Current Hematologic Malignancy Reports

, Volume 14, Issue 3, pp 197–205 | Cite as

Targeting BTK in CLL: Beyond Ibrutinib

  • David A. Bond
  • Jennifer A. WoyachEmail author
Part of the following topical collections:
  1. Topical Collection on Chronic Lymphocytic Leukemias


Purpose of Review

While the Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL), current limitations include off-target toxicities and the development of resistance. In this review, we summarize the emerging data for alternative BTKi.

Recent Findings

Second-generation BTKi include acalabrutinib, zanubrutinib, and tirabrutinib which offer greater BTK selectivity. While these agents may limit off-target toxicity, they do not overcome common mechanisms of ibrutinib resistance. Reversible BTKi including vecabrutinib and LOXO-305 inhibit BTK in the presence of C481S mutation, and non-selective reversible BTKi, including ARQ-531, may retain activity despite mutations within PLCG2. Early-phase studies are underway to establish the clinical efficacy and toxicity of these agents.


A randomized trial of ibrutinib versus acalabrutinib is ongoing, and acalabrutinib may be an option for ibrutinib-intolerant patients. Results from ongoing trials of alternate BTKi will help to define their role in CLL therapy as single agents or in combination therapy.


Acalabrutinib Tirabrutinib Zanubrutinib B cell receptor 


Compliance with Ethical Standards

Conflict of Interest

Jennifer A. Woyach reports grants and personal fees from Janssen, Pharmacyclics, and grants from Abbvie, Loxo, Morphosys, and Karyopharm outside the submitted work. David A. Bond declares that he has no conflict of interest.

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.


