Skip to main content

Advertisement

SpringerLink
Log in

Ibrutinib: from bench side to clinical implications

  • Review Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The activation of the B cell receptor (BCR) is nowadays known to play a primary role in the etiopathogenesis of a multitude of B cell malignancies, being one of the main factors responsible for the enhanced proliferation and survival of transformed cells. Thanks to the characterization and continuous discovery of the pathways driving B cell proliferation in consequence to BCR activation, it has been possible to develop a small molecule inhibitor specifically antagonizing the Bruton’s tyrosine kinase (BTK), an enzyme located in an early strategic position within the whole pathway. Ibrutinib, formerly PCI-32765, is a first in class, potent, specific, irreversible and relatively safe BTK inhibitor, demonstrating so far an impressive efficacy in the treatment of chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma (MCL), Waldenström macroglobulinemia and multiple myeloma. This review will summarize the most important pharmacological evidences available as of today and will take in consideration the latest findings regarding the mechanism of action of ibrutinib.

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

Fig. 1

Similar content being viewed by others

References

  1. Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol. 2002;2(12):945–56. doi:10.1038/nri955.

    Article  CAS  PubMed  Google Scholar 

  2. Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor signaling: roles in cell development and disease. Science. 2002;296(5573):1641–2. doi:10.1126/science.1071546.

    Article  CAS  PubMed  Google Scholar 

  3. Kurosaki T. Molecular dissection of B cell antigen receptor signaling (review). Int J Mol Med. 1998;1(3):515–27.

    CAS  PubMed  Google Scholar 

  4. Kurosaki T. Regulation of BCR signaling. Mol Immunol. 2011;48(11):1287–91. doi:10.1016/j.molimm.2010.12.007.

    Article  CAS  PubMed  Google Scholar 

  5. Wiestner A. Targeting B-Cell receptor signaling for anticancer therapy: the Bruton’s tyrosine kinase inhibitor ibrutinib induces impressive responses in B-cell malignancies. J Clin Oncol. 2013;31(1):128–30. doi:10.1200/JCO.2012.44.4281.

    Article  CAS  PubMed  Google Scholar 

  6. 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. doi:10.1146/annurev.immunol.021908.132649.

    Article  CAS  PubMed  Google Scholar 

  7. 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. doi:10.1002/cmdc.200600221.

    Article  CAS  PubMed  Google Scholar 

  8. 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(29):13075–80. doi:10.1073/pnas.1004594107.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. 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(23):6287–96. doi:10.1182/blood-2011-01-328484.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. 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. doi:10.1182/blood-2011-10-386417.

    Article  CAS  PubMed  Google Scholar 

  11. Audrito V, Vaisitti T, Serra S, Bologna C, Brusa D, Malavasi F, et al. Targeting the microenvironment in chronic lymphocytic leukemia offers novel therapeutic options. Cancer Lett. 2013;328(1):27–35. doi:10.1016/j.canlet.2012.08.012.

    Article  CAS  PubMed  Google Scholar 

  12. 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. doi:10.1200/JCO.2012.42.7906.

    Article  CAS  PubMed  Google Scholar 

  13. Brown JR. Ibrutinib in chronic lymphocytic leukemia and B cell malignancies. Leuk Lymphoma. 2014;55(2):263–9. doi:10.3109/10428194.2013.803226.

    Article  CAS  PubMed  Google Scholar 

  14. Wu M, Akinleye A, Zhu X. Novel agents for chronic lymphocytic leukemia. J Hematol Oncol. 2013;6:36. doi:10.1186/1756-8722-6-36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Danilov AV. Targeted therapy in chronic lymphocytic leukemia: past, present, and future. Clin Ther. 2013;35(9):1258–70. doi:10.1016/j.clinthera.2013.08.004.

