Skip to main content

Advertisement

SpringerLink
Log in

Bruton’s Tyrosine Kinase (BTK) Inhibitors in Clinical Trials

  • Chronic Leukemias (S O’Brien, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. The BTK inhibitor ibrutinib (PCI-32765, brand name: Imbruvica) demonstrated high clinical activity in B-cell malignancies, especially in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia (WM). Therefore, ibrutinib was granted a ‘breakthrough therapy’ designation for these indications and was recently approved for the treatment of relapsed MCL by the U.S. Food and Drug Administration. Other BTK inhibitors in earlier clinical development include CC-292 (AVL-292), and ONO-4059. In CLL and MCL, ibrutinib characteristically induces redistribution of malignant B cells from tissue sites into the peripheral blood, along with rapid resolution of enlarged lymph nodes and a surge in lymphocytosis. With continuous ibrutinib therapy, growth- and survival-inhibitory activities of ibrutinib result in the normalization of lymphocyte counts and remissions in a majority of patients. This review discusses the clinical advances with BTK inhibitor therapy, as well as its pathophysiological basis, and outlines perspectives for future use of BTK inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B-cell development and function: a genetic perspective. Immunol Rev. 2000;175:120–7.

    Article  CAS  PubMed  Google Scholar 

  2. 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(10):1539–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Ortolano S, Hwang IY, Han SB, Kehrl JH. Roles for phosphoinositide 3-kinases, Bruton's tyrosine kinase, and Jun kinases in B lymphocyte chemotaxis and homing. Eur J Immunol. 2006;36(5):1285–95.

    Article  CAS  PubMed  Google Scholar 

  4. 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(1):93–104.

    Article  PubMed  Google Scholar 

  5. 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(28):26258–64.

    Article  CAS  PubMed  Google Scholar 

  6. Lee KG, Xu S, Kang ZH, Huo J, Huang M, Liu D, et al. Bruton's tyrosine kinase phosphorylates Toll-like receptor 3 to initiate antiviral response. Proc Natl Acad Sci U S A. 2012;109(15):5791–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Matsuda T, Takahashi-Tezuka M, Fukada T, Okuyama Y, Fujitani Y, Tsukada S, et al. Association and activation of Btk and Tec tyrosine kinases by gp130, a signal transducer of the interleukin-6 family of cytokines. Blood. 1995;85(3):627–33.

    CAS  PubMed  Google Scholar 

  8. Takahashi-Tezuka M, Hibi M, Fujitani Y, Fukada T, Yamaguchi T, Hirano T. Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK. Oncogene. 1997;14(19):2273–82.

    Article  CAS  PubMed  Google Scholar 

  9. Liu X, Zhan Z, Li D, Xu L, Ma F, Zhang P, et al. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat Immunol. 2011;12(5):416–24.

    Article  CAS  PubMed  Google Scholar 

  10. Quek LS, Bolen J, Watson SP. A role for Bruton's tyrosine kinase (Btk) in platelet activation by collagen. Curr Biol. 1998;8(20):1137–40.

    Article  CAS  PubMed  Google Scholar 

  11. Honda F, Kano H, Kanegane H, Nonoyama S, Kim ES, Lee SK, et al. The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils. Nat Immunol. 2012;13(4):369–78.

    Article  CAS  PubMed  Google Scholar 

  12. 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(12):3100–5.

    Article  CAS  PubMed  Google Scholar 

  13. 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(5119):358–61.

    Article  CAS  PubMed  Google Scholar 

  14. 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(6409):226–33.

    Article  CAS  PubMed  Google Scholar 

  15. 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(2):279–90.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, et al. Bruton’s tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011 Mar 21.

  18. • 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(5):1182–9. CLL in vitro and in vivo models explain the clinical activity of ibrutinib in CLL, based on ibrutinib effects on CLL-cell migration and proliferation.

    Article  CAS  PubMed  Google Scholar 

  19. 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(1):88–94.

