Prognostic factors in chronic lymphocytic leukemia-what do we need to know?

Nature Reviews Clinical Oncology

Volumn 8, Issue 1, 2011, Pages 38-47

  Cramer, Paula ^a   Hallek, Michael ^a  

^a UNIVERSITY OF COLOGNE   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ALEMTUZUMAB; BETA 2 MICROGLOBULIN; CD23 ANTIGEN; CD38 ANTIGEN; CYCLOPHOSPHAMIDE; FLUDARABINE; PROTEIN KINASE ZAP 70; RITUXIMAB; THYMIDINE KINASE;

ANEMIA; ANTIGEN EXPRESSION; CANCER IMMUNOTHERAPY; CANCER INFILTRATION; CANCER STAGING; CANCER SURVIVAL; CELL KINETICS; CELL STRUCTURE; CHROMOSOME 11Q; CHROMOSOME 17P; CHROMOSOME ABERRATION; CHROMOSOME ANALYSIS; CHROMOSOME DELETION; CHRONIC LYMPHATIC LEUKEMIA; DISEASE ACTIVITY; DISEASE COURSE; DRUG TREATMENT FAILURE; ENZYME BLOOD LEVEL; FLUORESCENCE IN SITU HYBRIDIZATION; GENE; GENE MUTATION; HUMAN; IGHV GENE; LEUKEMIA CELL; LEUKEMIA REMISSION; LYMPHOCYTE COUNT; MINIMAL RESIDUAL DISEASE; OVERALL SURVIVAL; PRACTICE GUIDELINE; PRIORITY JOURNAL; PROGNOSIS; PROGRESSION FREE SURVIVAL; PROTEIN BLOOD LEVEL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SURVIVAL TIME; SYMPTOM; THROMBOCYTOPENIA; TREATMENT RESPONSE; TUMOR SUPPRESSOR GENE; VH3 21 GENE;

EID: 85027920745     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2010.167     Document Type: Review

References (131)

