The changing paradigm of chronic lymphocytic leukemia management

European Journal of Internal Medicine

Volumn 24, Issue 5, 2013, Pages 401-410

  Lobetti Bodoni, Chiara ^a,c   Bertoni, Francesco ^a,b   Stussi, Georg ^a   Cavalli, Franco ^a   Zucca, Emanuele ^a  

^a OSPEDALE SAN GIOVANNI   (Switzerland)

^b INSTITUTE OF ONCOLOGY RESEARCH   (Switzerland)

^c CITTÀ DELLA SALUTE E DELLA SCIENZA HOSPITAL   (Italy)

Author keywords

Chronic lymphocytic leukemia; Prognosis; Rituximab; Therapy

Indexed keywords

ALEMTUZUMAB; BENDAMUSTINE; CD38 ANTIGEN; CHLORAMBUCIL; CYCLOPHOSPHAMIDE; FLUDARABINE; LENALIDOMIDE; LIPOPROTEIN LIPASE; OFATUMUMAB; PROTEIN KINASE ZAP 70; PROTEIN P53; PURINE DERIVATIVE; RITUXIMAB;

BLOOD CELL COUNT; BLOOD SMEAR; CANCER COMBINATION CHEMOTHERAPY; CANCER DIAGNOSIS; CANCER RECURRENCE; CANCER RISK; CANCER STAGING; CANCER SURVIVAL; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL EVALUATION; CLINICAL INDICATOR; CYTOGENETICS; CYTOPENIA; DISEASE CLASSIFICATION; DISEASE MARKER; GENERAL PRACTITIONER; HIGH RISK PATIENT; HUMAN; IMMUNOPHENOTYPING; INFECTION RISK; INTERNIST; LEUKEMIA REMISSION; OPPORTUNISTIC INFECTION; OUTCOME ASSESSMENT; OVERALL SURVIVAL; PALLIATIVE THERAPY; PROTEIN EXPRESSION; REVIEW; TUMOR VOLUME;

ANTIBODIES, MONOCLONAL, MURINE-DERIVED; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CYCLOPHOSPHAMIDE; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; PROGNOSIS; VIDARABINE;

EID: 84879117145     PISSN: 09536205     EISSN: 18790828     Source Type: Journal    
DOI: 10.1016/j.ejim.2013.03.009     Document Type: Review

References (143)

