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BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future

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Abstract

The treatment of chronic lymphocytic leukemia (CLL) with inhibitors targeting B cell receptor signaling and other survival mechanisms holds great promise. Especially the early clinical success of Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), has received widespread attention. In this review we will focus on the fundamental and clinical aspects of BTK inhibitors in CLL, with emphasis on Ibrutinib as the best studied of this class of drugs. Furthermore, we summarize recent laboratory as well as clinical findings relating to the first cases of Ibrutinib resistance. Finally, we address combination strategies with Ibrutinib, and attempt to extrapolate its current status to the near future in the clinic.

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References

  1. Hallek M . Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies. Blood 2013; 122: 3723–3734.

    CAS  Google Scholar 

  2. Cramer P, Hallek M . Prognostic factors in chronic lymphocytic leukemia-what do we need to know? Nat Rev Clin Oncol 2011; 8: 38–47.

    CAS  Google Scholar 

  3. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. New Engl J Med 2000; 343: 1910–1916.

    CAS  Google Scholar 

  4. Pospisilova S, Gonzalez D, Malcikova J, Trbusek M, Rossi D, Kater AP et al. ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia 2012; 26: 1458–1461.

    CAS  Google Scholar 

  5. Messina M, Del Giudice I, Khiabanian H, Rossi D, Chiaretti S, Rasi S et al. Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness. Blood 2014; 123: 2378–2388.

    CAS  Google Scholar 

  6. Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013; 152: 714–726.

    Article  CAS  Google Scholar 

  7. Burger JA, Gribben JG . The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies. Semin Cancer Biol 2014; 24: 71–81.

    CAS  Google Scholar 

  8. de Weerdt I, Eldering E, van Oers MH, Kater AP . The biological rationale and clinical efficacy of inhibition of signaling kinases in chronic lymphocytic leukemia. Leuk Res 2013; 37: 838–847.

    CAS  Google Scholar 

  9. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 1164–1174.

    CAS  Google Scholar 

  10. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. New Engl J Med 2014; 370: 1101–1110.

    CAS  Google Scholar 

  11. Zenz T, Krober A, Scherer K, Habe S, Buhler A, Benner A 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 2008; 112: 3322–3329.

    CAS  Google Scholar 

  12. Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2010; 28: 1749–1755.

    CAS  Google Scholar 

  13. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993; 361: 226–233.

    CAS  Google Scholar 

  14. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993; 72: 279–290.

    CAS  Google Scholar 

  15. Thomas JD, Sideras P, Smith CI, Vorechovsky I, Chapman V, Paul WE . Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 1993; 261: 355–358.

    CAS  Google Scholar 

  16. Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, Cohen L et al. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science 1993; 261: 358–361.

    CAS  Google Scholar 

  17. Ellmeier W, Jung S, Sunshine MJ, Hatam F, Xu Y, Baltimore D et al. Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk. J Exp Med 2000; 192: 1611–1624.

    CAS  Google Scholar 

  18. de Weers M, Verschuren MC, Kraakman ME, Mensink RG, Schuurman RK, van Dongen JJ et al. The Bruton's tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages. Eur J Immunol 1993; 23: 3109–3114.

    CAS  Google Scholar 

  19. Martensson IL, Rolink A, Melchers F, Mundt C, Licence S, Shimizu T . The pre-B cell receptor and its role in proliferation and Ig heavy chain allelic exclusion. Semin Immunol 2002; 14: 335–342.

    CAS  Google Scholar 

  20. LeBien TW, Tedder TF . B lymphocytes: how they develop and function. Blood 2008; 112: 1570–1580.

    CAS  Google Scholar 

  21. Mensink EJ, Schuurman RK, Schot JD, Thompson A, Alt FW . Immunoglobulin heavy chain gene rearrangements in X-linked agammaglobulinemia. Eur J Immunol 1986; 16: 963–967.

    CAS  Google Scholar 

  22. Campana D, Farrant J, Inamdar N, Webster AD, Janossy G . Phenotypic features and proliferative activity of B cell progenitors in X-linked agammaglobulinemia. J Immunol 1990; 145: 1675–1680.

