BTK Inhibitors: Focus on Ibrutinib and Similar Agents

  • Mattias Mattsson
  • Lydia ScarfòEmail author
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 17)


Since Bruton tyrosine kinase (BTK) is a critical effector molecule for B cell development and lymphomagenesis, BTK inhibitors have been investigated in B cell malignancies during the last decade. Ibrutinib, a first-in-class, potent, orally administered covalently-binding inhibitor of BTK was recently approved for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström’s macroglobulinemia (WM) and marginal-zone lymphoma (MZL). Its use led to impressive responses in CLL, MCL, WM and MZL with a favorable safety profile. Mechanisms of resistance to ibrutinib are different according to disease biology and still need to be fully elucidated. In CLL and WM patients progressing on ibrutinib, BTK and downstream kinase Phospholipase Cγ2 (PLCγ2) mutations have been identified leading to resistance. BTK and PLCγ2 mutations are almost always absent at the beginning of treatment and they are detected at a later timepoint, suggesting the evolution of clonal dynamics under treatment pressure. Primary and secondary resistances in MCL are driven by mutations promoting the activation of the alternative NFκB-pathway and PI3K-AKT pathway. Further work needs to be done to elucidate the mechanisms behind primary refractory patients, to define the risk for clonal evolution/new mutations over time on treatment, and to identify prognostic/predictive markers for patients on BTK inhibitors.


BTK inhibitors Ibrutinib B cell malignancies Acalabrutinib ONO/GS4059 BGB-3111 CC-292 



The Authors would like to thank Dr. Panagiotis Baliakas for his critical review of the manuscript and his helpful suggestions.


