B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292

Jon E Arnason, Jennifer R Brown, Jon E Arnason, Jennifer R Brown

Abstract

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. The current treatment paradigm involves the use of chemoimmunotherapy, when patients develop an indication for therapy. With this strategy, a majority of patients will obtain a remission, though cure remains elusive. While treatable, the majority of CLL patients will die of complications of their disease. Recent advances in the understanding of the importance of the B cell receptor (BCR) pathway in CLL have led to the development of a number of agents targeting this pathway. In this review, we discuss recent developments in the targeting of the BCR pathway, with a focus on CC-292. CC-292 covalently binds to Bruton's tyrosine kinase, a key mediator of BCR signaling, and has demonstrated preclinical and clinical activity in CLL, with acceptable tolerability. Based on the success of CC-292 and other inhibitors of the BCR pathway, these agents are being investigated in combination with standard therapy, with the hope that they will increase the depth and length of response, without significant toxicity.

Keywords: Bruton’s tyrosine kinase inhibitor; ibrutinib.

Figures

Figure 1
Figure 1
Antigenic stimulation of the BCR recruits CD79a and CD79b, and activates SYK and LYN kinase, resulting in the phosphorylation of cytoplasmic ITAMs on the immunoglobulin domains of the receptor. The ITAM phosphorylation begins a cascade of activation involving BTK and PI3K. Activated BTK promotes the downstream release of intracellular Ca2+ stores and propagation of the BCR signal, resulting in increased proliferation, survival, and avoidance of apoptosis, mediated by the upregulation of transcription factors, including NF-κB. Abbreviations: BCR, B cell receptor signaling pathway; BTK, Bruton’s tyrosine kinase; CD, cluster of differentiation; ITAM, immunoreceptor tyrosine-based activation motif; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; PI3K, phosphoinositide 3′-kinase; PLCγ2, phospholipase C gamma 2; SYK, spleen tyrosine kinase.
Figure 2
Figure 2
The BCR pathway has been targeted in CLL, at multiple different sites. Abbreviations: BCR, B cell receptor signaling pathway; BTK, Bruton’s tyrosine kinase; CD, cluster of differentiation; CLL, chronic lymphocytic leukemia; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3′-kinase; PLCγ2, phospholipase C gamma 2; SYK, spleen tyrosine kinase; NF-κB, nuclear factor-kappa B.