    CAS  Google Scholar 

  23. Fearon ER, Winkelstein JA, Civin CI, Pardoll DM, Vogelstein B . Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome inactivation. New Engl J Med 1987; 316: 427–431.

    CAS  Google Scholar 

  24. Cyster JG . Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005; 23: 127–159.

    CAS  Google Scholar 

  25. Lo CG, Xu Y, Proia RL, Cyster JG . Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J Exp Med 2005; 201: 291–301.

    CAS  Google Scholar 

  26. Shiow LR, Rosen DB, Brdickova N, Xu Y, An J, Lanier LL et al. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 2006; 440: 540–544.

    CAS  Google Scholar 

  27. Spaargaren M, Beuling EA, Rurup ML, Meijer HP, Klok MD, Middendorp S et al. The B cell antigen receptor controls integrin activity through Btk and PLCgamma2. J Exp Med 2003; 198: 1539–1550.

    CAS  Google Scholar 

  28. de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012; 119: 2590–2594.

    CAS  Google Scholar 

  29. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B et al. 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 2010; 107: 13075–13080.

    CAS  Google Scholar 

  30. Kil LP, de Bruijn MJ, van Nimwegen M, Corneth OB, van Hamburg JP, Dingjan GM et al. Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice. Blood 2012; 119: 3744–3756.

    CAS  Google Scholar 

  31. Yu L, Mohamed AJ, Simonson OE, Vargas L, Blomberg KE, Bjorkstrand B et al. Proteasome-dependent autoregulation of Bruton tyrosine kinase (Btk) promoter via NF-kappaB. Blood 2008; 111: 4617–4626.

    CAS  Google Scholar 

  32. Ridderstad A, Nossal GJ, Tarlinton DM . The xid mutation diminishes memory B cell generation but does not affect somatic hypermutation and selection. J Immunol 1996; 157: 3357–3365.

    CAS  Google Scholar 

  33. Genevier HC, Hinshelwood S, Gaspar HB, Rigley KP, Brown D, Saeland S et al. Expression of Bruton's tyrosine kinase protein within the B cell lineage. Eur J Immunol 1994; 24: 3100–3105.

    CAS  Google Scholar 

  34. Ramadani F, Bolland DJ, Garcon F, Emery JL, Vanhaesebroeck B, Corcoran AE et al. The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development. Sci Signal 2010; 3: ra60.

    Google Scholar 

  35. Saito K, Scharenberg AM, Kinet JP . Interaction between the Btk PH domain and phosphatidylinositol-3,4,5-trisphosphate directly regulates Btk. J Biol Chem 2001; 276: 16201–16206.

    CAS  Google Scholar 

  36. Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 1996; 271: 822–825.

    CAS  Google Scholar 

  37. Kurosaki T, Kurosaki M . Transphosphorylation of Bruton's tyrosine kinase on tyrosine 551 is critical for B cell antigen receptor function. J Biol Chem 1997; 272: 15595–15598.

    CAS  Google Scholar 

  38. Middendorp S, Dingjan GM, Maas A, Dahlenborg K, Hendriks RW . Function of Bruton's tyrosine kinase during B cell development is partially independent of its catalytic activity. J Immunol 2003; 171: 5988–5996.

    CAS  Google Scholar 

  39. Park H, Wahl MI, Afar DE, Turck CW, Rawlings DJ, Tam C et al. Regulation of Btk function by a major autophosphorylation site within the SH3 domain. Immunity 1996; 4: 515–525.

    CAS  Google Scholar 

  40. Kang SW, Wahl MI, Chu J, Kitaura J, Kawakami Y, Kato RM et al. PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization. EMBO J 2001; 20: 5692–5702.

    CAS  Google Scholar 

  41. Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG . Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2. Mol Cell Biol 2004; 24: 9986–9999.