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

  1. 1.
    Herve M, Xu K, Ng YS, et al. Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J Clin Invest. 2005;115:1636–43.CrossRefGoogle Scholar
  2. 2.
    Contri A, Brunati AM, Trentin L, Cabrelle A, Miorin M, Cesaro L, et al. Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest. 2005;115:369–78.CrossRefGoogle Scholar
  3. 3.
    Ringshausen I, Schneller F, Bogner C, et al. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta. Blood. 2002;100:3741–8.CrossRefGoogle Scholar
  4. 4.
    Muzio M, Apollonio B, Scielzo C, Frenquelli M, Vandoni I, Boussiotis V, et al. Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy. Blood. 2008;112:188–95.CrossRefGoogle Scholar
  5. 5.
    Shanafelt TD, Rabe KG, Kay NE, Zent CS, Jelinek DF, Reinalda MS, et al. Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia. Cancer. 2010;116:4777–87.CrossRefGoogle Scholar
  6. 6.
    Strati P, Parikh SA, Chaffee KG, Kay NE, Call TG, Achenbach SJ, et al. Relationship between co-morbidities at diagnosis, survival and ultimate cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study. Br J Haematol. 2017;178:394–402.CrossRefGoogle Scholar
  7. 7.
    Herman SE, Gordon AL, Hertlein E, 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;117:6287–96.CrossRefGoogle Scholar
  8. 8.
    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;123:1207–13.CrossRefGoogle Scholar
  9. 9.
    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;119:1182–9.CrossRefGoogle Scholar
  10. 10.
    de Rooij MF, Kuil A, Geest CR, 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;119:2590–4.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. 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. 2008;111:5446–56.CrossRefGoogle Scholar
  13. 13.
    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;369:32–42.CrossRefGoogle Scholar
  14. 14.
    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;123:1810–7.CrossRefGoogle Scholar
  15. 15.
    Herman SE, Mustafa RZ, Jones J, Wong DH, Farooqui M, Wiestner A. Treatment with ibrutinib inhibits BTK- and VLA-4-dependent adhesion of chronic lymphocytic leukemia cells in vivo. Clin Cancer Res. 2015;21:4642–51.CrossRefGoogle Scholar
  16. 16.
    Byrd JC, Brown JR, O’Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–23.CrossRefGoogle Scholar
  17. 17.
    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;15:48–58.CrossRefGoogle Scholar
  18. 18.
    •• 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 First published phase 3 study establishing ibrutinib as a frontline therapy for patients with CLL. CrossRefGoogle Scholar
  19. 19.
    • Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517–28 Phase 3 study establishing superior PFS with ibrutinib compared with chemoimmunotherapy in older CLL patients and establishing lack of additional efficacy of rituximab combined with ibrutinib. CrossRefGoogle Scholar
  20. 20.
    O’Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131:1910–9.CrossRefGoogle Scholar
  21. 21.
    Shanafelt TD, Wang V, Kay NE. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912) [ABSTRACT]. Blood. 2018;132:LBA-4.CrossRefGoogle Scholar
  22. 22.
    Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370:2352–4.CrossRefGoogle Scholar
  23. 23.
    Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–94.CrossRefGoogle Scholar
  24. 24.
    • 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 Serial deep sequencing of five CLL patients who developed ibrutinib resistance describing clonal evoluation during treatment. CrossRefGoogle Scholar
  25. 25.
    • Woyach JA, Ruppert AS, Guinn D, et al. BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35:1437–43 Analysis of CLL patients treated with ibrutinib across four prospective studies characterizing prevalence of BTK and PLCγ2 mutations and chronological relationship with disease progression. CrossRefGoogle Scholar
  26. 26.
    Liu TM, Woyach JA, Zhong Y, Lozanski A, Lozanski G, Dong S, et al. Hypermorphic mutation of phospholipase C, gamma2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood. 2015;126:61–8.CrossRefGoogle Scholar
  27. 27.
    Landau DA, Sun C, Rosebrock D, Herman SEM, Fein J, Sivina M, et al. The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nat Commun. 2017;8:2185.CrossRefGoogle Scholar
  28. 28.
    Kadri S, Lee J, Fitzpatrick C, Galanina N, Sukhanova M, Venkataraman G, et al. Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL. Blood Adv. 2017;1:715–27.CrossRefGoogle Scholar
  29. 29.