1. R. Siegel, D. Naishadham, and A. Jemal Cancer statistics, 2012 CA Cancer J Clin 62 2012 10 29
2. C. Rozman, F. Bosch, and E. Montserrat Chronic lymphocytic leukemia: a changing natural history? Leukemia 11 1997 775 778
3. T. Zenz, D. Mertens, R. Kuppers, H. Dohner, and S. Stilgenbauer From pathogenesis to treatment of chronic lymphocytic leukaemia Nat Rev Cancer 10 2010 37 50
4. T.D. Shanafelt, N.E. Kay, K.G. Rabe, D.J. Inwards, C.S. Zent, and J.F. Leis Hematologist/oncologist disease-specific expertise and survival: lessons from chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) Cancer 118 2012 1827 1837
5. M. Hallek, B.D. Cheson, D. Catovsky, F. Caligaris-Cappio, G. Dighiero, and H. Dohner 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 2008 5446 5456
6. B. Eichhorst, M. Dreyling, T. Robak, E. Montserrat, and M. Hallek Group ObotEGW. Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 22 2011 vi50 vi54
7. I. Soubeyran, and A. de Mascarel Small B-cell lymphoproliferative disorders: an overview of diagnostic approach Crit Rev Oncol Hematol 35 2000 3 11
8. A.C. Rawstron, F.L. Bennett, S.J. O'Connor, M. Kwok, J.A. Fenton, and M. Plummer Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia N Engl J Med 359 2008 575 583
9. K.R. Rai, A. Sawitsky, E.P. Cronkite, A.D. Chanana, R.N. Levy, and B.S. Pasternack Clinical staging of chronic lymphocytic leukemia Blood 46 1975 219 234
10. J.L. Binet, A. Auquier, G. Dighiero, C. Chastang, H. Piguet, and J. Goasguen A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis Cancer 48 1981 198 206
11. G. Dighiero, K. Maloum, B. Desablens, B. Cazin, M. Navarro, and R. Leblay Chlorambucil in indolent chronic lymphocytic leukemia. French cooperative group on chronic lymphocytic leukemia N Engl J Med 338 1998 1506 1514
12. W.G. Wierda, S. O'Brien, X. Wang, S. Faderl, A. Ferrajoli, and K.A. Do Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia Blood 109 2007 4679 4685
13. P. Cramer, and M. Hallek Prognostic factors in chronic lymphocytic leukemia - what do we need to know? Nat Rev Clin Oncol 8 2011 38 47
14. E. Montserrat, J. Sanchez-Bisono, N. Vinolas, and C. Rozman Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance Br J Haematol 62 1986 567 575
15. K.A. Foon, and M.J. Hallek Changing paradigms in the treatment of chronic lymphocytic leukemia Leukemia 24 2010 500 511
16. C. Rozman, E. Montserrat, J.M. Rodriguez-Fernandez, R. Ayats, T. Vallespi, and R. Parody Bone marrow histologic pattern - the best single prognostic parameter in chronic lymphocytic leukemia: a multivariate survival analysis of 329 cases Blood 64 1984 642 648
17. M. Hallek, L. Wanders, M. Ostwald, R. Busch, R. Senekowitsch, and S. Stern Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma Leuk Lymphoma 22 1996 439 447
18. T.D. Shanafelt, G. Jenkins, T.G. Call, C.S. Zent, S. Slager, and D.A. Bowen Validation of a new prognostic index for patients with chronic lymphocytic leukemia Cancer 115 2009 363 372
19. W.G. Wierda, S. O'Brien, X. Wang, S. Faderl, A. Ferrajoli, and K.A. Do Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment J Clin Oncol 27 2009 1637 1643
20. P. Bulian, M. Tarnani, D. Rossi, F. Forconi, G. Del Poeta, and F. Bertoni Multicentre validation of a prognostic index for overall survival in chronic lymphocytic leukaemia Hematol Oncol 29 2011 91 99
21. P. Bulian, D. Rossi, F. Forconi, G. Del Poeta, F. Bertoni, and E. Zucca IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia J Transl Med 10 2012 18
22. H. Dohner, S. Stilgenbauer, A. Benner, E. Leupolt, A. Krober, and L. Bullinger Genomic aberrations and survival in chronic lymphocytic leukemia N Engl J Med 343 2000 1910 1916