    CAS  Google Scholar 

  42. Takata M, Kurosaki T . A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. J Exp Med 1996; 184: 31–40.

    CAS  Google Scholar 

  43. de Gorter DJ, Vos JC, Pals ST, Spaargaren M . The B cell antigen receptor controls AP-1 and NFAT activity through Ras-mediated activation of Ral. J Immunol 2007; 178: 1405–1414.

    CAS  Google Scholar 

  44. Rawlings DJ . Bruton's tyrosine kinase controls a sustained calcium signal essential for B lineage development and function. Clin Immunol 1999; 91: 243–253.

    CAS  Google Scholar 

  45. Genevier HC, Callard RE . Impaired Ca2+ mobilization by X-linked agammaglobulinaemia (XLA) B cells in response to ligation of the B cell receptor (BCR). Clin Exp Immunol 1997; 110: 386–391.

    CAS  Google Scholar 

  46. Petro JB, Rahman SM, Ballard DW, Khan WN . Bruton's tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. J Exp Med 2000; 191: 1745–1754.

    CAS  Google Scholar 

  47. Antony P, Petro JB, Carlesso G, Shinners NP, Lowe J, Khan WN . B-cell antigen receptor activates transcription factors NFAT (nuclear factor of activated T-cells) and NF-kappaB (nuclear factor kappaB) via a mechanism that involves diacylglycerol. Biochem Soc Trans 2004; 32: 113–115.

    CAS  Google Scholar 

  48. McLeod SJ, Ingham RJ, Bos JL, Kurosaki T, Gold MR . Activation of the Rap1 GTPase by the B cell antigen receptor. J Biol Chem 1998; 273: 29218–29223.

    CAS  Google Scholar 

  49. Petro JB, Khan WN . Phospholipase C-gamma 2 couples Bruton's tyrosine kinase to the NF-kappaB signaling pathway in B lymphocytes. J Biol Chem 2001; 276: 1715–1719.

    CAS  Google Scholar 

  50. Saito K, Tolias KF, Saci A, Koon HB, Humphries LA, Scharenberg A et al. BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity. Immunity 2003; 19: 669–678.

    CAS  Google Scholar 

  51. Yang W, Desiderio S . BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement. Proc Natl Acad Sci USA 1997; 94: 604–609.

    CAS  Google Scholar 

  52. Novina CD, Kumar S, Bajpai U, Cheriyath V, Zhang K, Pillai S et al. Regulation of nuclear localization and transcriptional activity of TFII-I by Bruton's tyrosine kinase. Mol Cell Biol 1999; 19: 5014–5024.

    CAS  Google Scholar 

  53. Webb CF, Yamashita Y, Ayers N, Evetts S, Paulin Y, Conley ME et al. The transcription factor Bright associates with Bruton's tyrosine kinase, the defective protein in immunodeficiency disease. J Immunol 2000; 165: 6956–6965.

    CAS  Google Scholar 

  54. Rajaiya J, Hatfield M, Nixon JC, Rawlings DJ, Webb CF . Bruton's tyrosine kinase regulates immunoglobulin promoter activation in association with the transcription factor Bright. Mol Cell Biol 2005; 25: 2073–2084.

    CAS  Google Scholar 

  55. Rajaiya J, Nixon JC, Ayers N, Desgranges ZP, Roy AL, Webb CF . Induction of immunoglobulin heavy-chain transcription through the transcription factor Bright requires TFII-I. Mol Cell Biol 2006; 26: 4758–4768.

    CAS  Google Scholar 

  56. Ashworth T, Roy AL . Cutting Edge: TFII-I controls B cell proliferation via regulating NF-kappaB. J Immunol 2007; 178: 2631–2635.

    CAS  Google Scholar 

  57. Kawakami Y, Yao L, Miura T, Tsukada S, Witte ON, Kawakami T . Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking. Mol Cell Biol 1994; 14: 5108–5113.

    CAS  Google Scholar 

  58. Hata D, Kawakami Y, Inagaki N, Lantz CS, Kitamura T, Khan WN et al. Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production. J Exp Med 1998; 187: 1235–1247.