    Article  CAS  PubMed  Google Scholar 

  16. 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 Investig. 2005;115(3):755–64. doi:10.1172/JCI23409.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. ten Hacken E, Burger JA. Molecular pathways: targeting the microenvironment in chronic lymphocytic leukemia–focus on the B-cell receptor. Clin Cancer Res. 2014;20(3):548–56. doi:10.1158/1078-0432.CCR-13-0226.

    Article  PubMed  Google Scholar 

  18. 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-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563–74. doi:10.1182/blood-2010-05-284984.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Burger JA, Chiorazzi N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol. 2013;34(12):592–601. doi:10.1016/j.it.2013.07.002.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. 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. doi:10.1038/nature11309.

    Article  PubMed  Google Scholar 

  21. 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(3):649–57. doi:10.1038/leu.2013.358.

    Article  CAS  PubMed  Google Scholar 

  22. 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(1):32–42. doi:10.1056/NEJMoa1215637.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Neffendorf JE, Gout I, Hildebrand GD. Ibrutinib in relapsed chronic lymphocytic leukemia. New Engl J Med. 2013;369(13):1277. doi:10.1056/NEJMc1309710#SA1.

    Article  CAS  PubMed  Google Scholar 

  24. O’Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58. doi:10.1016/S1470-2045(13)70513-8.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Burger J, Keating M, Wierda W, Hoellenriegel J, Jeyakumar G, Ferrajoli A, Faderl S, Cardenas-Turanzas M, Lerner S, Zacharian G, Huang X, Kantarjian H, O’Brien S. 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 

  26. Hallek M, Kay NE, Osterborg A, Chanan-Khan AA, Mahler M, Salman M, et al. The HELIOS trial protocol: a phase III study of ibrutinib in combination with bendamustine and rituximab in relapsed/refractory chronic lymphocytic leukemia. Future Oncol. 2015;11(1):51–9. doi:10.2217/fon.14.119.

    Article  CAS  PubMed  Google Scholar 

  27. Aalipour A, Advani RH. Bruton’s tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib. Therap Adv Hematol. 2014;5(4):121–33. doi:10.1177/2040620714539906.

    Article  CAS  Google Scholar 

  28. 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. doi:10.1038/nature08638.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Wilson W, Gerecitano J, Goy A, de Vos S, Kenkre V, Barr P, Blum K, Shustov A, Advani R, Lih J, Williams M, Schmitz R, Yang Y, Pittaluga S, Wright G, Kunkel L, McGreivy J, Balasubramanian S, Cheng M, Moussa D, Buggy J, Staudt L. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study [abstract 686]. Blood. 2012;120(Suppl. 1):686.

    Google Scholar 

  30. Irish JM, Czerwinski DK, Nolan GP, Levy R. Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells. Blood. 2006;108(9):3135–42. doi:10.1182/blood-2006-02-003921.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Fowler N, Advani R, Sharman J, Smith S, MvGreivy J, Kunkel L, Troung V, Zhou C, Boyd T. The Bruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765) is active and tolerated in relapsed follicular lymphoma [Abstract 156]. Presented at the 2012 ASH Annual Meeting December 9, 2012. 2012.

  32. Cinar M, Hamedani F, Mo Z, Cinar B, Amin HM, Alkan S. Bruton tyrosine kinase is commonly overexpressed in mantle cell lymphoma and its attenuation by Ibrutinib induces apoptosis. Leuk Res. 2013;37(10):1271–7. doi:10.1016/j.leukres.2013.07.028.

    Article  CAS  PubMed  Google Scholar 

  33. 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(6):507–16. doi:10.1056/NEJMoa1306220.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Study of Ibrutinib (a Bruton’s Tyrosine Kinase Inhibitor), versus temsirolimus in patients with relapsed or refractory mantle cell lymphoma who have received at least one prior Therapy. https://clinicaltrials.gov/ct2/show/NCT01646021 [database on the Internet]. Accessed.

  35. Shah N, Hutchinson C, Rule S. Ibrutinib for the treatment of mantle cell lymphoma. Expert Rev Hematol. 2014;7(5):521–31. doi:10.1586/17474086.2014.951323.