23. A. Krober, T. Seiler, A. Benner, L. Bullinger, E. Bruckle, and P. Lichter V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia Blood 100 2002 1410 1416
24. D. Catovsky, S. Richards, E. Matutes, D. Oscier, M.J. Dyer, and R.F. Bezares Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 trial): a randomised controlled trial Lancet 370 2007 230 239
25. M.R. Grever, D.M. Lucas, G.W. Dewald, D.S. Neuberg, J.C. Reed, and S. Kitada 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 25 2007 799 804
26. H. Dohner, S. Stilgenbauer, K. Fischer, M. Bentz, and P. Lichter Cytogenetic and molecular cytogenetic analysis of B cell chronic lymphocytic leukemia: specific chromosome aberrations identify prognostic subgroups of patients and point to loci of candidate genes Leukemia 11 1997 S19 S24
27. F. Dicker, H. Herholz, S. Schnittger, A. Nakao, N. Patten, and L. Wu The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype Leukemia 23 2009 117 124
28. D. Rossi, M. Cerri, C. Deambrogi, E. Sozzi, S. Cresta, and S. Rasi The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness Clin Cancer Res 15 2009 995 1004
29. H. Dohner, K. Fischer, M. Bentz, K. Hansen, A. Benner, and G. Cabot p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias Blood 85 1995 1580 1589
30. S. Stilgenbauer, and H. Dohner Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy N Engl J Med 347 2002 452 453
31. S. Stilgenbauer, T. Zenz, D. Winkler, A. Buhler, R.F. Schlenk, and S. Groner Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group J Clin Oncol 27 2009 3994 4001
32. G. Lozanski, N.A. Heerema, I.W. Flinn, L. Smith, J. Harbison, and J. Webb Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions Blood 103 2004 3278 3281
33. A.R. Pettitt, R. Jackson, S. Carruthers, J. Dodd, S. Dodd, and M. Oates Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the National Cancer Research Institute CLL206 Trial J Clin Oncol 30 2012 1647 1655
34. M. Hallek, B.D. Cheson, D. Catovsky, F. Caligaris-Cappio, G. Dighiero, and H. Dohner Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 guidelines Blood 111 2008 5446 5456
35. H. Parker, M.J. Rose-Zerilli, A. Parker, T. Chaplin, R. Wade, and A. Gardiner 13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia Leukemia 25 2010 489 497
36. P. Ouillette, R. Collins, S. Shakhan, J. Li, E. Peres, and L. Kujawski Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia Blood 118 2011 3051 3061
37. A. Rinaldi, M. Mian, I. Kwee, D. Rossi, C. Deambrogi, and A.A. Mensah Genome-wide DNA profiling better defines the prognosis of chronic lymphocytic leukaemia Br J Haematol 154 2011 590 599
38. P. Ouillette, R. Collins, S. Shakhan, J. Li, C. Li, and K. Shedden The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia Clin Cancer Res 17 2011 6778 6790
39. M. Mian, A. Rinaldi, A.A. Mensah, D. Rossi, M. Ladetto, and F. Forconi Del(13q14.3) length matters: an integrated analysis of genomic, fluorescence in situ hybridization and clinical data in 169 chronic lymphocytic leukaemia patients with 13q deletion alone or a normal karyotype Hematol Oncol 30 2012 46 49
40. R.N. Damle, T. Wasil, F. Fais, F. Ghiotto, A. Valetto, and S.L. Allen Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia Blood 94 1999 1840 1847
41. T.J. Hamblin, Z. Davis, A. Gardiner, D.G. Oscier, and F.K. Stevenson Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia Blood 94 1999 1848 1854
42. E.M. Ghia, S. Jain, G.F. Widhopf II, L.Z. Rassenti, M.J. Keating, and W.G. Wierda Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection Blood 111 2008 5101 5108