    CAS  Google Scholar 

  59. Rock J, Schneider E, Grun JR, Grutzkau A, Kuppers R, Schmitz J et al. CD303 (BDCA-2) signals in plasmacytoid dendritic cells via a BCR-like signalosome involving Syk, Slp65 and PLCgamma2. Eur J Immunol 2007; 37: 3564–3575.

    Google Scholar 

  60. Jongstra-Bilen J, Puig CA, Hasija M, Xiao H, Smith CI, Cybulsky MI . Dual functions of Bruton's tyrosine kinase and Tec kinase during Fcgamma receptor-induced signaling and phagocytosis. J Immunol 2008; 181: 288–298.

    CAS  Google Scholar 

  61. Wang D, Feng J, Wen R, Marine JC, Sangster MY, Parganas E et al. Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity 2000; 13: 25–35.

    Google Scholar 

  62. Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H et al. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 2008; 132: 794–806.

    CAS  Google Scholar 

  63. Oda A, Ikeda Y, Ochs HD, Druker BJ, Ozaki K, Handa M et al. Rapid tyrosine phosphorylation and activation of Bruton's tyrosine/Tec kinases in platelets induced by collagen binding or CD32 cross-linking. Blood 2000; 95: 1663–1670.

    CAS  Google Scholar 

  64. Zorn CN, Keck S, Hendriks RW, Leitges M, Freudenberg MA, Huber M . Bruton's tyrosine kinase is dispensable for the Toll-like receptor-mediated activation of mast cells. Cell Signal 2009; 21: 79–86.

    CAS  Google Scholar 

  65. Gagliardi MC, Finocchi A, Orlandi P, Cursi L, Cancrini C, Moschese V et al. Bruton's tyrosine kinase defect in dendritic cells from X-linked agammaglobulinaemia patients does not influence their differentiation, maturation and antigen-presenting cell function. Clin Exp Immunol 2003; 133: 115–122.

    CAS  Google Scholar 

  66. Futatani T, Watanabe C, Baba Y, Tsukada S, Ochs HD . Bruton's tyrosine kinase is present in normal platelets and its absence identifies patients with X-linked agammaglobulinaemia and carrier females. Br J Haematol 2001; 114: 141–149.

    CAS  Google Scholar 

  67. de Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, van Gils JM, Hendriks RW et al. Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity 2007; 26: 93–104.

    CAS  Google Scholar 

  68. Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C et al. Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem 2003; 278: 26258–26264.

    CAS  Google Scholar 

  69. Jefferies CA, O'Neill LA . Bruton's tyrosine kinase (Btk)-the critical tyrosine kinase in LPS signalling? Immunol Lett 2004; 92: 15–22.

    CAS  Google Scholar 

  70. Horwood NJ, Page TH, McDaid JP, Palmer CD, Campbell J, Mahon T et al. Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. J Immunol 2006; 176: 3635–3641.

    CAS  Google Scholar 

  71. Horwood NJ, Mahon T, McDaid JP, Campbell J, Mano H, Brennan FM et al. Bruton's tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha production. J Exp Med 2003; 197: 1603–1611.

    CAS  Google Scholar 

  72. Jiang Y, Ma W, Wan Y, Kozasa T, Hattori S, Huang XY . The G protein G alpha12 stimulates Bruton's tyrosine kinase and a rasGAP through a conserved PH/BM domain. Nature 1998; 395: 808–813.

    CAS  Google Scholar 

  73. Tsukada S, Simon MI, Witte ON, Katz A . Binding of beta gamma subunits of heterotrimeric G proteins to the PH domain of Bruton tyrosine kinase. Proc Natl Acad Sci USA 1994; 91: 11256–11260.

    CAS  Google Scholar 

  74. Lowry WE, Huang XY . G Protein beta gamma subunits act on the catalytic domain to stimulate Bruton's agammaglobulinemia tyrosine kinase. J Biol Chem 2002; 277: 1488–1492.

