 42, 109–114 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Ghia, P. et al. The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression. Blood 101, 1262–1269 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Rassenti, L. Z. et al. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood 112, 1923–1930 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Del Giudice, I. et al. Zeta-chain associated protein 70 and CD38 combined predict the time to first treatment in patients with chronic lymphocytic leukemia. Cancer 104, 2124–2132 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Matrai, Z. et al. CD38 expression and Ig VH gene mutation in B-cell chronic lymphocytic leukemia. Blood 97, 1902–1903 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Hamblin, T. J. et al. Immunoglobulin V genes and CD38 expression in CLL. Blood 95, 2455–2457 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Thunberg, U. et al. CD38 expression is a poor predictor for VH gene mutational status and prognosis in chronic lymphocytic leukemia. Blood 97, 1892–1894 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Chen, L. et al. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood 100, 4609–4614 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Crespo, M. et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N. Engl. J. Med. 348, 1764–1775 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Dürig, J. et al. ZAP-70 expression is a prognostic factor in chronic lymphocytic leukemia. Leukemia 17, 2426–2434 (2003).

    Article  PubMed  CAS  Google Scholar 

  101. Rassenti, L. Z. 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. 351, 893–901 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Wiestner, A. et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 101, 4944–4951 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Keating, M. J. et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 92, 1165–1171 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Tam, C. S. et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 112, 975–980 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Catovsky, D., Fooks, J. & Richards, S. Prognostic factors in chronic lymphocytic leukaemia: the importance of age, sex and response to treatment in survival. A report from the MRC CLL 1 trial. MRC Working Party on Leukaemia in Adults. Br. J. Haematol. 72, 141–149 (1989).

    Article  CAS  PubMed  Google Scholar 

  106. Tsimberidou, A. M. et al. Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia. Cancer 115, 373–380 (2009).

    Article  PubMed  Google Scholar 

  107. Hallek, M. et al. First-line treatment with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) improves overall survival (OS) in previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a randomized phase III trial on behalf of an international group of investigators and the German CLL Study Group [abstract]. Blood 114, a535 (2009).

    Article  Google Scholar 

  108. Böttcher, S. et al. Quantitative MRD assessments predict progression free survival in CLL patients treated with fludarabine and cyclophosphamide with or without rituximab—a prospective analysis in 471 patients from the randomized GCLLSG CLL8 trial [abstract]. Blood 112, a326 (2008).

    Article  Google Scholar 

  109. Kwok, M., Rawstron, A. C., Varghese, A. & Hillmen, P. Minimal residual disease is a predictor for progression-free and overall survival in chronic lymphocytic leukemia (CLL) that is independent of the type or line of therapy [abstract]. Blood 114, a540 (2009).

    Article  Google Scholar 

  110. Böttcher, S. et al. Standardized MRD flow and ASO IGH RQ-PCR for MRD quantification in CLL patients after rituximab-containing immunochemotherapy: a comparative analysis. Leukemia 23, 2007–2017 (2009).

    Article  PubMed  CAS  Google Scholar 

  111. Sah, S. P., Matutes, E., Wotherspoon, A. C., Morilla, R. & Catovsky, D. A comparison of flow cytometry, bone marrow biopsy, and bone marrow aspirates in the detection of lymphoid infiltration in B cell disorders. J. Clin. Pathol. 56, 129–132 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rawstron, A. C. et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia 21, 956–964 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Wendtner, C. M. et al. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Moreton, P. et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J. Clin. Oncol. 23, 2971–2979 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Bosch, F. et al. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rates and disease eradication. Clin. Cancer Res. 14, 155–161 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Rawstron, A. C. 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 98, 29–35 (2001).

    Article  CAS  PubMed  Google Scholar 

  117. Varghese, A. M., Rawstron, A. C. & Hillmen, P. Eradicating minimal residual disease in chronic lymphocytic leukemia: should this be the goal of treatment? Curr. Hematol. Malig. Rep. 5, 35–44 (2010).

    Article  PubMed  Google Scholar 

  118. Del Poeta, G. et al. Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia. Cancer 112, 119–128 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Montillo, M. et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J. Clin. Oncol. 24, 2337–2342 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Schweighofer, C. D. et al. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br. J. Haematol. 144, 95–98 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Weiss, M. A. 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 14, 1577–1582 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Thurmes, P. et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk. Lymphoma 49, 49–56 (2008).

    Article  PubMed  Google Scholar 

  123. Eichhorst, B., Goede, V. & Hallek, M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk. Lymphoma 50, 171–178 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Cramer, P. et al. Impact of different chemotherapy regimen in comorbid patients with advanced chronic lymphocytic leukemia: metaanalysis of two phase-III-trials of the German CLL Study Group [abstract]. Blood 108, a2840 (2006).

    Article  Google Scholar 

  125. Balducci, L. & Extermann, M. Management of cancer in the older person: a practical approach. Oncologist 5, 224–237 (2000).

    Article  CAS  PubMed  Google Scholar 

  126. Balducci, L. The geriatric cancer patient: equal benefit from equal treatment. Cancer Control 8 (Suppl. 2), 1–25 (2001).

    CAS  PubMed  Google Scholar 

  127. Balducci, L. Aging, frailty, and chemotherapy. Cancer Control 14, 7–12 (2007).

    Article  PubMed  Google Scholar 

  128. Shanafelt, T. D. Predicting clinical outcome in CLL: how and why. Hematology Am. Soc. Hematol. Educ. Program 421–429 (2009).

    Article  Google Scholar 

  129. Zenz, T., Mertens, D., Küppers, R., Döhner, H. & Stilgenbauer, S. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat. Rev. Cancer 10, 37–50 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Wierda, W. G. et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood 109, 4679–4685 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Shanafelt, T. D. et al. Validation of a new prognostic index for patients with chronic lymphocytic leukemia. Cancer 115, 363–372 (2009).

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine I, Center for Integrated Oncology Köln–Bonn, Cluster of Excellence on Cellular Stress Responses in Aging-associated Diseases (CECAD Cologne), University of Cologne, Joseph-Stelzmann Straße 9, Cologne, 50924, Germany

    Paula Cramer & Michael Hallek

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  1. Paula Cramer
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P. Cramer and M. Hallek contributed to the researching of data, discussion of content, writing and revision of this Review.

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Correspondence to Michael Hallek.

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Cramer, P., Hallek, M. Prognostic factors in chronic lymphocytic leukemia—what do we need to know?. Nat Rev Clin Oncol 8, 38–47 (2011). https://doi.org/10.1038/nrclinonc.2010.167

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