43. F. Fais, F. Ghiotto, S. Hashimoto, B. Sellars, A. Valetto, and S.L. Allen Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors J Clin Invest 102 1998 1515 1525
44. D. Rossi, V. Spina, M. Cerri, S. Rasi, C. Deambrogi, and L. De Paoli Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome Clin Cancer Res 15 2009 4415 4422
45. M. Herve, K. Xu, Y.S. Ng, H. Wardemann, E. Albesiano, and B.T. Messmer Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity J Clin Invest 115 2005 1636 1643
46. A. Lanemo Myhrinder, E. Hellqvist, E. Sidorova, A. Soderberg, H. Baxendale, and C. Dahle A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies Blood 111 2008 3838 3848
47. G.F. Widhopf II, C.J. Goldberg, T.L. Toy, L.Z. Rassenti, W.G. Wierda, and J.C. Byrd Nonstochastic pairing of immunoglobulin heavy and light chains expressed by chronic lymphocytic leukemia B cells is predicated on the heavy chain CDR3 Blood 111 2008 3137 3144
48. A. Hadzidimitriou, A. Agathangelidis, N. Darzentas, F. Murray, M.H. Delfau-Larue, and L.B. Pedersen Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases Blood 118 2011 3088 3095
49. G. Tobin, U. Thunberg, A. Johnson, I. Thorn, O. Soderberg, and M. Hultdin Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia Blood 99 2002 2262 2264
50. R. Bomben, M. Dal-Bo, D. Benedetti, D. Capello, F. Forconi, and D. Marconi Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features Clin Cancer Res 16 2010 620 628
51. J.A. Orchard, R.E. Ibbotson, Z. Davis, A. Wiestner, A. Rosenwald, and P.W. Thomas ZAP-70 expression and prognosis in chronic lymphocytic leukaemia Lancet 363 2004 105 111
52. L.Z. Rassenti, L. Huynh, T.L. Toy, L. Chen, M.J. Keating, and J.G. Gribben 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 2004 893 901
53. L.Z. Rassenti, S. Jain, M.J. Keating, W.G. Wierda, M.R. Grever, and J.C. Byrd Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia Blood 112 2008 1923 1930
54. A. Krober, J. Bloehdorn, S. Hafner, A. Buhler, T. Seiler, and D. Kienle 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 2006 969 975
55. M.I. Del Principe, G. Del Poeta, F. Buccisano, L. Maurillo, A. Venditti, and A. Zucchetto Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia Blood 108 2006 853 861
56. M. Crespo, F. Bosch, N. Villamor, B. Bellosillo, D. Colomer, and M. Rozman ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia N Engl J Med 348 2003 1764 1775
57. P. Bulian, G. Del Poeta, and V. Gattei How would I manage a sample submitted for flow cytometry analysis for suspicious chronic lymphocytic leukaemia Hematol Oncol 27 2009 186 189
58. M.A. Catherwood, C. Matthews, R. Niblock, E. Dobbin, T.C. Morris, and H.D. Alexander ZAP-70 mRNA quantification in B-cell chronic lymphocytic leukaemia Eur J Haematol 76 2006 294 298
59. L. Munoz, A. Lasa, M.T. Carricondo, C. Hernandez, J. Ubeda, and J.F. Nomdedeu Comparative analysis of ZAP-70 expression and Ig VH mutational status in B-cell chronic lymphocytic leukemia Cytometry B Clin Cytom 72 2007 96 102
60. T.J. Hamblin, J.A. Orchard, R.E. Ibbotson, Z. Davis, P.W. Thomas, and F.K. Stevenson 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 2002 1023 1029
61. T. Zenz, S. Frohling, D. Mertens, H. Dohner, and S. Stilgenbauer Moving from prognostic to predictive factors in chronic lymphocytic leukaemia (CLL) Best Pract Res Clin Haematol 23 2010 71 84
62. D. Rossi, C. Lobetti Bodoni, E. Genuardi, L. Monitillo, D. Drandi, and M. Cerri Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia Leukemia 23 2009 1062 1072
63. I. Ricca, A. Rocci, D. Drandi, R. Francese, M. Compagno, and C. Lobetti Bodoni Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients Leukemia 21 2007 697 705