    Kanagal-Shamanna R, Jain P, Patel KP, et al. Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor-resistant chronic lymphocytic leukemia with disease progression and Richter transformation. Cancer. 2019;125:559–74.Google Scholar
  30. 30.
    Brown JR, Moslehi J, O’Brien S, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102:1796–805.CrossRefGoogle Scholar
  31. 31.
    Ganatra S, Sharma A, Shah S, Chaudhry GM, Martin DT, Neilan TG, et al. Ibrutinib-associated atrial fibrillation. JACC Clin Electrophysiol. 2018;4:1491–500.CrossRefGoogle Scholar
  32. 32.
    Leong DP, Caron F, Hillis C, Duan A, Healey JS, Fraser G, et al. The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis. Blood. 2016;128:138–40.CrossRefGoogle Scholar
  33. 33.
    Beyer A, Ganti B, Majkrzak A, Theyyunni N. A perfect storm: tyrosine kinase inhibitor-associated polymorphic ventricular tachycardia. J Emerg Med. 2017;52:e123–e7.CrossRefGoogle Scholar
  34. 34.
    Cheng C, Woronow D, Nayernama A, Wroblewski T, Jones SC. Ibrutinib-associated ventricular arrhythmia in the FDA adverse event reporting system. Leuk Lymphoma. 2018;59:3016–7.CrossRefGoogle Scholar
  35. 35.
    Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, Banerji V, et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood. 2017;129:2581–4.CrossRefGoogle Scholar
  36. 36.
    Tomcsanyi J, Nenyei Z, Matrai Z, Bozsik B. Ibrutinib, an approved tyrosine kinase inhibitor as a potential cause of recurrent polymorphic ventricular tachycardia. JACC Clin Electrophysiol. 2016;2:847–9.CrossRefGoogle Scholar
  37. 37.
    Wallace N, Wong E, Cooper D, Chao H. A case of new-onset cardiomyopathy and ventricular tachycardia in a patient receiving ibrutinib for relapsed mantle cell lymphoma. Clin Case Rep. 2016;4:1120–1.CrossRefGoogle Scholar
  38. 38.
    Guha A, Derbala MH, Zhao Q, Wiczer TE, Woyach JA, Byrd JC, et al. Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies. J Am Coll Cardiol. 2018;72:697–8.CrossRefGoogle Scholar
  39. 39.
    McMullen JR, Boey EJ, Ooi JY, Seymour JF, Keating MJ, Tam CS. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124:3829–30.CrossRefGoogle Scholar
  40. 40.
    Byrd JC, O’Brien S, James DF. Ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:1278–9.CrossRefGoogle Scholar
  41. 41.
    Brown JR, Moslehi J, Ewer MS, O’Brien SM, Ghia P, Cymbalista F, et al. Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: an integrated analysis. Br J Haematol. 2019;184:558–69.CrossRefGoogle Scholar
  42. 42.
    Caron F, Leong DP, Hillis C, Fraser G, Siegal D. Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis. Blood Adv. 2017;1:772–8.CrossRefGoogle Scholar
  43. 43.
    Atkinson BT, Ellmeier W, Watson SP. Tec regulates platelet activation by GPVI in the absence of Btk. Blood. 2003;102:3592–9.CrossRefGoogle Scholar
  44. 44.
    Quek LS, Bolen J, Watson SP. A role for Bruton’s tyrosine kinase (Btk) in platelet activation by collagen. Curr Biol. 1998;8:1137–40.CrossRefGoogle Scholar
  45. 45.
    Nicolson PLR, Hughes CE, Watson S, et al. Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation to GPVI. Haematologica. 2018;103:2097–108.Google Scholar
  46. 46.
    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;346:219–28.CrossRefGoogle Scholar
  47. 47.
    Brown JR, Harb WA, Hill BT, Gabrilove J, Sharman JP, Schreeder MT, 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.CrossRefGoogle Scholar
  48. 48.
    •• 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 Phase 1/2 study of acalabrutinib in CLL and comparison of kinase selectivity of acalabrutinib versus ibrutinib. CrossRefGoogle Scholar
  49. 49.
    Herman SEM, Montraveta A, Niemann CU, Mora-Jensen H, Gulrajani M, Krantz F, et al. The Bruton tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia. Clin Cancer Res. 2017;23:2831–41.CrossRefGoogle Scholar
  50. 50.
    Barf T, Covey T, Izumi R, van de Kar B, Gulrajani M, van Lith B, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363:240–52.CrossRefGoogle Scholar
  51. 51.
    Byrd JC, Wierda W, Schuh A. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 study [Abstract]. Blood. 2017;130:498.Google Scholar
  52. 52.
    Byrd JC, Woyach J, Furman RR. Acalabrutinib in treatment-naive (TN) chronic lymphocytic leukemia (CLL): updated results from the phase 1/2 ACE-CL-001 study [Abstract]. Blood. 2018;132:692.CrossRefGoogle Scholar
  53. 53.
    Falchi L, Vitale C, Keating MJ, Lerner S, Wang X, Elhor Gbito KY, et al. Incidence and prognostic impact of other cancers in a population of long-term survivors of chronic lymphocytic leukemia. Ann Oncol. 2016;27:1100–6.CrossRefGoogle Scholar
