Chronic Lymphocytic Leukemia

Chapter
Part of the Principles and Practice book series (PRINCIPLES)

Abstract

Human chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. CLL has long been believed to be a single disease, but recent insights underline the biological and clinical heterogeneity of CLL. Recognition of CLL subgroups with a completely different pathophysiology and clinical course, has paved the way to better define high-risk CLL patients based on prognostic factors, to predict response to therapy, and to estimate progression-free and overall survival. Moreover, knowledge of different aspects of the (immuno) pathogenesis of CLL (genomic and epigenetic aberrations, antigenic stimulation, microenvironmental stimuli) has greatly increased. These insights are key to further develop preventive strategies and to design innovative therapeutic strategies.

Keywords

Chronic Lymphocytic Leukemia TP53 Mutation Chronic Lymphocytic Leukemia Patient Chronic Lymphocytic Leukemia Cell IGHV Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Andritsos LA, Byrd JC, Hewes B, Kipps TJ, Johns D, Burger JA (2010) Preliminary results from a phase I/II dose escalation study to determine the maximum tolerated dose of plerixafor in combination with rituximab in patients with relapsed chronic lymphocytic leukemia. Haematologica 95:A772Google Scholar
  2. Austen B, Skowronska A, Baker C, Powel JE, Gardiner A, Oscier D, Majid A, Dyer M, Siebert R, Taylor AM, Moss PA, Stankovic T (2007) 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 25:5448–5457PubMedCrossRefGoogle Scholar
  3. Belessi CJ, Davi FB, Stamatopoulos KE, Degano M, Andreou TM, Moreno C, Merle-Béral H, Crespo M, Laoutaris NP, Montserrat E, Caligaris-Cappio F, Anagnostopoulos AZ, Ghia P (2006) IGHV gene insertions and deletions in chronic lymphocytic leukemia: “CLL-biased” deletions in a subset of cases with stereotyped receptors. Eur J Immunol 36:1963–1974PubMedCrossRefGoogle Scholar
  4. Blair A, Purue MP, Weisenburger DD, Baris D (2007) Chemical exposures and risk of chronic lymphocytic leukemia. Br J Haematol 139:753–761PubMedCrossRefGoogle Scholar
  5. Burger JA, Quiroga MP, Hartmann E, Burkle A, Wierda WG, Keating MJ, Rosenwald A (2009) High-level expression of T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurse like cell cocultures and after BCR stimulation. Blood 113:3050–3058PubMedCrossRefGoogle Scholar
  6. Burger JA (2011) Mechanisms of leukemia cell trafficking, homing, and tissue retention in CLL. Hematol Education 5:91–99Google Scholar
  7. Chiorazzi N, Ferrarini M (2011) Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood 117:1781–1791PubMedCrossRefGoogle Scholar
  8. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM (2002) Frequent deletions and down-regulation of miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99:15524–15529PubMedCrossRefGoogle Scholar
  9. Catera R, Silverman GJ, Hatzi K, Seiler T, Didier S, Zhang L, Hervé M, Meffre E, Oscier DG, Vlassara H, Scofield RH, Chen Y, Allen SL, Kolitz J, Rai KR, Chu CC, Chiorazzi N (2008) Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and oxidation. Mol Med 14:665–674PubMedCrossRefGoogle Scholar
  10. Chu CC, Catera R, Hatzi K, Yan XJ, Zhang L, Wang XB, Fales HM, Allen SL, Kolitz JE, Rai KR, Chiorazzi N (2008) Chronic lymphocytic leukemia antibodies with a common stereotypic rearrangement recognize nonmuscle myosin heavy chain IIA. Blood 112:5122–5129PubMedCrossRefGoogle Scholar
  11. Crowther-Swanepoel D, Broderick P, Di Bernardo MC, Dobbins SE, Torres M, Mansouri M, Ruiz-Ponte C, Enjuanes A, Rosenquist R, Carracedo A, Jurlander J, Campo E, Juliusson G, Montserrat E, Smedby KE, Dyer MJS, Matutues E, Dearden C, Sunter NJ, Hall AG, Mainou-Fowler T, Jackson GH, Summerfield G, Harris RJ, Pettitt AR, Allsup DJ, Bailey JR, Pratt G, Pepper C, Fegan C, Parker A, Oscier D, Allan JM, Catovsky D, Houlston RS (2010) Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat Genet 42:132–136PubMedCrossRefGoogle Scholar