64. R.N. Damle, F.M. Batliwalla, F. Ghiotto, A. Valetto, E. Albesiano, and C. Sison Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations Blood 103 2004 375 382
65. V. Gattei, P. Bulian, M.I. Del Principe, A. Zucchetto, L. Maurillo, and F. Buccisano Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia Blood 111 2008 865 873
66. D. Rossi, A. Zucchetto, F.M. Rossi, D. Capello, M. Cerri, and C. Deambrogi CD49d expression is an independent risk factor of progressive disease in early stage chronic lymphocytic leukemia Haematologica 93 2008 1575 1579
67. T.D. Shanafelt, S.M. Geyer, N.D. Bone, R.C. Tschumper, T.E. Witzig, and G.S. Nowakowski CD49d expression is an independent predictor of overall survival in patients with chronic lymphocytic leukaemia: a prognostic parameter with therapeutic potential Br J Haematol 140 2008 537 546
68. D. Rossi, C.L. Bodoni, A. Zucchetto, S. Rasi, L. De Paoli, and M. Fangazio Low CD49d expression and long telomere identify a chronic lymphocytic leukemia subset with highly favourable outcome Am J Hematol 85 2010 619 622
69. G.A. Calin, M. Ferracin, A. Cimmino, G. Di Leva, M. Shimizu, and S.E. Wojcik A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia N Engl J Med 353 2005 1793 1801
70. G.A. Calin, and C.M. Croce Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein-coding genes Blood 114 2009 4761 4770
71. S.P. Nana-Sinkam, and C.M. Croce MicroRNA in chronic lymphocytic leukemia: transitioning from laboratory-based investigation to clinical application Cancer Genet Cytogenet 203 2010 127 133
72. B. Stamatopoulos, N. Meuleman, B. Haibe-Kains, P. Saussoy, E. Van Den Neste, and L. Michaux microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification Blood 113 2009 5237 5245
73. E. Moussay, V. Palissot, L. Vallar, H.A. Poirel, T. Wenner, and V. El Khoury Determination of genes and microRNAs involved in the resistance to fludarabine in vivo in chronic lymphocytic leukemia Mol Cancer 9 2010 115
74. X.S. Puente, M. Pinyol, V. Quesada, L. Conde, G.R. Ordonez, and N. Villamor Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia Nature 475 2011 101 105
75. G. Fabbri, S. Rasi, D. Rossi, V. Trifonov, H. Khiabanian, and J. Ma Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation J Exp Med 208 2011 1389 1401
76. D. Rossi, M. Fangazio, S. Rasi, T. Vaisitti, S. Monti, and S. Cresta Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild type chronic lymphocytic leukemia Blood 119 2012 2854 2862
77. L. Wang, M.S. Lawrence, Y. Wan, P. Stojanov, C. Sougnez, and K. Stevenson SF3B1 and other novel cancer genes in chronic lymphocytic leukemia N Engl J Med 365 2011 2497 2506
78. D. Rossi, S. Rasi, V. Spina, A. Bruscaggin, S. Monti, and C. Ciardullo Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia Blood 121 2013 1403 1412
79. M. Mian, A. Rinaldi, A.A. Mensah, D. Rossi, M. Ladetto, and F. Forconi Large genomic aberrations detected by SNP array are independent prognosticators of a shorter time to first treatment in chronic lymphocytic leukemia patients with normal FISH Ann Oncol 2013 10.1093/annonc/mds646 [Electronic publication ahead of print]
80. J.G. Gribben, and S. O'Brien Update on therapy of chronic lymphocytic leukemia J Clin Oncol 29 2011 544 550
81. J.G. Gribben How I, treat CLL up front Blood 115 2010 187 197
82. G. Dighiero, and T.J. Hamblin Chronic lymphocytic leukaemia Lancet 371 2008 1017 1029
83. E. Montserrat, N. Villamor, A. Urbano-Ispizua, J.M. Ribera, M. Lozano, and J.L. Vives-Corrons Treatment of early stage-B chronic lymphocytic leukemia with alpha-2b interferon after chlorambucil reduction of the tumoral mass Ann Hematol 63 1991 15 19