1. Rozman, C. & Montserrat, E. Chronic lymphocytic leukemia. N. Engl. J. Med. 333, 1052-1057 (1995).
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).
3. Jemal, A. et al. Cancer statistics, 2007. CA Cancer J. Clin. 57, 43-66 (2007). (Pubitemid 46148091)
4. National Cancer Institute. SEER stat fact sheets: chronic lymphocytic leukemia [online], http:// seer.cancer.gov/statfacts/html/clyl.html (2009).
5. Molica, S. Sex differences in incidence and outcome of chronic lymphocytic leukemia patients. Leuk. Lymphoma 47, 1477-1480 (2006). (Pubitemid 44364010)
6. Morton, L. M. et al. Lymphoma incidence patterns by wHO subtype in the United States, 1992-2001. Blood 107, 265-276 (2006).
7. watson, L., wyld, P. & Catovsky, D. Disease burden of chronic lymphocytic leukemia within the European Union. Eur. J. Haematol. 81, 253-258 (2008).
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).
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).
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).
11. Rai, K. R. et al. Clinical staging of chronic lymphocytic leukemia. Blood 46, 219-234 (1975).
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).
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).
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).
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).
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). (Pubitemid 26046512)
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).
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). (Pubitemid 29071271)
19. Rozman, C., Hernandez-Nieto, L., Montserrat, E. & Brugues, R. Prognostic significance of bonemarrow patterns in chronic lymphocytic leukemia. Br. J. Hematol. 47, 529-537 (1981). (Pubitemid 11051353)
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). (Pubitemid 14073482)
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). (Pubitemid 14025608)
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).
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).
24. Molica, S. & Alberti, A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer 60, 2712-2716 (1987). (Pubitemid 17161803)
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). (Pubitemid 17094208)
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). (Pubitemid 16130192)
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).
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).
29. Simonsson, B., wibell, L. & Nilsson, K. Beta 2-microglobulin in chronic lymphocytic leukemia. Scand. J. Haematol. 24, 174-180 (1980).
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). (Pubitemid 26341010)
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).
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). (Pubitemid 19186451)
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). (Pubitemid 10021393)
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). (Pubitemid 44154637)
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). (Pubitemid 40663094)
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). (Pubitemid 34082920)
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).
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). (Pubitemid 13089615)
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). (Pubitemid 15223387)
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). (Pubitemid 36175898)
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). (Pubitemid 44337324)
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). (Pubitemid 29102502)
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). (Pubitemid 126506582)
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).
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).
46. Saka, B. et al. Prognostic importance of soluble CD23 in B-cell chronic lymphocytic leukemia. Clin. Lab. Haematol. 28, 30-35 (2006).
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).
48. Sarfati, M. et al. Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia. Blood 88, 4259-4264 (1996). (Pubitemid 26399173)
49. Reinisch, w. et al. Soluble CD23 reliably reflects disease activity in B-cell chronic lymphocytic leukemia. J. Clin. Oncol. 12, 2146-2152 (1994). (Pubitemid 24356033)
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).
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).
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). (Pubitemid 27143300)
53. Döhner, H. et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N. Engl. J. Med. 343, 1910-1916 (2000). (Pubitemid 32064784)
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). (Pubitemid 34864299)
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).
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).
57. Stilgenbauer, S. et al. Incidence and clinical significance of 6q deletions in B cell chronic lymphocytic leukemia. Leukemia 13, 1331-1334 (1999). (Pubitemid 29429758)
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). (Pubitemid 350144184)
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).
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).
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). (Pubitemid 39166521)
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).
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). (Pubitemid 46646223)
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). (Pubitemid 26347210)
65. Thomas, A., Pepper, C., Hoy, T. & Bentley, P. Bcl-2 and bax expression and chlorambucilinduced apoptosis in the T-cells and leukaemic B-cells of untreated B-cell chronic lymphocytic leukaemia patients. Leuk. Res. 24, 813-821 (2000).
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).
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). (Pubitemid 41565916)
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). (Pubitemid 350232222)
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).
70. Oscier, D., Fitchett, M., Herbert, T. & Lambert, R. Karyotypic evolution in B-cell chronic lymphocytic leukaemia. Genes Chromosomes Cancer 3, 16-20 (1991).
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). (Pubitemid 28485503)
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). (Pubitemid 34122071)
73. Dyer, M. J. & Oscier, D. G. The configuration of the immunoglobulin genes in B cell chronic lymphocytic leukemia. Leukemia 16, 973-984 (2002). (Pubitemid 34618836)
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). (Pubitemid 44768432)
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).
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).
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). (Pubitemid 29430400)
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). (Pubitemid 34525519)
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). (Pubitemid 36857759)
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).
81. Montserrat, E. New prognostic markers in CLL. Hematology Am. Soc. Hematol. Educ. Program 279-284 (2006).
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).
83. Orchard, J. A. et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363, 105-111 (2004). (Pubitemid 38068326)
84. Patten, P. E. et al. CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment. Blood 111, 5173-5181 (2008).
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). (Pubitemid 44232007)
86. Domingo-Doménech, E. et al. CD38 expression in B-chronic lymphocytic leukemia: association with clinical presentation and outcome in 155 patients. Haematologica 87, 1021-1027 (2002). (Pubitemid 35192212)
87. Dürig, J. et al. CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. Leukemia 16, 30-35 (2002). (Pubitemid 34105596)
88. Del Poeta, G. et al. Clinical significance of CD38 expression in chronic lymphocytic leukemia. Blood 98, 2633-2639 (2001). (Pubitemid 33787596)
89. Ibrahim, S. et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 98, 181-186 (2001).
90. Morabito, F. et al. Peripheral blood CD38 expression predicts survival in B-cell chronic lymphocytic leukemia. Leuk. Res. 25, 927-932 (2001). (Pubitemid 32946799)
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). (Pubitemid 32700928)
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). (Pubitemid 36182494)
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).
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). (Pubitemid 41579958)
95. Matrai, Z. et al. CD38 expression and Ig vH gene mutation in B-cell chronic lymphocytic leukemia. Blood 97, 1902-1903 (2001). (Pubitemid 32217269)
96. Hamblin, T. J. et al. Immunoglobulin v genes and CD38 expression in CLL. Blood 95, 2455-2457 (2000).
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).
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). (Pubitemid 35429705)
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). (Pubitemid 36514707)
100. Dürig, J. et al. ZAP-70 expression is a prognostic factor in chronic lymphocytic leukemia. Leukemia 17, 2426-2434 (2003). (Pubitemid 38072581)
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).
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). (Pubitemid 36857758)
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).
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).
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). (Pubitemid 19151132)
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).
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).
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).
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).
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).
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). (Pubitemid 36177256)
112. Rawstron, A. C. et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia 21, 956-964 (2007).
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).
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). (Pubitemid 46224116)
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). (Pubitemid 351377991)
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).
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).
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).
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). (Pubitemid 46630666)
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).
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).
122. Thurmes, P. et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk. Lymphoma 49, 49-56 (2008). (Pubitemid 351146882)
123. Eichhorst, B., Goede, v. & Hallek, M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk. Lymphoma 50, 171-178 (2009).
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).
125. Balducci, L. & Extermann, M. Management of cancer in the older person: a practical approach. Oncologist 5, 224-237 (2000). (Pubitemid 30429942)
126. Balducci, L. The geriatric cancer patient: equal benefit from equal treatment. Cancer Control 8 (Suppl. 2), 1-25 (2001).
127. Balducci, L. Aging, frailty, and chemotherapy. Cancer Control 14, 7-12 (2007).
128. Shanafelt, T. D. Predicting clinical outcome in CLL: how and why. Hematology Am. Soc. Hematol. Educ. Program 421-429 (2009).
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).
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).
131. Shanafelt, T. D. et al. validation of a new prognostic index for patients with chronic lymphocytic leukemia. Cancer 115, 363-372 (2009).