    CAS  Google Scholar 

  75. Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom macroglobulinemia. Blood 2013; 122: 1222–1232.

    CAS  Google Scholar 

  76. Perez de DR, Lopez-Granados E, Pozo M, Rodriguez C, Sabina P, Ferreira A et al. Bruton's tyrosine kinase is not essential for LPS-induced activation of human monocytes. J Allergy Clin Immunol 2006; 117: 1462–1469.

    Google Scholar 

  77. Burger JA, Landau D, Hoellenriegel J, Sougnez C, Schlesner M, Ishaque N et al. Clonal Evolution In Patients With Chronic Lymphocytic Leukemia (CLL) Developing Resistance To BTK Inhibition. Blood 2013; 122: 866.

    Google Scholar 

  78. Ghia P, Scielzo C, Frenquelli M, Muzio M, Caligaris-Cappio F . From normal to clonal B cells: chronic lymphocytic leukemia (CLL) at the crossroad between neoplasia and autoimmunity. Autoimmun Rev 2007; 7: 127–131.

    CAS  Google Scholar 

  79. Messmer BT, Albesiano E, Efremov DG, Ghiotto F, Allen SL, Kolitz J et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med 2004; 200: 519–525.

    CAS  Google Scholar 

  80. Hoogeboom R, van Kessel KP, Hochstenbach F, Wormhoudt TA, Reinten RJ, Wagner K et al. A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi. J Exp Med 2013; 210: 59–70.

    CAS  Google Scholar 

  81. Duhren-von MM, Ubelhart R, Schneider D, Wossning T, Bach MP, Buchner M et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 2012; 489: 309–312.

    Google Scholar 

  82. Coelho V, Krysov S, Steele A, Sanchez HM, Johnson PW, Chana PS et al. Identification in CLL of circulating intraclonal subgroups with varying B-cell receptor expression and function. Blood 2013; 122: 2664–2672.

    CAS  Google Scholar 

  83. Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-{kappa}B activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 2011; 117: 563–574.

    CAS  Google Scholar 

  84. Burger JA . Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2011; 2011: 96–103.

    Google Scholar 

  85. Spaner DE, Masellis A . Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia. Leukemia 2007; 21: 53–60.

    CAS  Google Scholar 

  86. Rozkova D, Novotna L, Pytlik R, Hochova I, Kozak T, Bartunkova J et al. Toll-like receptors on B-CLL cells: expression and functional consequences of their stimulation. Int J Cancer 2010; 126: 1132–1143.

    CAS  Google Scholar 

  87. Wolska A, Cebula-Obrzut B, Smolewski P, Robak T . Effects of Toll-like receptor 7 and Toll-like receptor 9 signaling stimulators and inhibitors on chronic lymphocytic leukemia cells ex vivo and their interactions with cladribine. Leuk Lymphoma 2013; 54: 1268–1278.

    CAS  Google Scholar 

  88. Peng SL . Signaling in B cells via Toll-like receptors. Curr Opin Immunol 2005; 17: 230–236.

    CAS  Google Scholar 

  89. Monroe JG, Keir ME . Bridging Toll-like- and B cell-receptor signaling: meet me at the autophagosome. Immunity 2008; 28: 729–731.

    CAS  Google Scholar 

  90. Sharma S, Orlowski G, Song W . Btk regulates B cell receptor-mediated antigen processing and presentation by controlling actin cytoskeleton dynamics in B cells. J Immunol 2009; 182: 329–339.

    CAS  Google Scholar 

  91. Souwer Y, Chamuleau ME, van de Loosdrecht AA, Tolosa E, Jorritsma T, Muris JJ et al. Detection of aberrant transcription of major histocompatibility complex class II antigen presentation genes in chronic lymphocytic leukaemia identifies HLA-DOA mRNA as a prognostic factor for survival. Br J Haematol 2009; 145: 334–343.

    CAS  Google Scholar 

  92. Kremer AN, van der Meijden ED, Honders MW, Pont MJ, Goeman JJ, Falkenburg JH et al. Human leukocyte antigen-DO regulates surface presentation of human leukocyte antigen class II-restricted antigens on B cell malignancies. Biol Blood Marrow Transplant 2014; 20: 742–747.

