Abstract
Bruton’s tyrosine kinase (BTK), a mediator in B cell receptor signaling has been successfully exploited as a therapeutic target in treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a BTK inhibitor that has shown excellent efficacy in treatment-naïve, heavily pre-treated, and high-risk CLL/SLL. With remarkable efficacy, good oral bioavailability, and modest adverse events profile, ibrutinib use is likely to continue to increase. As data with ibrutinib use in CLL matures, concerns regarding adverse events and drug resistance have emerged. New insights into mechanisms of ibrutinib resistance in CLL have uncovered potential therapeutic targets. Several promising novel agents are currently in early phases of development for overcoming ibrutinib resistance in CLL/SLL. We provide a comprehensive analysis of emerging adverse events profile of ibrutinib, summarize our current understanding of ibrutinib resistance in CLL, and review promising novel therapeutic tools to overcome this challenge.
Similar content being viewed by others
References
Pazdur R. New drug application approval—Imbruvica (Department of Health and Human Services. Food and Drug administration). Ref ID 3395788; 2013
IMBRUVICA US Prescribing information, March 2016
Bruton OC (1952) Agammaglobulinemia. Pediatrics 9(6):722–728
Vetrie D, Vorechovsky I, Sideras P et al (1993) The gene involved in X-linked agammaglobulinaemia is a member of src family of protein tyrosine kinases. Nature 361:226–233
Rawlings DJ, Saffran DC, Tsukada S et al (1993) Mutation of unique region of Bruton’s tyrosine kinase in immunodeficient XID mice. Science 261(5119):358–361
Herishanu Y, Pérez-Galán P, Liu D et al (2011) The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117:563–574
Duhren von-Minden M, Ubelhart R, Schneider D et al (2012) Chronic lymphocytic leukemia is driven by antigen-independent cell-autonomous signaling. Nature 489:309–312
Burger JA, Chiorazi N (2013) B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol 34:592–601
Woyach JA, Johnson AJ, Byrd JC (2012) B-cell receptor signaling as a therapeutic target in CLL. Blood 120(6):1175–1184
Yu L, Smith CL (2011) Tec family kinases. FEBS J 278:1969
Cheng S, Guo A, Lu P et al (2014) BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia 28:649–657
King LB, Freedman BD (2009) B-lymphocyte calcium influx. Immunol Rev 231:265–277
Chen SS, Chang BY, Chang S (2016) BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. Leukemia 30(4):833–843
Arana E, Harwood NE, Batista FD (2008) Regulation of integrin activation through the B-cell receptor. J Cell Sci 121(pt 14):2279–2286
Spaargaren M, Beuling EA, Rurup ML et al (2003) The B cell antigen receptor controls integrin activity through Btk and PLCgamma2. J Exp Med 198(10):1539–1550
de Gorter DJ, Beuling EA, Kersseboom R et al (2007) Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity 26(1):93–104
Herman SEM, Gordon AL, Hertlein E et al (2011) Bruton tyrosine kinase represents as promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 117(23):6287–6296
Ponader S, Chen SS, Buggy JJ et al (2012) The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 119:1182–1189
Honigberg LA, Smith AM, Sirisawad M et al (2010) The Bruton’s tyrosine kinase inhibitor PCI-32765 block B cell activation and is efficacious in models of auto-immune disease and B-cell malignancy. Proc Natl Acad Sci U S A 107(29):13075–13080
Burger JA, Buggy JJ (2013) Emerging drug profiles: Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765). Leuk Lymphoma 54(11):2385–2391
Herman SEM, McAuley EM, Wong DH et al (2015) Ibrutinib inhibits both T-cell receptor and toll-like receptor signaling in chronic lymphocytic leukemia. Blood 125(23):313
Advani RH, Buggy JJ, Sharman JP et al (2013) Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 31(1):88–94. doi:10.1200/JCO.2012.42.7906
Byrd JC, Furman RR, Coutre SE et al (2013) Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369(1):32–42. doi:10.1056/NEJMoa1215637
Byrd JC, Furman RR, Coutre SE et al (2015) Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutnib. Blood 125(16):2479–2506
O’Brien S, Furman RR, Coutre SE et al (2014) 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. 15(1):48–58. doi:10.1016/S1470-2045(13)70513-8
Farooqui MZ, Valdex J, Martyr S et al (2015) Ibrutinib for previously untreated and relapsed or refractory chronic lymhocytic leukemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 16(2):169–176
Byrd JC, Brown JR, O’Brien S et al (2014) Ibrutinib versus ofatumumab in previously treated chronic lymphocytic leukemia. N Engl J Med 371(3):213–223
Burger JA, Tedeschi A, Barr PM et al (2015) Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373(25):2425–2437
Sun C, Tian X, Lee YS et al (2015) Partial reconstitution of humoral immunity with fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood 126(19):2213–2219
Brown JR, Barrientos JC, Barr PM et al (2015) The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood 125:2915–2922
Chanan-Khan A, Cramer P, Demirkan F et al (2016) Ibrutiib combined with bendamustine and rituximab compared with placebo, bendamustine and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomized, double-blind, phase 3 study. Lancet Oncol 17(2):200–211
Burger JA, Keating MJ, Wierda WG et al (2014) Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol 15:1090–1099
Jaglowski SM, Jones JA, Nagar V et al (2015) Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1B/2 study. Blood 126:842–850
Levade M, David E, Garcia C et al (2014) Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet function. Blood 124(26):3991–3995