84. C. Shustik, R. Mick, R. Silver, A. Sawitsky, K. Rai, and L. Shapiro Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation Hematol Oncol 6 1988 7 12
85. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group J Natl Cancer Inst 91 1999 861 868
86. P.A. Parmelee, P.D. Thuras, I.R. Katz, and M.P. Lawton Validation of the cumulative illness rating scale in a geriatric residential population J Am Geriatr Soc 43 1995 130 137
87. M. Hallek State-of-the-art treatment of chronic lymphocytic leukemia ASH Educ Prog Book 2009 440 449 [Education Program]
88. K.R. Rai, B.L. Peterson, F.R. Appelbaum, J. Kolitz, L. Elias, and L. Shepherd Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia N Engl J Med 343 2000 1750 1757
89. K.R. Rai, and A. Hollweg Fludarabine versus chlorambucil: is the debate over? Clin Lymphoma Myeloma Leuk 11 2011 S7 S9
90. D. Catovsky, M. Else, and S. Richards Chlorambucil - still not bad: a reappraisal Clin Lymphoma Myeloma Leuk 11 2011 S2 S6
91. T. Ichida Systematic review of purine analog treatment for chronic lymphocytic leukemia: lessons for future trials Haematologica 97 2012 428 436
92. B.F. Eichhorst, R. Busch, S. Stilgenbauer, M. Stauch, M.A. Bergmann, and M. Ritgen First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia Blood 114 2009 3382 3391
93. W.U. Knauf, T. Lissichkov, A. Aldaoud, A. Liberati, J. Loscertales, and R. Herbrecht Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia J Clin Oncol 27 2009 4378 4384
94. B.F. Eichhorst, R. Busch, G. Hopfinger, R. Pasold, M. Hensel, and C. Steinbrecher Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia Blood 107 2006 885 891
95. I.W. Flinn, D.S. Neuberg, M.R. Grever, G.W. Dewald, J.M. Bennett, and E.M. Paietta Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997 J Clin Oncol 25 2007 793 798
96. M.J. Keating, S. O'Brien, M. Albitar, S. Lerner, W. Plunkett, and F. Giles Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia J Clin Oncol 23 2005 4079 4088
97. C.S. Tam, S. O'Brien, W. Wierda, H. Kantarjian, S. Wen, and K.A. Do Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia Blood 112 2008 975 980
98. M. Hallek, K. Fischer, G. Fingerle-Rowson, A.M. Fink, R. Busch, and J. Mayer Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial Lancet 376 2010 1164 1174
99. K. Fischer, P. Cramer, R. Busch, S. Stilgenbauer, J. Bahlo, and C.D. Schweighofer Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group J Clin Oncol 29 2011 3559 3566
100. K. Fischer, P. Cramer, R. Busch, S. Bottcher, J. Bahlo, and J. Schubert Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group J Clin Oncol 30 2012 3209 3216
101. C.L. Toze, C.B. Dalal, T.J. Nevill, T.L. Gillan, Y.R. Abou Mourad, and M.J. Barnett Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort Br J Haematol 158 2012 174 185
102. P. Dreger, P. Corradini, E. Kimby, M. Michallet, D. Milligan, and J. Schetelig Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus Leukemia 21 2007 12 17
103. C.D. Schweighofer, M. Ritgen, B.F. Eichhorst, R. Busch, W. Abenhardt, and M. Kneba 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 2009 95 98
104. P. Hillmen, A.B. Skotnicki, T. Robak, B. Jaksic, A. Dmoszynska, and J. Wu Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia J Clin Oncol 25 2007 5616 5623
105. S. Stilgenbauer, F. Cymbalista, V. Leblond, A. Delmer, T. Zenz, and D. Winkler Subcutaneous alemtuzumab combined with oral dexamethasone, followed by alemtuzumab maintenance or Allo-SCT in CLL with 17p - or refractory to fludarabine - interim analysis of the CLL2O trial of the GCLLSG and FCGCLL/MW ASH Annu Meet Abstr 116 2010 920