    CAS  Google Scholar 

  93. Bagnara D, Kaufman MS, Calissano C, Marsilio S, Patten PE, Simone R et al. A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease. Blood 2011; 117: 5463–5472.

    CAS  Google Scholar 

  94. Dazzi F, D'Andrea E, Biasi G, De SG, Gaidano G, Schena M et al. Failure of B cells of chronic lymphocytic leukemia in presenting soluble and alloantigens. Clin Immunol Immunopathol 1995; 75: 26–32.

    CAS  Google Scholar 

  95. Pascutti MF, Jak M, Tromp JM, Derks IA, Remmerswaal EB, Thijssen R et al. IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells. Blood 2013; 122: 3010–3019.

    CAS  Google Scholar 

  96. Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G . B-cell receptor signaling in chronic lymphocytic leukemia. Blood 2011; 118: 4313–4320.

    CAS  Google Scholar 

  97. Conley ME, Dobbs AK, Farmer DM, Kilic S, Paris K, Grigoriadou S et al. Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol 2009; 27: 199–227.

    CAS  Google Scholar 

  98. Kil LP, de Bruijn MJ, van Hulst JA, Langerak AW, Yuvaraj S, Hendriks RW . Bruton's tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res 2013; 3: 71–83.

    CAS  Google Scholar 

  99. Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA et al. Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood 2014; 123: 1207–1213.

    CAS  Google Scholar 

  100. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 2012; 119: 1182–1189.

    CAS  Google Scholar 

  101. Herman SE, Mustafa RZ, Gyamfi JA, Pittaluga S, Chang S, Chang B et al. Ibrutinib inhibits B-cell receptor and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with chronic lymphocytic leukemia. Blood 2014; 123: 3286–3295.

    CAS  Google Scholar 

  102. Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2013; 31: 88–94.

    CAS  Google Scholar 

  103. Woyach JA, Smucker K, Smith LL, Lozanski A, Zhong Y, Ruppert AS et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014; 123: 1810–1817.

    CAS  Google Scholar 

  104. Herman SE, Niemann CU, Farooqui M, Jones J, Mustafa RZ, Lipsky A et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia (e-pub ahead of print 4 April 2014; doi:10.1038/leu.2014.122).

    CAS  Google Scholar 

  105. Herman SE, Sun X, McAuley EM, Hsieh MM, Pittaluga S, Raffeld M et al. Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Leukemia 2013; 27: 2311–2321.

    CAS  Google Scholar 

  106. Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 2011; 117: 6287–6296.

    CAS  Google Scholar 

  107. Cheng S, Ma J, Guo A, Lu P, Leonard JP, Coleman M et al. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia 2014; 28: 649–657.

    CAS  Google Scholar 

  108. Chang BY, Francesco M, de Rooij MF, Magadala P, Steggerda SM, Huang MM et al. Egress of CD19(+)CD5(+) cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood 2013; 122: 2412–2424.

    CAS  Google Scholar 

  109. Wiestner A . Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood 2012; 120: 4684–4691.

    CAS  Google Scholar 

  110. Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest 2005; 115: 755–764.

    CAS  Google Scholar 

  111. Schmid C, Isaacson PG . Proliferation centres in B-cell malignant lymphoma, lymphocytic (B-CLL): an immunophenotypic study. Histopathology 1994; 24: 445–451.

    CAS  Google Scholar 

  112. van Gent R, Kater AP, Otto SA, Jaspers A, Borghans JA, Vrisekoop N et al. In vivo dynamics of stable chronic lymphocytic leukemia inversely correlate with somatic hypermutation levels and suggest no major leukemic turnover in bone marrow. Cancer Res 2008; 68: 10137–10144.

    CAS  Google Scholar 

  113. Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. Chem Med Chem 2007; 2: 58–61.