    Article  CAS  PubMed  Google Scholar 

  36. 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(7):1222–32. doi:10.1182/blood-2012-12-475111.

    Article  CAS  PubMed  Google Scholar 

  37. Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. New Engl J Med. 2015;372(15):1430–40. doi:10.1056/NEJMoa1501548.

    Article  CAS  PubMed  Google Scholar 

  38. 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. doi:10.1182/blood-2011-12-396853.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Tai YT, Anderson KC. Bruton’s tyrosine kinase: oncotarget in myeloma. Oncotarget. 2012;3(9):913–4.

    PubMed Central  PubMed  Google Scholar 

  40. Murray MY, Zaitseva L, Auger MJ, Craig JI, MacEwan DJ, Rushworth SA, et al. Ibrutinib inhibits BTK-driven NF-kappaB p65 activity to overcome bortezomib-resistance in multiple myeloma. Cell Cycle. 2015;. doi:10.1080/15384101.2014.998067.

    Google Scholar 

  41. Rushworth SA, Bowles KM, Barrera LN, Murray MY, Zaitseva L, MacEwan DJ. BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-kappaB. Cell Signal. 2013;25(1):106–12. doi:10.1016/j.cellsig.2012.09.008.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang SQ, Smith SM, Zhang SY, Lynn Wang Y. Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma. Br J Haematol. 2015;. doi:10.1111/bjh.13427.

    Google Scholar 

  43. Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A, et al. Ibrutinib resistance in chronic lymphocytic leukemia. New Engl J Med. 2014;370(24):2352–4. doi:10.1056/NEJMc1402716.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. New Engl J Med. 2014;370(24):2286–94. doi:10.1056/NEJMoa1400029.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Tsang M, Shanafelt TD, Call TG, Ding W, Chanan-Khan A, Leis JF, et al. The efficacy of ibrutinib in the treatment of Richter syndrome. Blood. 2015;125(10):1676–8. doi:10.1182/blood-2014-12-610782.

    Article  CAS  PubMed  Google Scholar 

  46. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497–506. doi:10.1182/blood-2014-10-606038.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Maffei R, Fiorcari S, Martinelli S, Potenza L, Luppi M, Marasca R. Targeting neoplastic B cells and harnessing microenvironment: the “double face” of ibrutinib and idelalisib. J Hematol Oncol. 2015;8(1):60. doi:10.1186/s13045-015-0157-x.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy

    Davide Grisafi, Alessandra Maestro, Camilla Grumi, Ludovica Piazzoni, Giampaolo Tirone, Walter Fiore, Roberto Tessari, Valeria Gianardi, Milo Gatti, Francesca Tasca, Daniele Generali & Francesco Scaglione

  2. Molecular Therapy and Pharmacogemomic Unit, AO Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100, Cremona, Italy

    Daniele Generali

  3. Hematology CTMO Unit, AO Istituti Ospitalieri di Cremona, Cremona, Italy

    Andrea Ravelli & Francesco Lanza

Authors
  1. Davide Grisafi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandra Maestro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Camilla Grumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ludovica Piazzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giampaolo Tirone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Walter Fiore
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Roberto Tessari
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Valeria Gianardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Milo Gatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Francesca Tasca
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniele Generali
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andrea Ravelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Francesco Lanza
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Francesco Scaglione
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniele Generali.

Ethics declarations

Conflict of interest

There are no financial or other interests with regard to the submitted manuscript that might be construed as a conflict of interest.

Ethical standard

The manuscript has been approved by the Scientific Committee of the Ethical Committee—AO Istituti Ospitalieri di Cremona, Cremona, Italy (N: Prot: 0107-15/CE).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Grisafi, D., Maestro, A., Grumi, C. et al. Ibrutinib: from bench side to clinical implications. Med Oncol 32, 225 (2015). https://doi.org/10.1007/s12032-015-0669-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-015-0669-9

Keywords

Search

Navigation