Lipsky AH, Farooqui MZH, Tian X et al (2015) Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib. Hematologica 100(12):1572–1578
Mato AR, Islam P, Daniel C et al (2016) Ibrutinib-induced pneumonitis in patients with chronic lymphocytic leukemia. Blood 127(8):1064–1067
Klien BEK, Klein R, Lee KE et al (2008) Incidence of age-related cataract over a 15-year interval: the Beaver Dam Eye Study. Ophthalmology 115:477–482
Kaur V, Mehta P, Johnsurd J et al (2014) Tumor lysis syndrome in a patient with chronic lymphocytic leukemia. Blood 124(23):3503–3505
Maddocks K, Ruppert AS, Lozanski G et al (2015) Etiology of ibrutinib discontinuation and outcomes in chronic lymphocytic leukemia patients. JAMA Oncol 1(1):80–87
Furman RR, Cheung S, Lu P et al (2014) Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med 370:2352–2354
Woyach JA, Furman RR, Liu TM et al (2014) Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med 370:2286–2294
Burger JA, Landau DA, Taylor-Weiner A et al (2016) Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun 7:11589
Thompson PA et al (2015) 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 121:3612–3621
Cheng S, Guo A, Lu P et al (2015) Functional characterization of BTK C481S mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia 29(4):895–900
Liu TM, Woyach JA, Zhong Y et al (2015) Hypomorphic mutation of phospholipase C, y2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cel receptor activation. Blood 126(1):61–68
Rubio-Moscardo F et al (2005) Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor agents. Blood 106:3214–3222
Cosson A, Chapiro E, Lambert J, et al. (2015) The Gain of short arm of chromosome 2 (2p+) induces XPO1 overexpression and drug resistance in chronic lymphocytic leukemia. Blood 126: abstract 492
Senapedis WT, Baloglu E, Landesman Y (2014) Clinical translation of nuclear export inhibitors in cancer. Semin Cancer Biol 27C:74–86
Fornerod M, van Baal S, Valentine V et al (1997) Chromosomal localization of genes encoding CAN/Nup214-interacting proteins—human CRM1 localizes to 2p16, whereas Nup88 localizes to 17p13 and is physically linked to SF2p32. Genomics 42(3):538–540
Goede V, Fischer K, Busch R et al (2014) Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370:1101–1110
Jain P, Keating M, Wierda W et al (2015) Outcomes of patients with chronic lymphocytic leukemia after discontinuation of ibrutinib. Blood 125(13):2062–2067
Gardner HL, Harrington BK, Izumi R, et al. ACP-196: a second generation Btk inhibitor demonstrates biologic activity in a canine model of B-cell non-Hodgkin lymphoma. American Association for Cancer Research Annual Meeting, San Diego, CA, April 5–9, 2014. abstract
Byrd JC, Harrington B, O’Brien S et al (2016) Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 374(4):323–332
Blunt MD, Parnell J, Larrayoz M et al (2015) The SYK/JAK inhibitor cerdulatinib (PRT062070) shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing B cell receptor and microenvironment signaling. Blood 126(23):1716
Seymore JF, Davis MS, Pagel JM, et al. (2014) ABT-199 (GDC-0199) in relapsed/refractor (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): high complete-response rate and durable disease control. J Clin Oncol 32(5s):abstract 7015
Deng J, Isik E, Farnandez S et al (2015) Ibrutinib therapy increases BCL-2 dependence and enhances sensitivity to venetoclax in CLL. Blood 126(23):490
Jones JA, Wierda WG, Choi MY, et al. (2016) Venetoclax activity in CLL patients who have relapsed after or are refractory to ibrutinib or idelalisib. J Clin Oncol 34(suppl; abstr 7519)
Roberts AW, Ma S, Brander DM et al. Determination of recommended phase 2 dose of ABT- 199 (GDC-0199) combined with Rituximab 9R) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL_. Blood 2014; Abstract 325
Stilgenbauer S, Eichhorst B, Schetelig J et al (2016) Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicenter, open-label, phase 2 study. Lancet Oncol 17(6):768–778
Chiron D, Di Liberto M, Martin P et al (2014) Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov 4(9):1022–1035
Porcu P, Flinn I, Kahl BS, et al. (2014) Clinical activity of duvelisib (IPI-145), a phosphoinositide-3-kinase d, y inhibitor in patients previously treated with ibrutinib. Blood 124(21): abstract 3335
Dong S, Guinn D, Dubovksy JA et al (2014) IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood 124(24):3583–3586
Hing ZA, Mantel R, Beckwith KA et al (2015) Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic lymphoma. Blood 125(20):3128–3132
Hing ZA, Fung HY, Ranganathan P et al (2016) Next generation XOP1 inhibitor shows improved efficacy and invivo tolerability in hematologic malignancies. Leukemia 30(12):2364–2372
Thijssen R, Burg J, Garrick B et al (2016) Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood 128(4):574–583
Kuo H, Crowley R, Xue L, et al. (2014) Combination of ibrutinib and BCL-2 or SYK inhibitors in ibrutinib resistant ABC-subtype of diffuse large B-cell lymphoma. Blood 124(21): abstract 505
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Funding
This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Additional information
This manuscript was prepared for exclusive consideration of Annals of Hematology
Rights and permissions
About this article
Cite this article
Kaur, V., Swami, A. Ibrutinib in CLL: a focus on adverse events, resistance, and novel approaches beyond ibrutinib. Ann Hematol 96, 1175–1184 (2017). https://doi.org/10.1007/s00277-017-2973-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-017-2973-2