    CAS  Google Scholar 

  114. Advani R, Sharman JP, Smith SM, Pollyea DA, Boyd TE, Grant BW et al. Effect of Btk inhibitor PCI-32765 monotherapy on responses in patients with relapsed aggressive NHL: Evidence of antitumor activity from a phase I study. J Clin Oncol 2010; 28: 15.

    Google Scholar 

  115. Fowler N, Sharman JP, Smith SM, Boyd T, Grant B, Kolibaba KS et al. The Btk inhibitor, PCI-32765, induces durable responses with minimal toxicity in patients with relapsed/refractory B-cell malignancies: results from a phase I study. Blood 2010; 116: 425.

    Google Scholar 

  116. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. New Engl J Med 2013; 369: 32–42.

    CAS  Google Scholar 

  117. Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol 2012; 30: 2820–2822.

    CAS  Google Scholar 

  118. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. New Engl J Med 2013; 369: 507–516.

    CAS  Google Scholar 

  119. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND et al. Idelalisib, an inhibitor of phosphatidylinositol 3 kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014; 123: 3390–3397.

    CAS  Google Scholar 

  120. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. New Engl J Med 2014; 370: 997–1007.

    CAS  Google Scholar 

  121. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013; 122: 2539–2549.

    CAS  Google Scholar 

  122. Schulzke JD, Ploeger S, Amasheh M, Fromm A, Zeissig S, Troeger H et al. Epithelial tight junctions in intestinal inflammation. Ann NY Acad Sci 2009; 1165: 294–300.

    Google Scholar 

  123. Chang BY, Furman RR, Zapatka M, Barrientos JC, Li D, Steggerda S et al. Use of tumor genomic profiling to reveal mechanisms of resistance to the BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) (2013 ASCO Annual Meeting Proceedings). J Clin Oncol 2013; 31 (suppl; abstr 7014).

  124. Furman RR, Cheng S, Lu P, Setty M, Perez A, Guo A et al. A novel mutation in bruton tyrosine kinase confers acquired resistance to ibrutinib (PCI-32765) in CLL. Blood 2013; 122: 4914.

    Google Scholar 

  125. Hantschel O, Rix U, Schmidt U, Burckstummer T, Kneidinger M, Schutze G et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci USA 2007; 104: 13283–13288.

    CAS  Google Scholar 

  126. Rossi D, Khiabanian H, Spina V, Ciardullo C, Bruscaggin A, Famà R et al. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia. Blood 2014; 123: 2139–2147.

    CAS  Google Scholar 

  127. Ouillette P, Saiya-Cork K, Seymour E, Li C, Shedden K, Malek SN . Clonal evolution, genomic drivers, and effects of therapy in chronic lymphocytic leukemia. Clin Cancer Res 2013; 19: 2893–2904.

    CAS  Google Scholar 

  128. Zenz T, Habe S, Denzel T, Mohr J, Winkler D, Buhler A et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial. Blood 2009; 114: 2589–2597.

    CAS  Google Scholar 

  129. Keating MJ, Wierda WG, Hoellenriegel J, Jeyakumar G, Ferrajoli A, Faderl SH et al. Ibrutinib in combination with rituximab (iR) is well tolerated and induces a high rate of durable remissions in patients with high-risk chronic lymphocytic leukemia (CLL): new, updated results of a phase II trial in 40 patients. Blood 2013; 122: 675.

    Google Scholar 

  130. Barrientos JC, Barr PM, Flinn I, Burger JA, Salman Z, Clow F et al. Ibrutinib in combination with bendamustine and rituximab is active and tolerable in patients with relapsed/refractory CLL/SLL: final results of a phase 1b study. Blood 2013; 122: 525.

    Google Scholar 

  131. Kohrt HE, Sagiv-Barfi I, Rafiq S, Herman SE, Butchar JP, Cheney C et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 2014; 123: 1957–1960.

    CAS  Google Scholar 

  132. Axelrod M, Ou Z, Brett LK, Zhang L, Lopez ER, Tamayo AT et al. Combinatorial drug screening identifies synergistic co-targeting of Bruton/'s tyrosine kinase and the proteasome in mantle cell lymphoma. Leukemia 2014; 28: 407–410.