106. T. Elter, L. Gercheva-Kyuchukova, H. Pylylpenko, T. Robak, B. Jaksic, and G. Rekhtman Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial Lancet Oncol 12 2011 1204 1213
107. J.C. Wade Viral infections in patients with hematological malignancies Hematology Am Soc Hematol Educ Program 2006 368 374
108. A. Osterborg, R. Foa, R.F. Bezares, C. Dearden, M.J. Dyer, and C. Geisler Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia Leukemia 23 2009 1980 1988
109. S. Pospisilova, D. Gonzalez, J. Malcikova, M. Trbusek, D. Rossi, and A.P. Kater ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia Leukemia 26 2012 1458 1461
110. A. Chanan-Khan, K.C. Miller, L. Musial, D. Lawrence, S. Padmanabhan, and K. Takeshita Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study J Clin Oncol 24 2006 5343 5349
111. A. Ferrajoli, B.N. Lee, E.J. Schlette, S.M. O'Brien, H. Gao, and S. Wen Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia Blood 111 2008 5291 5297
112. T. Sher, K.C. Miller, D. Lawrence, A. Whitworth, F. Hernandez- Ilizaliturri, and M.S. Czuczman Efficacy of lenalidomide in patients with chronic lymphocytic leukemia with high-risk cytogenetics Leuk Lymphoma 51 2010 85 88
113. W.G. Wierda, T.J. Kipps, J. Mayer, S. Stilgenbauer, C.D. Williams, and A. Hellmann Ofatumumab as single-agent CD20 immunotherapy in fludarabine- refractory chronic lymphocytic leukemia J Clin Oncol 28 2010 1749 1755
114. F. Morschhauser, J.P. Leonard, L. Fayad, B. Coiffier, M.O. Petillon, and M. Coleman Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin's lymphoma: phase I/II results J Clin Oncol 27 2009 3346 3353
115. S. O'Brien Novel therapies in chronic lymphocytic leukemia 2011 ASCO Educational Book 238 241 [Spring]
116. R. Gitendra Wickremasinghe, A.G. Prentice, and A.J. Steele Aberrantly activated anti-apoptotic signalling mechanisms in chronic lymphocytic leukaemia cells: clues to the identification of novel therapeutic targets Br J Haematol 153 2011 545 556
117. M.S. Davids, and J.R. Brown Targeting the B cell receptor pathway in chronic lymphocytic leukemia Leuk Lymphoma 16 2012 4193 4203
118. H. Griffiths, V. Brennan, J. Lea, C. Bunch, M. Lee, and H. Chapel Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors Blood 73 1989 366 368
119. D.A. Eichenauer, A. Engert, and M. Dreyling Hodgkin's lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 22 2011 vi55 vi58
120. V.A. Morrison Management of infectious complications in patients with chronic lymphocytic leukemia Hematology Am Soc Hematol Educ Program 2007 332 338
121. C. Dearden Disease-specific complications of chronic lymphocytic leukemia Hematology Am Soc Hematol Educ Program 2008 450 456
122. C. Moreno, K. Hodgson, G. Ferrer, M. Elena, X. Filella, and A. Pereira Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance Blood 116 2010 4771 4776
123. F.R. Mauro, R. Foa, R. Cerretti, D. Giannarelli, S. Coluzzi, and F. Mandelli Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features Blood 95 2000 2786 2792
124. J.A. Burger, P. Ghia, A. Rosenwald, and F. Caligaris-Cappio The microenvironment in mature B-cell malignancies: a target for new treatment strategies Blood 114 2009 3367 3375
125. J.C. Riches, A.G. Ramsay, and J.G. Gribben T-cell function in chronic lymphocytic leukaemia Semin Cancer Biol 20 2010 431 438
126. J.A. Burger Nurture versus nature: the microenvironment in chronic lymphocytic leukemia Hematology Am Soc Hematol Educ Program 2011 96 103
127. M. Ponzoni, C. Doglioni, and F. Caligaris-Cappio Chronic lymphocytic leukemia: the pathologist's view of lymph node microenvironment Semin Diagn Pathol 28 2011 161 166