References

    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30.
    1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804–815.
    1. Hallek M, Cheson BD, Catovsky D, et al. International Workshop on Chronic Lymphocytic Leukemia 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(12):5446–5456.
    1. Hallek M, Fischer K, Fingerle-Rowson G, et al. International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164–1174.
    1. Tam CS, O’Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975–980.
    1. Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011;29(26):3559–3566.
    1. Kater AP, van Oers MHJ, Kipps TJ. Cellular immune therapy for chronic lymphocytic leukemia. Blood. 2007;110(8):2811–2818.
    1. Bernal A, Pastore RD, Asgary Z, et al. Survival of leukemic B cells promoted by engagement of the antigen receptor. Blood. 2001;98(10):3050–3057.
    1. Genevier HC, Hinshelwood S, Gaspar HB, et al. Expression of Bruton’s tyrosine kinase protein within the B cell lineage. Eur J Immunol. 1994;24(12):3100–3105.
    1. Hendriks RW, Bredius RG, Pike-Overzet K, Staal FJ. Biology and novel treatment options for XLA, the most common monogenetic immunodeficiency in man. Expert Opin Ther Targets. 2011;15(8):1003–1021.
    1. Mohamed AJ, Yu L, Bäckesjö CM, et al. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009;228(1):58–73.
    1. Dühren-von Minden M, Übelhart R, Schneider D, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature. 2012;489(7415):309–312.
    1. Chiorazzi N, Efremov DG. Chronic lymphocytic leukemia: a tale of one or two signals? Cell Res. 2013;23(2):182–185.
    1. Lanemo Myhrinder A, Hellqvist E, Sidorova E, et al. A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies. Blood. 2008;111(7):3838–3848.
    1. Catera R, Silverman GJ, Hatzi K, et al. Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and oxidation. Mol Med. 2008;14(11–12):665–674.
    1. Chu CC, Catera R, Zhang L, et al. Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. Blood. 2010;115(19):3907–3915.
    1. Messmer BT, Albesiano E, Efremov DG, et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med. 2004;200(4):519–525.
    1. Agathangelidis A, Darzentas N, Hadzidimitriou A, et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012;119(19):4467–4475.
    1. 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(11):2590–2594.
    1. de Gorter DJ, Beuling EA, Kersseboom R, et al. Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26(1):93–104.
    1. 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(23):6287–6296.
    1. 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(29):13075–13080.
    1. Ponader S, Chen SS, Buggy JJ, 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):1182–1189.
    1. 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(1):88–94.
    1. M.D. Anderson Cancer Center Phase 2 Study of the Combination of Bruton’s Tyrosine Kinase Inhibitor PCI-32765 and Rituximab in High-Risk Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients. [Accessed November 26, 2013]. Available from: . NLM identifier: NCT01520519.
    1. National Cancer Institute (NCI) Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma. [Accessed November 26, 2013]. Available from: . NLM identifier: NCT01886859.
    1. Janssen Research and Development, LLC A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma. [Accessed November 26, 2013]. Available from: . NLM identifier: NCT01611090.
    1. Brown J, Barrientos J, Flinn I, et al. The Bruton’s Tyrosine Kinase (BTK) inhibitor ibrutinib combined with bendamustine and rituximab is active and tolerable in patients with relapsed/refractory CLL, interim results of a phase Ib/II study. Program and abstracts of the 17th Congress of the European Hematology Association; June 14–17, 2012; Amsterdam, The Netherlands. Abstract 0543.
    1. Pharmacyclics Efficacy and Safety Study of PCI-32765 Combine With Ofatumumab in CLL (PCYC-1109-CA) [Accessed November 26, 2013]. Available from: . NLM identifier: NCT01217749.
    1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.
    1. Chang BY, Furman RR, Zapatka M, et al. Use of tumor genomic profiling to reveal mechanisms of resistance to the BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL). Program and abstracts of the ASCO Annual Meeting; November 1–2, 2013; San Diego, CA. Abstract 7014.
    1. Herishanu Y, Pérez-Galán P, Liu D, 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):563–574.
    1. 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(23):2820–2822.
    1. Hallek M, Cheson BD, Catovsky D, et al. Response assessment in chronic lymphocytic leukemia treated with novel agents causing an increase of peripheral blood lymphocytes. Blood. 2012
    1. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078–2088.
    1. Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110 delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591–594.
    1. Brown JR, Furman RR, Flinn I, et al. Final results of a phase I study of idelalisib (GS-1101) a selective inhibitor of PI3Kδ, in patients with relapsed or refractory CLL. Program and abstracts of the 2013 ASCO Annual Meeting; November 1–2, 2013; San Diego, CA; Abstract 7003.
    1. Coutre SE, Leonard JP, Furman RR, et al. Combinations of the selective phosphatidylinositol 3-kinase-delta (PI3K delta) inhibitor GS-1101 (CAL-101) with rituximab and/or bendamustine are tolerable and highly active in patients with relapsed or refractory chronic lymphocytic leukemia (CLL): Results From a Phase I Study. Program and abstracts of the 54th ASH Annual Meeting and Exposition; December 7–11, 2012; Atlanta, GA. Abstract 191.
    1. Gilead Sciences A Randomized, Double-Blind and Placebo-Controlled Study of Idelalisib in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia (CLL) [Accessed November 26, 2013]. Available from: . NLM identifier: NCT01539512.
    1. Gilead Sciences A Randomized, Double-Blind and Placebo-Controlled Study of Idelalisib in Combination With Bendamustine and Rituximab for Previously Treated Chronic Lymphocytic Leukemia (CLL) [Accessed November 26, 2013]. Available from: . NLM identifier: NCT01569295.
    1. Papadopoulos KP, Abrisqueta P, Chambers G, et al. A Phase I dose expansion cohort study of the safety, pharmacokinetics and pharmacodynamics of SAR245409 (S09), an orally administered PI3K/mTOR Inhibitor, in patients with lymphoma. Program and abstracts of the 53rd ASH Annual Meeting and Exposition; December 10–13, 2011; San Diego, CA.
    1. Flinn IW, Horwitz SM, Patel M, et al. Clinical safety and activity in a Phase 1 trial of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with advanced hematologic malignancies. Program and abstracts of the 54th ASH Annual Meeting and Exposition; December 7–11, 2012; Atlanta, GA. Abstract 3663.
    1. Contri A, Brunati AM, Trentin L, et al. Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest. 2005;115(2):369–378.
    1. Amrein PC, Attar EC, Takvorian T, et al. Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res. 2011;17(9):2977–2986.
    1. Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115(13):2578–2585.
    1. Zent CS, LaPlant BR, Johnston PB, et al. The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer. 2010;116(9):2201–2207.
    1. Evans EK, Tester R, Aslanian S, et al. Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans. J Pharmacol Exp Ther. 2013;346(2):219–228.
    1. Karp R, Evans E, Aslanian S, et al. Inhibition of BTK with AVL- 292 translates to protective activity in rodent models of rheumatoid arthritis. Program and abstracts of the Inflammation Research Association Sixteenth International Conference; September 26–29, 2010; Chantilly, VA. Abstract A113.
    1. Evans E, Ponader S, Karp R, et al. AVL-292: A targeted therapy for Bruton’s tyrosine kinase in B cell malignancies. Poster presented at: the 16th Congress of the European Hematology Association; June 9–12, 2011; London, UK.
    1. Brown JR, Harb WA, Sharman JP, et al. Phase 1 study of single agent CC-292, a highly selective Bruton’s tyrosine kinase inhibitor (BTK), in relapsed/refractory chronic lymphocytic leukemia (CLL). Program and abstracts of the 15th International Workshop on CLL (IWCLL); September 9–11, 2013; Cologne, Germany. Abstract.
    1. Celgene Corporation Safety Study of CC-292 and Lenalidomide in Subjects With Chronic Lymphocytic Leukemia/Small Lympho-cytic Lymphoma. [Accessed November 26, 2013]. Available from: . NLM identifier: NCT01732861.
    1. Celgene Corporation Safety Study of CC-292 and Rituximab in Subjects With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. [Accessed November 26, 2013]. Available from: . NLM identifier: NCT01744626.
    1. Pierce DW, Heise C, Nacht M, et al. Preclinical and phase 1 translational studies of CC-292, a potent and selective inhibitor of Bruton’s tyrosine kinase, in CLL patients. Program and abstracts of the 15th International Workshop on CLL (IWCLL); September 9–11, 2013; Cologne, Germany. Abstract 4.31.
    1. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539–2549.
    1. 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):2596–2603.
    1. Rushworth SA, MacEwan DJ, Bowles KM. Ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(13):1277–1278.

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