    CAS  Google Scholar 

  133. Tiao G, Kiezun A, Wang Y, Werner L, Sougnez C, Tesar B et al. NF-kB pathway mutations modulate cell survival and ibrutinib response in chronic lymphocytic leukemia. Blood 2013; 122: 670.

    Google Scholar 

  134. Hallaert DY, Jaspers A, van Noesel CJ, van Oers MH, Kater AP, Eldering E . c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches. Blood 2008; 112: 5141–5149.

    CAS  Google Scholar 

  135. Kelley TW, Alkan S, Srkalovic G, Hsi ED . Treatment of human chronic lymphocytic leukemia cells with the proteasome inhibitor bortezomib promotes apoptosis. Leuk Res 2004; 28: 845–850.

    CAS  Google Scholar 

  136. Smit LA, Hallaert DY, Spijker R, de Goeij B, Jaspers A, Kater AP et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity. Blood 2007; 109: 1660–1668.

    CAS  Google Scholar 

  137. O'Connor OA, Wright J, Moskowitz C, Muzzy J, Gregor-Cortelli B, Stubblefield M et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 2005; 23: 676–684.

    CAS  Google Scholar 

  138. Faderl S, Rai K, Gribben J, Byrd JC, Flinn IW, O'Brien S et al. Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia. Cancer 2006; 107: 916–924.

    CAS  Google Scholar 

  139. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH . Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006; 107: 4907–4916.

    CAS  Google Scholar 

  140. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013; 19: 202–208.

    CAS  Google Scholar 

  141. Davids MS, Pagel JM, Kahl BS, Wierda WG, Miller TP, Gerecitano JF et al. Bcl-2 inhibitor ABT-199 (GDC-0199) monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Blood 2013; 122: 872.

    Google Scholar 

  142. Tam CCS, Seymour JF, Bell A, Westerman DA, Juneja S, Huang DCS et al. Selective Bcl-2 inhibition with ABT-199 is highly active against chronic lymphocytic leukemia (CLL) irrespective of TP53 mutation or dysfunction. Blood 2013; 122: 1304.

    Google Scholar 

  143. Karlin L, Rule S, Shah N, Morschhauser F, Terriou L, Dyer MJ et al. A phase I study of the oral Btk inhibitor ONO-4059 in patients with relapsed/refractory and high risk chronic lymphocytic leukaemia (CLL). Blood 2013; 122: 676.

    Google Scholar 

  144. Amrein PC, Attar EC, Takvorian T, Hochberg EP, Ballen KK, Leahy KM et al. Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res 2011; 17: 2977–2986.

    CAS  Google Scholar 

  145. Brown JR, Hill BT, Gabrilove J, Sharman JP, Schreeder MT, Barr PM et al. Phase 1 study of single agent CC-292, a highly selective Bruton's tyrosine kinase (BTK) inhibitor, in relapsed/refractory chronic lymphocytic leukemia (CLL). Blood 2013; 122: 1630.

    Google Scholar 

  146. O'Brien S, Furman RR, Fowler N, Coutre SE, Sharman JP, Blum KA et al. The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) monotherapy demonstrates long-term safety and durability of response in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in an open-label extension study. Blood 2013; 122: 4163.

    Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    M Spaargaren & M F M de Rooij

  2. Lymphoma and Myeloma Center Amsterdam - LYMMCARE, Academic Medical Center, Amsterdam, The Netherlands

    M Spaargaren, A P Kater & E Eldering

  3. Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    A P Kater

  4. Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    E Eldering

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MS has received research support from Pharmacyclics. The other authors declare no conflict of interest.

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Spaargaren, M., de Rooij, M., Kater, A. et al. BTK inhibitors in chronic lymphocytic leukemia: a glimpse to the future. Oncogene 34, 2426–2436 (2015). https://doi.org/10.1038/onc.2014.181

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