  54. 54.
    Hisada M, Biggar RJ, Greene MH, Fraumeni JF Jr, Travis LB. Solid tumors after chronic lymphocytic leukemia. Blood. 2001;98:1979–81.CrossRefGoogle Scholar
  55. 55.
    Travis LB, Curtis RE, Hankey BF, Fraumeni JF Jr. Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst. 1992;84:1422–7.CrossRefGoogle Scholar
  56. 56.
    Tsimberidou AM, Wen S, McLaughlin P, O’Brien S, Wierda WG, Lerner S, et al. Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2009;27:904–10.CrossRefGoogle Scholar
  57. 57.
    Sun C, Nierman P, Ahn IE. Acalabrutinib in patients with relapsed/refractory (R/R) and high-risk, treatment-naive (TN) chronic lymphocytic leukemia (CLL) [Abstract]. Blood. 2018;132:4424.CrossRefGoogle Scholar
  58. 58.
    Awan FT, Schuh A, Brown JR. Acalabrutinib monotherapy in patients with ibrutinib intolerance: results from the phase 1/2 ACE-CL-001 clinical study [Abstract]. Blood. 2016;128:638.CrossRefGoogle Scholar
  59. 59.
    Li N, Sun Z, Liu Y. BGB-3111 is a novel and highly selective Bruton’s tyrosine kinase (BTK) inhibitor [Abstract]. Cancer Res. 2015;75:2597.Google Scholar
  60. 60.
    Kaptein A, de Bruin G. Emmelot-van Hoek M. Potency and selectivity of BTK inhibitors in clinical development for B-cell malignancies [Abstract]. Blood. 2018;132:1871.CrossRefGoogle Scholar
  61. 61.
    Tam CS, Opat S, Cull G. Twice daily dosing with the highly specific BTK inhibitor, Bgb-3111, acheives 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) [Abstract]. Blood. 2016;128:642.Google Scholar
  62. 62.
    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.CrossRefGoogle Scholar
  63. 63.
    • Johnson AR, Kohli PB, Katewa A, et al. Battling Btk mutants with noncovalent inhibitors that overcome Cys481 and Thr474 mutations. ACS Chem Biol. 2016;11:2897–907 Description of reversible, non-covalent BTK inhibitors in C481S-mutated CLL. CrossRefGoogle Scholar
  64. 64.
    Crawford JJ, Johnson AR, Misner DL, Belmont LD, Castanedo G, Choy R, et al. Discovery of GDC-0853: a potent, selective, and noncovalent Bruton’s tyrosine kinase inhibitor in early clinical development. J Med Chem. 2018;61:2227–45.CrossRefGoogle Scholar
  65. 65.
    Reiff SD, Muhowski EM, Guinn D, Lehman A, Fabian CA, Cheney C, et al. Noncovalent inhibition of C481S Bruton tyrosine kinase by GDC-0853: a new treatment strategy for ibrutinib-resistant CLL. Blood. 2018;132:1039–49.CrossRefGoogle Scholar
  66. 66.
    Byrd JC, Smith S, Wagner-Johnston N, Sharman J, Chen AI, Advani R, et al. First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. Oncotarget. 2018;9:13023–35.CrossRefGoogle Scholar
  67. 67.
    Binnerts ME, Otipoby KL, Hopkins BT. SNS-062 is a potent noncovalent BTK inhibitor with comparable activity against wide type BTK and BTK with an acquired resistance mutation [Abstract]. Mol Cancer Ther. 2015;14:C186.CrossRefGoogle Scholar
  68. 68.
    Fabian CA, Reiff SD, Guinn D. SNS-062 demonstrates efficacy in chronic lymphocytic leukemia in vitro and inhibits C481S mutated Bruton tyrosine kinase [Abstract]. Cancer Res. 2017;77:1207.Google Scholar
  69. 69.
    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;122:2539–49.CrossRefGoogle Scholar
  70. 70.
    Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest. 2017;127:3052–64.CrossRefGoogle Scholar
  71. 71.
    Neuman LL, Ward R, Arnold D. First-in-human phase 1a study of the safety, pharmacokinetics, and pharmacodynamics of the noncovalent Bruton tyrosine kinase (BTK) inhibitor SNS-062 in healthy subjects [Abstract]. Blood. 2016;128:2032.Google Scholar
  72. 72.
    Brandhuber B, Gomez E, Smith S. Abstract CLL-200: LOXO-305, a next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors [Abstract]. Clin Lymphoma Myeloma Leuk. 2018;18:S216.CrossRefGoogle Scholar
  73. 73.
    • Reiff SD, Mantel R, Smith LL, et al. The BTK inhibitor ARQ 531 targets ibrutinib-resistant CLL and Richter transformation. Cancer Discov. 2018;8:1300–15 Preclinical characterization of ARQ 531 in both C481S- and PLCγ2-mutated CLL. CrossRefGoogle Scholar
  74. 74.
    Woyach J, Flinn I, Stephens DM. A phase 1 dose escalation study of ARQ 531 in selected patients with relapsed or refractory hematologic malignancies [Abstract]. Blood. 2018;132:3136.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Internal Medicine, Division of Hematology, Arthur G James Comprehensive Cancer CenterThe Ohio State University Wexner Medical CenterColumbusUSA

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