  12. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N (1999) Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840–1847PubMedGoogle Scholar
  13. Darzentas N, Hadzidimitriou A, Murray F, Hatzi K, Josefsson P, Laoutaris N, Moreno C, Anagnostopoulos A, Jurlander J, Tsaftaris A, Chiorazzi N, Belessi C, Ghia P, Rosenquist R, Davi F, Stamatopoulos K (2010) A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence. Leukemia 24:125–132PubMedCrossRefGoogle Scholar
  14. Di Bernardo MC, Crowther-Swanepoel D, Broderick P, Webb E, Sellick G, Wild R, Sullivan K, Vijayakrishnan J, Wang Y, Pittman AM, Sunter NJ, Hall AG, Dyer MJS, Matutues E, Dearden C, Mainou-Fowler T, Jackson GH, Summerfield G, Harris RJ, Pettitt AR, Hillmen P, Allsup DJ, Bailey JR, Pratt G, Pepper C, Fegan C, Allan JM, Catovsky D, Houlston RS (2008) A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat Genet 40:1204–1210PubMedCrossRefGoogle Scholar
  15. Dighiero G, Hamblin TJ (2008) Chronic lymphocytic leukaemia. Lancet 371:1017–1029PubMedCrossRefGoogle Scholar
  16. Döhner H, Stilgenbauer S, Benner A, Leupot E, Krober A, Bullinger L, Döhner K, Bentz M, Lichter P (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916PubMedCrossRefGoogle Scholar
  17. Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S (2010) Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL study group CLL3X trial. Blood 116:2438–2447PubMedCrossRefGoogle Scholar
  18. Fais F, Ghiotto F, Hashimoto S, Sellars B, Valetto A, Allen SL, Schulman P, Vinciguerra VP, Rai K, Rassenti LZ, Kipps TJ, Dighiero G, Schroeder HW Jr, Ferrarini M, Chiorazzi N (1998) Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 102:1515–1525PubMedCrossRefGoogle Scholar
  19. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, Shipp MA (2010) Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 115:2578–2585PubMedCrossRefGoogle Scholar
  20. Ganster C, Neesen J, Zehetmeyer S, Jager U, Esterbauer H, Mannhalter C, Kluge B, Fonatsch C (2009) DNA repair polymorphisms associated with cytogenetic subgroups in B-cell chronic lymphocytic leukemia. Genes Chromosom Cancer 48:760–767PubMedCrossRefGoogle Scholar
  21. Ghia P, Stamatopoulos K, Belessi C, Moreno C, Stella S, Guida G, Michel A, Crespo M, Laoutaris N, Montserrat E, Anagnostopoulos A, Dighiero G, Fassas A, Caligaris-Cappio F, Davi F (2005) Geographic patterns and pathogenetic implications of IGHV gene usage in chronic lymphocytic leukemia: the lesson of the IGHV3-21 gene. Blood 105:1678–1685PubMedCrossRefGoogle Scholar
  22. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376:1164–1174PubMedCrossRefGoogle Scholar
  23. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ (2008) 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 111:5446–5456PubMedCrossRefGoogle Scholar
  24. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848–1854PubMedGoogle Scholar
  25. Heintel D, Kienle D, Shehata M, Kröber A, Kroemer E, Schwarzinger I, Mitteregger D, Le T, Gleiss A, Mannhalter C, Chott A, Schwarzmeier J, Fonatsch C, Gaiger A, Döhner H, Stilgenbauer S, Jäger U (2005) High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia. Leukemia 19:1216–1223PubMedCrossRefGoogle Scholar
  26. Hervé M, Xu K, Ng YS, Wardemann H, Albesiano E, Messmer BT, Chiorazzi N, Meffre E (2005) Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J Clin Invest 115:1636–1643PubMedCrossRefGoogle Scholar
  27. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, Li S, Pan Z, Thamm DH, Miller RA, Buggy JJ (2010) The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 107:13075–13080PubMedCrossRefGoogle Scholar
  28. Johnson TA, Rassenti LZ, Kipps TJ (1997) Ig VH1 genes expressed in B cell chronic lymphocytic leukemia exhibit distinctive molecular features. J Immunol 158:235–246PubMedGoogle Scholar