128. M.D. Bo, R. Bomben, A. Zucchetto, G. Del Poeta, G. Gaidano, and S. Deaglio Microenvironmental interactions in chronic lymphocytic leukemia: hints for pathogenesis and identification of targets for rational therapy Curr Pharm Des 18 2012 3323 3334
129. C. Visco, M. Ruggeri, M. Laura Evangelista, R. Stasi, R. Zanotti, and I. Giaretta Impact of immune thrombocytopenia on the clinical course of chronic lymphocytic leukemia Blood 111 2008 1110 1116
130. C. Visco, I. Giaretta, M. Ruggeri, D. Madeo, A. Tosetto, and F. Rodeghiero Un-mutated IgVH in chronic lymphocytic leukemia is associated with a higher risk of immune thrombocytopenia Leukemia 21 2007 1092 1093
131. P. Rodon, P. Breton, and G. Courouble Treatment of pure red cell aplasia and autoimmune haemolytic anaemia in chronic lymphocytic leukaemia with Campath-1H Eur J Haematol 70 2003 319 321
132. D. Gomez-Almaguer, M. Solano-Genesta, L. Tarin-Arzaga, J.L. Herrera-Garza, O.G. Cantu-Rodriguez, and C.H. Gutierrez-Aguirre Low-dose rituximab and alemtuzumab combination therapy for patients with steroid-refractory autoimmune cytopenias Blood 116 2010 4783 4785
133. A.M. Tsimberidou, S. O'Brien, I. Khouri, F.J. Giles, H.M. Kantarjian, and R. Champlin Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or hemoimmunotherapy with or without stem-cell transplantation J Clin Oncol 24 2006 2343 2351
134. D. Rossi, and G. Gaidano Richter syndrome: molecular insights and clinical perspectives Hematol Oncol 27 2009 1 10
135. D. Rossi, V. Spina, C. Deambrogi, S. Rasi, L. Laurenti, and K. Stamatopoulos The genetics of Richter syndrome reveals disease heterogeneity and predicts survival post-transformation Blood 117 2011 3391 3401
136. A.M. Tsimberidou, and M.J. Keating Richter syndrome: biology, incidence, and therapeutic strategies Cancer 103 2005 216 228
137. D. Rossi, M. Cerri, D. Capello, C. Deambrogi, F.M. Rossi, and A. Zucchetto Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome Br J Haematol 142 2008 202 215
138. R. Bomben, M. Dal-Bo, D. Benedetti, D. Capello, F. Forconi, and D. Marconi Chronic lymphocytic leukemia subset expressing mutated IGHV3-23 has peculiar clinical and biological features ASH Annu Meet Abstr 114 2009 1256
139. A. Rinaldi, E. Chigrinova, I. Kwee, D. Rossi, P.M. Rancoita, and J.C. Strefford SNP-arrays provide new insights into the pathogenesis of Richter syndrome (RS) ASH Annu Meet Abstr 118 2011 263
140. T. Robak, K. Jamroziak, J. Gora-Tybor, B. Stella-Holowiecka, L. Konopka, and B. Ceglarek Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study) J Clin Oncol 28 2010 1863 1869
141. T. Robak, J. Blonski, K. Jamroziak, M. Calbecka, J. Dwilewicz-Trojaczek, and P. Boguradzki Cladribine alone and in combination with cyclophosphamide or cyclophosphamide and mitoxantrone in previously untreated patients with chronic lymphocytic leukemia (CLL): long-term follow-up of the Polish Adult Leukemia Group (PALG CLL2) study ASH Annu Meet Abstr 118 2011 3915
142. C. Reynolds, N. Di Bella, R.M. Lyons, W. Hyman, D.A. Richards, and G.J. Robbins A Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia Invest New Drugs 30 2012 1232 1240
143. C.H. Geisler, M.M. van 't Veer, W. van Putten, J. Jurlander, J. Walewski, and G. Tjonnfjord Immunochemotherapy with low-dose subcutaneous alemtuzumab (a) plus oral fludarabine and cyclophosphamide (fc) is safe and induces more and deeper complete remissions in untreated patients with high-risk chronic lymphocytic leukemia (cll) than chemotherapy with fc alone. An early analysis of the randomized phase-III HOVON68 CLL trial ASH Annu Meet Abstr 118 2011 290