    Article  CAS  PubMed  Google Scholar 

  20. •• 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 U S A. 2010;107(29):13075–80. In-depth characterization of ibrutinib in preclinical models.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Chang BY, Huang MM, Francesco M, Chen J, Sokolove J, Magadala P, et al. The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells. Arthritis Res Ther. 2011;13(4):R115.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, et al. Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis. Nat Chem Biol. 2011;7(1):41–50.

    Article  PubMed  Google Scholar 

  23. Bernal A, Pastore RD, Asgary Z, Keller SA, Cesarman E, Liou HC, et al. Survival of leukemic B cells promoted by engagement of the antigen receptor. Blood. 2001;98(10):3050–7.

    Article  CAS  PubMed  Google Scholar 

  24. Longo PG, Laurenti L, Gobessi S, Sica S, Leone G, Efremov DG. The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood. 2008;111(2):846–55.

    Article  CAS  PubMed  Google Scholar 

  25. Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor signaling: roles in cell development and disease. Science. 2002;296(5573):1641–2.

    Article  CAS  PubMed  Google Scholar 

  26. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev. 2005;5(4):251–62.

    Article  Google Scholar 

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

  28. Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011;118(16):4313–20.

    Google Scholar 

  29. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120(6):1175–84.

    Article  CAS  PubMed  Google Scholar 

  30. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Chen SS, Batliwalla F, Holodick NE, Yan XJ, Yancopoulos S, Croce CM, et al. Autoantigen can promote progression to a more aggressive TCL1 leukemia by selecting variants with enhanced B-cell receptor signaling. Proc Natl Acad Sci U S A. 2013;110(16):E1500–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Duhren-von Minden M, 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(7415):309–12.

    Article  PubMed  Google Scholar 

  33. Lenz G, Davis RE, Ngo VN, Lam L, George TC, Wright GW, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319(5870):1676–9.

    Article  CAS  PubMed  Google Scholar 

  34. 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(1):59–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Binder M, Lechenne B, Ummanni R, Scharf C, Balabanov S, Trusch M, et al. Stereotypical chronic lymphocytic leukemia B-cell receptors recognize survival promoting antigens on stromal cells. PLoS One. 2010;5(12):e15992.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Chu CC, Catera R, Hatzi K, Yan XJ, Zhang L, Wang XB, et al. Chronic lymphocytic leukemia antibodies with a common stereotypic rearrangement recognize nonmuscle myosin heavy chain IIA. Blood. 2008;112(13):5122–9.

    Article  CAS  PubMed  Google Scholar 

  37. Hoogeboom R, Wormhoudt TA, Schipperus MR, Langerak AW, Dunn-Walters DK, Guikema JE, et al. A novel chronic lymphocytic leukemia subset expressing mutated IGHV3-7-encoded rheumatoid factor B-cell receptors that are functionally proficient. Leukemia. 2012 Aug 20.

  38. 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(11):2590–4.

    Article  PubMed  Google Scholar 

  39. Schwamb J, Feldhaus V, Baumann M, Patz M, Brodesser S, Brinker R, et al. B-cell receptor triggers drug sensitivity of primary CLL cells by controlling glucosylation of ceramides. Blood. 2012;120(19):3978–85.

    Article  CAS  PubMed  Google Scholar 

  40. Yang Y, Shaffer 3rd AL, Emre NC, Ceribelli M, Zhang M, Wright G, et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012;21(6):723–37.

    Article  CAS  PubMed  Google Scholar 

  41. Tai YT, Chang BY, Kong SY, Fulciniti M, Yang G, Calle Y, et al. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood. 2012;120(9):1877–87.

    Article  CAS  PubMed  Google Scholar 

  42. 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(14):2412–24.

    Article  CAS  PubMed  Google Scholar 

  43. Burger JA, Montserrat E. Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling. Blood. 2013;121(9):1501–9.

    Article  CAS  PubMed  Google Scholar 

  44. Singh J, Petter RC, Kluge AF. Targeted covalent drugs of the kinase family. Curr Opin Chem Biol. 2010;14(4):475–80.

    Article  CAS  PubMed  Google Scholar 

  45. Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem. 2007;2(1):58–61.