  29. Kanduri M, Cahill N, Goransson H, Enström C, Ryan F, Isaksson A, Rosenquist R (2010) Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia. Blood 115:296–305PubMedCrossRefGoogle Scholar
  30. Kipps TJ, Tomhave E, Pratt LF, Duffy S, Chen PP, Carson DA (1989) Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 86:5913–5917PubMedCrossRefGoogle Scholar
  31. Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H, Freedman A, Inghirami G, Cro L, Baldini L, Neri A, Califano A, Dalla-Favera R (2001) Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogenous phenotype related to memory B cells. J Exp Med 194:1625–1638PubMedCrossRefGoogle Scholar
  32. Klein U, Lia M, Crespo M, Siegel R, Shen Q, Mo T, Ambesi-Impiombato A, Califano A, Migliazza A, Bhagat G, Dalla-Favera R (2010) The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 17:28–40PubMedCrossRefGoogle Scholar
  33. Kröber A, Seiler T, Benner A, Bullinger L, Brückle E, Lichter P, Döhner H, Stilgenbauer S (2002) V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:1410–1416PubMedGoogle Scholar
  34. Lannuti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, Byrd JC, Tyner JW, Loriaux MM, Deininger M, Druker BJ, Puri KD, Ulrich RG, Giese NA (2011) CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3 K signalling and cellular viability. Blood 117:591–594CrossRefGoogle Scholar
  35. Lin K, Manocha S, Harris RJ, Matrai Z, Sherrington PD, Pettitt AR (2003) High frequency of p53 dysfunction and low level of VH mutation in chronic lymphocytic leukemia patients using the VH3-21 gene segment. Blood 102:1145–1146PubMedCrossRefGoogle Scholar
  36. Mackus WJ, Frakking FN, Grummels A, Gamadia LE, De Bree GJ, Hamann D, Van Lier RA, Van Oers MH (2003) Expansion of CMV-specific CD8 + CD45RA + CD27- T-cells in B-cell chronic lymphocytic leukemia. Blood 102:1057–1063PubMedCrossRefGoogle Scholar
  37. Mockridge CI, Potter KN, Wheatley I, Neville LA, Packham G, Stevenson FK (2007) Reversible anergy of sIgM-mediated signaling in two subsets of CLL defined by VH-gene mutational status. Blood 109:4424–4431PubMedCrossRefGoogle Scholar
  38. Murray F, Darzentas N, Hadzidimitriou A, Tobin G, Boudjogra M, Scielzo C, Laoutaris N, Karlsson K, Baran-Marzsak F, Tsaftaris A, Moreno C, Anagnostopoulos A, Caligaris-Cappio F, Vaur D, Ouzounis C, Belessi C, Ghia P, Davi F, Rosenquist R, Stamatopoulos K (2008) Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood 111:1524–1533PubMedCrossRefGoogle Scholar
  39. Ocana E, Delgado-Perez L, Campos-Caro A, Munoz J, Paz A, Franco R, Brieva JA (2007) The prognostic role of CXCR3 expression by chronic lymphocytic leukemia B cells. Haematologica 92:349–356PubMedCrossRefGoogle Scholar
  40. Oppezzo P, Vasconcelos Y, Settegrana C, Jeannel D, Vuillier F, Legarff-Tavernier M, Kimura EY, Bechet S, Dumas G, Brissard M, Merle-Béral H, Yamamoto M, Dighiero G, Davi F (2005) The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia. Blood 106:650–657PubMedCrossRefGoogle Scholar
  41. Potter KN, Orchard J, Critchley E, Mockridge CI, Jose A, Stevenson FK (2003) Features of the overexpressed V1-69 genes in the unmutated subset of chronic lymphocytic leukemia are distinct from those in the healthy elderly repertoire. Blood 101:3082–3084PubMedCrossRefGoogle Scholar
  42. Raveche ES, Salerno E, Scaglione BJ, Manohar V, Abbasi F, Lin YC, Fredrickson T, Landgraf P, Ramachandra S, Huppi K, Toro JR, Zenger VE, Metcalf RA, Marti GE (2007) Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood 109:5079–5086PubMedCrossRefGoogle Scholar
  43. Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, Yang L, Pickeral OK, Rassenti LZ, Powell J, Botstein D, Byrd JC, Grever MR, Cheson BD, Chiorazzi N, Wilson WH, Kipps TJ, Brown PO, Staudt LM (2001) Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 194:1639–1647PubMedCrossRefGoogle Scholar