  1. 1.
    Gauld SB, Dal Porto JM, Cambier JCB. Cell antigen receptor signaling: roles in cell development and disease. Science. 2002;296:1641–2.CrossRefPubMedGoogle Scholar
  2. 2.
    Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier JB. Cell antigen receptor signaling 101. Mol Immunol. 2004;41:599–613.CrossRefPubMedGoogle Scholar
  3. 3.
    Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9:722–8.PubMedGoogle Scholar
  4. 4.
    Naor D, Bentwich Z, Cividalli G. Inability of peripheral lymphoid cells of agammaglobulinaemic patients to bind radioiodinated albumins. Aust J Exp Biol Med Sci. 1969;47:759–61.CrossRefPubMedGoogle Scholar
  5. 5.
    Cooper MD, Lawton AR, Bockman DE. Agammaglobulinaemia with B lymphocytes. Specific defect of plasma-cell differentiation. Lancet. 1971;2:791–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Niemann CU, Wiestner A. B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol. 2013;23:410–21.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Singh J, Petter RC, Kluge AF. Targeted covalent drugs of the kinase family. Curr Opin Chem Biol. 2010;14:475–80.CrossRefPubMedGoogle Scholar
  8. 8.
    Wiestner A. BCR pathway inhibition as therapy for chronic lymphocytic leukemia and lymphoplasmacytic lymphoma. Hematology Am Soc Hematol Educ Program. 2014;2014:125–34.PubMedGoogle Scholar
  9. 9.
    Spaargaren M, Beuling EA, Rurup ML, et al. The B cell antigen receptor controls integrin activity through Btk and PLCgamma2. J Exp Med. 2003;198:1539–50.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Honigberg LA, Smith AM, Sirisawad M, 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;107:13075–80.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wiestner A. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia. Haematologica. 2015;100:1495–507.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Herman SE, Niemann CU, Farooqui M, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014;28:2188–96.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30:2820–2.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Advani RH, Buggy JJ, Sharman JP, 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.CrossRefPubMedGoogle Scholar
  15. 15.
    Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–23.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497–506.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Burger JA, Styles L, Kipps TJ. Ibrutinib for chronic lymphocytic leukemia. N Engl J Med. 2016;374:1594–5.PubMedGoogle Scholar
  19. 19.
    Scheers E, Leclercq L, de Jong J, et al. Absorption, metabolism, and excretion of oral (1)(4)C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men. Drug Metab Dispos. 2015;43:289–97.CrossRefPubMedGoogle Scholar
  20. 20.
    Waldron M, Winter A, Hill BT. Pharmacokinetic and Pharmacodynamic considerations in the treatment of chronic lymphocytic leukemia: Ibrutinib, Idelalisib, and Venetoclax. Clin Pharmacokinet. 2017;56:1255–66.CrossRefPubMedGoogle Scholar
  21. 21.
    Marostica E, Sukbuntherng J, Loury D, et al. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemother Pharmacol. 2015;75:111–21.CrossRefPubMedGoogle Scholar
  22. 22.
    de Zwart L, Snoeys J, De Jong J, Sukbuntherng J, Mannaert E, Monshouwer M. Ibrutinib dosing strategies based on interaction potential of CYP3A4 perpetrators using physiologically based pharmacokinetic modeling. Clin Pharmacol Ther. 2016;100:548–57.CrossRefPubMedGoogle Scholar
  23. 23.
    de Vries R, Smit JW, Hellemans P, et al. Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults. Br J Clin Pharmacol. 2016;81:235–45.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Finnes HD, Chaffee KG, Call TG, et al. Pharmacovigilance during ibrutinib therapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in routine clinical practice. Leuk Lymphoma. 2017;58:1376–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–37.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80–7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Winqvist M, Asklid A, Andersson PO, et al. Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish chronic lymphocytic leukemia group. Haematologica. 2016;101:1573–80.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients. Haematologica. 2016;101:1563–72.Google Scholar
  29. 29.
    Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood. 2014;123:1810–7.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Jain P, Keating MJ, Wierda WG, et al. Long-term follow-up of treatment with Ibrutinib and rituximab in patients with high-risk chronic lymphocytic leukemia. Clin Cancer Res. 2016; 23(9): 2154–58.Google Scholar
  31. 31.
    Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17:200–11.CrossRefPubMedGoogle Scholar
  32. 32.
    Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507–16.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015;126:739–45.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016;387:770–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenstrom's macroglobulinemia. N Engl J Med. 2015;372:1430–40.CrossRefPubMedGoogle Scholar
  36. 36.
    Dimopoulos MA, Trotman J, Tedeschi A, et al. Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017;18:241–50.CrossRefPubMedGoogle Scholar
  37. 37.
    Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017;129:2224–32.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21:922–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370:2352–4.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–94.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Komarova NL, Burger JA, Wodarz D. Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL). Proc Natl Acad Sci U S A. 2014;111:13906–11.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Fama R, Bomben R, Rasi S, et al. Ibrutinib-naive chronic lymphocytic leukemia lacks Bruton tyrosine kinase mutations associated with treatment resistance. Blood. 2014;124:3831–3.CrossRefPubMedGoogle Scholar
  43. 43.
    Burger JA, Landau DA, Taylor-Weiner A, et al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun. 2016;7:11589.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    O'Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17:1409–18.CrossRefPubMedGoogle Scholar
  45. 45.
    Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16:169–76.CrossRefPubMedGoogle Scholar
  46. 46.
    Te Raa GD, Kater AP. TP53 dysfunction in CLL: implications for prognosis and treatment. Best Pract Res Clin Haematol. 2016;29:90–9.CrossRefGoogle Scholar
  47. 47.
    Blanco G, Puiggros A, Baliakas P, et al. Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations. Oncotarget. 2016;7:80916–24.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Thompson PA, O'Brien SM, Wierda WG, et al. Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib-based regimens. Cancer. 2015;121:3612–21.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Jones D, Woyach JA, Zhao W, et al. PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment. Leukemia. 2017;31:1645–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to Ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437–43. JCO2016702282.CrossRefPubMedGoogle Scholar
  51. 51.
    Ahn IE, Underbayev C, Albitar A, et al. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017;129:1469–79.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Albitar A, Ma W, DeDios I, et al. Using high-sensitivity sequencing for the detection of mutations in BTK and PLC gamma 2 genes in cellular and cell- free DNA and correlation with progression in patients treated with BTK inhibitors. Oncotarget. 2017;8:17936–44.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Coutre SE, Furman RR, Flinn IW, et al. Extended treatment with single-agent Ibrutinib at the 420 mg dose leads to durable responses in chronic lymphocytic leukemia/small lymphocytic lymphoma. Clin Cancer Res. 2017;23:1149–55.CrossRefPubMedGoogle Scholar
  54. 54.
    O'Brien S, Furman RR, Coutre SE, 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;15:48–58.CrossRefPubMedGoogle Scholar
  55. 55.
    Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062–7.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Mato AR, Nabhan C, Barr PM, et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood. 2016;128:2199–205.CrossRefPubMedGoogle Scholar
  57. 57.
    Chiron D, Di Liberto M, Martin P, et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4:1022–35.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Rahal R, Frick M, Romero R, et al. Pharmacological and genomic profiling identifies NF-kappaB-targeted treatment strategies for mantle cell lymphoma. Nat Med. 2014;20:87–92.CrossRefPubMedGoogle Scholar
  59. 59.
    Zhao X, Lwin T, Silva A, et al. Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nat Commun. 2017;8:14920.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Stephens DM, Spurgeon SE. Ibrutinib in mantle cell lymphoma patients: glass half full? evidence and opinion. Ther Adv Hematol. 2015;6:242–52.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127:1559–63.CrossRefPubMedGoogle Scholar
  62. 62.
    Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. N Engl J Med. 2012;367:826–33.CrossRefPubMedGoogle Scholar
  63. 63.
    Treon SP, Xu L, Hunter Z. MYD88 mutations and response to Ibrutinib in Waldenstrom's Macroglobulinemia. N Engl J Med. 2015;373(6):584.CrossRefPubMedGoogle Scholar
  64. 64.
    Xu L, Tsakmaklis N, Yang G, et al. Acquired mutations associated with ibrutinib resistance in Waldenstrom Macroglobulinemia. Blood. 2017;129(18):2519–25.CrossRefPubMedGoogle Scholar
  65. 65.
    Byrd JC, Harrington B, O'Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323–32.CrossRefPubMedGoogle Scholar
  66. 66.
    Walter HS, Rule SA, Dyer MJ, et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016;127:411–9.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Wu J, Liu C, Tsui ST, Liu D. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016;9:80.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Tam CS, Opat S, Cull G, et al. Twice daily dosing with the highly specific BTK inhibitor, Bgb-3111, achieves complete and continuous BTK occupancy in lymph nodes, and is associated with durable responses in patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Blood. 2016;128: 642.Google Scholar
  69. 69.
    Tam CS, Trotman J, Opat S, et al. High major response rate, including very good partial responses (VGPR), in patients (pts) with Waldenstrom Macroglobulinemia (WM) treated with the high-ly specific BTK inhibitor Bgb-3111: expansion phase results from an ongoing phase I study. Blood. 2016;128: 1216.Google Scholar
  70. 70.
    Brown JR, Harb WA, Hill BT, et al. Phase I study of single-agent CC-292, a highly selective Bruton’s tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2016;101:e295–8.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of HematologyUppsala University Hospital and Department of Immunology, Genetics and Pathology, Uppsala University UppsalaUppsalaSweden
  2. 2.Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San RaffaeleMilanItaly

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