    Article  CAS  PubMed  Google Scholar 

  46. Burger JA, Buggy JJ. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765). Leuk Lymphoma. 2013;54(11):2385–91.

    Article  CAS  PubMed  Google Scholar 

  47. 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(15):2539–49.

    Article  CAS  PubMed  Google Scholar 

  48. •• 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. N Engl J Med. 2013;369(6):507–16. First paper to describe the activity of ibrutinib in MCL and a basis for the FDA approval of ibrutinib for relapsed MCL in November 2013.

    Article  CAS  PubMed  Google Scholar 

  49. •• Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. First paper to describe the single-agent experience of ibrutinib in CLL.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. 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(23):2820–2.

    Article  CAS  PubMed  Google Scholar 

  51. Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115(13):2578–85.

    Article  CAS  PubMed  Google Scholar 

  52. Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118(13):3603–12.

    Article  CAS  PubMed  Google Scholar 

  53. Farooqui M, Lozier JN, Valdez J, Saba N, Wells A, Soto S, et al. Ibrutinib (PCI 32765) Rapidly Improves Platelet Counts in Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) Patients and Has Minimal Effects On Platelet Aggregation Blood. 2012;120(21):abstract 1789.

  54. Liu J, Fitzgerald ME, Berndt MC, Jackson CW, Gartner TK. Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo. Blood. 2006;108(8):2596–603.

    Article  CAS  PubMed  Google Scholar 

  55. Jackson SP, Cranmer S, Mangin P, Yuan Y. Are Erk, Btk, and PECAM-1 major players in GPIb signaling? The challenge of unraveling signaling events downstream of platelet GPIb. Blood. 2007;109(2):846–7. discussion 47–8.

    Article  CAS  PubMed  Google Scholar 

  56. 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). J Clin Oncol. 2013;31:suppl; abstr 7014.

    Google Scholar 

  57. Mahajan S, Ghosh S, Sudbeck EA, Zheng Y, Downs S, Hupke M, et al. Rational design and synthesis of a novel anti-leukemic agent targeting Bruton's tyrosine kinase (BTK), LFM-A13 [alpha-cyano-beta-hydroxy-beta-methyl-N-(2, 5-dibromophenyl)propenamide]. J Biol Chem. 1999;274(14):9587–99.

    Article  CAS  PubMed  Google Scholar 

  58. Uckun FM, Tibbles H, Venkatachalam T, DuMez D, Erbeck D. Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting anti-leukemic drug candidate, alpha-cyano-beta-hydroxy-beta-methyl-N- (2,5-dibromophenyl) propenamide (LFM-A13). Arzneimittelforschung. 2007;57(1):31–46.

    CAS  PubMed  Google Scholar 

  59. Evans EK, Tester R, Aslanian S, Karp R, Sheets M, Labenski MT, et al. Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans. J Pharmacol Exp Ther. 2013 May 24.

  60. Burger JA, Keating MJ, Wierda WG, Hoellenriegel J, Ferrajoli A, Faderl S, et al. The Btk Inhibitor Ibrutinib (PCI-32765) in Combination with Rituximab Is Well Tolerated and Displays Profound Activity in High-Risk Chronic Lymphocytic Leukemia (CLL) Patients Blood. 2012;120(21):Abstract 187.

Download references

Acknowledgment

This manuscript was supported by a Leukemia & Lymphoma Society Scholar Award in Clinical Research, a Cancer Prevention and Research Institute of Texas (CPRIT) grant, and the MD Anderson CLL Moon Shot Program.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Dr. Jan Burger has received grants from Pharmacyclics, Gilead, and Noxxon.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Unit 428, PO Box 301402, Houston, TX, 77230-1402, USA

    Jan A. Burger

Authors
  1. Jan A. Burger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan A. Burger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burger, J.A. Bruton’s Tyrosine Kinase (BTK) Inhibitors in Clinical Trials. Curr Hematol Malig Rep 9, 44–49 (2014). https://doi.org/10.1007/s11899-013-0188-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-013-0188-8

Keywords

Search

Navigation