  44. Rudd MF, Sellick GS, Webb EL, Catovsky D, Houlston RS (2006) Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia. Blood 108:638–644PubMedCrossRefGoogle Scholar
  45. Schroeder HW Jr, Dighiero G (1994) The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunol Today 15:288–294PubMedCrossRefGoogle Scholar
  46. Sellick GS, Webb EL, Allinson R, Matutes E, Dyer MJS, Jønsson V, Langerak AW, Mauro FR, Fuller S, Wiley J, Lyttelton M, Callea V, Yuille M, Catovsky D, Houlston RS (2005) A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia susceptibility loci. Am J Hum Genet 77:420–429PubMedCrossRefGoogle Scholar
  47. Sivina M, Hartmann E, Kipps TJ, Rassenti L, Krupnik D, Lerner S, LaPushin R, Xiao L, Huang X, Werner L, Neuberg D, Kantarjian H, O’Brien S, Wierda WG, Keating MJ, Rosenwald A, Burger JA (2011) CCL3 (MIP-1α) plasma levels and the risk for disease progression in chronic lymphocytic leukemia. Blood 117:1662–1669PubMedCrossRefGoogle Scholar
  48. Stamatopoulos K, Belessi C, Moreno C, Boudjograh M, Guida G, Smilevska T, Belhoul L, Stella S, Stavroyianni N, Crespo M, Hadzidimitriou A, Sutton L, Bosch F, Laoutaris N, Anagnostopoulos A, Montserrat E, Fassas A, Dighiero G, Caligaris-Cappio F, Merle-Béral H, Ghia P, Davi F (2007) Over 20 % of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations. Blood 109:259–270PubMedCrossRefGoogle Scholar
  49. Stamatopoulos K (2009) Stereotyped B cell receptors in CLL. In: Ghia P, Rosenquist R, Davi F (eds) Immunoglobulin gene analysis in chronic lymphocytic leukemia. Wolters Kluwer Health Italy Ltd, Milan, pp 95–111Google Scholar
  50. Sutton LA, Kostareli E, Hadzidimitriou A, Darzentas N, Tsaftaris A, Anagnostopoulos A, Rosenquist R, Stamatopoulos K (2009) Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigen. Blood 114:4460–4468PubMedCrossRefGoogle Scholar
  51. Thorsélius M, Kröber A, Murray F, Thunberg U, Tobin G, Bühler A, Kienle D, Albesiano E, Maffei R, Dao-Ung LP, Wiley J, Vilpo J, Laurell A, Merup M, Roos G, Karlsson K, Chiorazzi N, Marasca R, Döhner H, Stilgenbauer S, Rosenquist R (2006) Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-utilizing chronic lymphocytic leukemia independent of geographical origin and mutational status. Blood 107:2889–2894PubMedCrossRefGoogle Scholar
  52. Tobin G, Thunberg U, Johnson A, Thörn I, Söderberg O, Hultdin M, Botling J, Enblad G, Sällström J, Sundström C, Roos G, Rosenquist R (2002) Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 99:2262–2264PubMedCrossRefGoogle Scholar
  53. Tobin G, Thunberg U, Johnson A, Eriksson I, Söderberg O, Karlsson K, Merup M, Juliusson G, Vilpo J, Enblad G, Sundström C, Roos G, Rosenquist R (2003) Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted Vlambda2-14 gene use and homologous CDR3 s: implicating recognition of a common antigen epitope. Blood 101:4952–4957PubMedCrossRefGoogle Scholar
  54. Widhopf GF 2nd, Kipps TJ (2001) Normal B cells express 51p1-encoded Ig heavy chains that are distinct from those expressed by chronic lymphocytic leukemia B cells. J Immunol 166:95–102PubMedGoogle Scholar
  55. Wierda WG, Cantwell MJ, Woods SJ, Rassenti LZ, Prussak CE, Kipps TJ (2000) CD40 ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood 96:2917–2924PubMedGoogle Scholar
  56. Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Robak T, Furman RR, Hillmen P, Trneny M, Dyer MJ, Padmanabhan S, Piotrowska M, Kozak T, Chan G, Davis R, Losic N, Wilms J, Russell CA, Osterborg A (2010) Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 28:1749–1755PubMedCrossRefGoogle Scholar
  57. Zenz T, Mertens D, Küppers R, Döhner H, Stilgenbauer S (2010) From pathogenesis to treatment of chronic lymphocytic leukemia. Nat Rev Cancer 10:37–50PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Immunology, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands
  2. 2.Department of Internal Medicine, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands

Personalised recommendations