Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses

References

• SEER stat fact sheets: Chronic lymphocytic leukemia (CLL) [Internet]. 2016 [ cited2016 May 17]. Available from: http://seer.cancer.gov/statfacts/html/clyl.html
   Google Scholar
• Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120:1175–1184.
   PubMed Web of Science ®Google Scholar
• Del Gaizo Moore V, Brown JR, Certo M, et al. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007;117:112–121. .
   PubMed Web of Science ®Google Scholar
• Byrd JC, Jones JJ, Woyach JA, et al. Entering the era of targeted therapy for chronic lymphocytic leukemia: Impact on the practicing clinician. J Clin Oncol. 2014;32:3039–3047.
   PubMed Web of Science ®Google Scholar
• Jain N, O’Brien S. Initial treatment of CLL: integrating biology and functional status. Blood. 2015;126:463–470.
   PubMed Web of Science ®Google Scholar
• Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–2437.
   PubMed Web of Science ®Google Scholar
• de Claro RA, McGinn KM, Verdun N, et al. FDA approval: ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2015;21:3586–3590.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–223.
   PubMed Web of Science ®Google Scholar
• 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;16:169–176.
   PubMed Web of Science ®Google Scholar
• O’Brien S, Jones JA, Coutre S, et al. Efficacy and safety of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia with 17p deletion: Results from the phase II RESONATE™-17 trial. Blood. 2014;124:327.
   Web of Science ®Google Scholar
• 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. Haematologica. 2016; pii:haematol.2016.144576. [Epub ahead of print].
   PubMedGoogle Scholar
• Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323–332.
   PubMed Web of Science ®Google Scholar
• 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;127:411–419.
   PubMed Web of Science ®Google Scholar
• Tam C, Grigg AP, Opat S, et al. The BTK inhibitor, bgb-3111, is safe, tolerable, and highly active in patients with relapsed/refractory B-cell malignancies: Initial report of a phase 1 first-in-human trial. Blood. 2015;126:832.
   Web of Science ®Google Scholar
• Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997–1007.
   PubMed Web of Science ®Google Scholar
• Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101–1110.
   PubMed Web of Science ®Google Scholar
• Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–208.
   PubMed Web of Science ®Google Scholar
• Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–322.
   PubMed Web of Science ®Google Scholar
• Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: A multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:768–778.
   PubMed Web of Science ®Google Scholar
• Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide and rituximab achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303–309.
   Google Scholar
• Strati P, Keating MJ, O’Brien SM, et al. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood. 2014;123:3727–3732.
   PubMed Web of Science ®Google Scholar
• Benjamini O, Jain P, Trinh L, et al. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: Distribution and clinical outcomes. Leuk Lymphoma. 2015;56:1643–1650.
   PubMed Web of Science ®Google Scholar
• Guo A, Lu P, Galanina N, et al. Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib. Oncotarget. 2016;7:4598–4610.
   PubMed Web of Science ®Google Scholar
• 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;125:2497–2506.
   PubMed Web of Science ®Google Scholar
• Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–2294.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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;121:3612–3621.
   PubMed Web of Science ®Google Scholar
• Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015;21:3705–3715.
   PubMed Web of Science ®Google Scholar
• McMullen JR, Boey EJ, Ooi JY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-akt signaling. Blood. 2014;124:3829–3830.
   PubMed Web of Science ®Google Scholar
• Alberelli MA, Innocenti I, Sica S, et al. PO-54 - clinical and laboratory characterization of platelet dysfunction caused by ibrutinib treatment in patients with chronic lymphocytic leukemia. Thromb Res. 2016;140(Suppl 1):S196,3848(16)30187-6. Epub 2016 Apr 8.
   PubMed Web of Science ®Google Scholar
• Levade M, David E, Garcia C, et al. Ibrutinib treatment affects collagen and von willebrand factor-dependent platelet functions. Blood. 2014;124:3991–3995.
   PubMed Web of Science ®Google Scholar
• Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29:783–787.
   PubMed Web of Science ®Google Scholar
• Gao W, Wang M, Wang L, et al. Selective antitumor activity of ibrutinib in EGFR-mutant non-small cell lung cancer cells. J Natl Cancer Inst. 2014:106. Print 2014 Sep. DOI:10.1093/jnci/dju204
   Google Scholar
• 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;122:2539–2549.
   PubMed Web of Science ®Google Scholar
• 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;107:13075–13080.
   PubMed Web of Science ®Google Scholar
• Berglof A, Hamasy A, Meinke S, et al. Targets for ibrutinib beyond B cell malignancies. Scand J Immunol. 2015;82:208–217.
   PubMed Web of Science ®Google Scholar
• Jain N, Chen Q, Ayer T, et al. Prevalence and economic burden of CLL in the era of oral targeted therapies. Blood. 2015;126:871.
   Web of Science ®Google Scholar
• Shanafelt TD, Borah BJ, Finnes HD, et al. Impact of ibrutinib and idelalisib on the pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal levels. J Oncol Pract. 2015;11:252–258.
   PubMed Web of Science ®Google Scholar
• Cancer drugs fund decision summary: ibrutinib for the treatment of relapsed or refractory chronic lymphatic leukaemia [Internet]; 2015 [ cited 2015 Jan]. Available from: https://www.england.nhs.uk/wp-content/uploads/2015/01/ncdf-summ-ibrutnb-relps-rfract-cll.pdf
   Google Scholar
• Ibrutinib for treating chronic lymphocytic leukaemia. NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE [Internet]. 2016 [cited 2016 May]. Available from: https://www.nice.org.uk/guidance/GID-TAG492/documents/appraisal-consultation-document
   Google Scholar
• NICE asks company to put leukaemia drug forward for new cancer drugs fund. National Institute for Health and Care Excellence [Internet]. 2016 [cited 2016 Jun 1]. Available from: https://www.nice.org.uk/news/press-and-media/nice-asks-company-to-put-leukaemia-drug-forward-for-new-cancer-drugs-fund
   Google Scholar
• Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507–516.
   PubMed Web of Science ®Google Scholar
• Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated waldenstrom’s macroglobulinemia. N Engl J Med. 2015;372:1430–1440.
   PubMed Web of Science ®Google Scholar
• Davids MS, Brown JR. Ibrutinib: a first in class covalent inhibitor of bruton’s tyrosine kinase. Future Oncol. 2014;10:957–967.
   PubMed Web of Science ®Google Scholar
• Ponader S, Burger JA. Bruton’s tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies. J Clin Oncol. 2014;32:1830–1839.
   PubMed Web of Science ®Google Scholar
• Woyach JA, Bojnik E, Ruppert AS, et al. Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123:1207–1213.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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;117:6287–6296.
   PubMed Web of Science ®Google Scholar
• Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123:3286–3295.
   PubMed Web of Science ®Google Scholar
• Herman SE, Sun X, McAuley EM, et al. Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Leukemia. 2013;27:2311–2321.
   PubMed Web of Science ®Google Scholar
• 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;119:1182–1189.
   PubMed Web of Science ®Google Scholar
• Dubovsky JA, Chappell DL, Harrington BK, et al. Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing. Blood. 2013;122:3308–3316.
   PubMed Web of Science ®Google Scholar
• Patrussi L, Capitani N, Martini V, et al. Enhanced chemokine receptor recycling and impaired S1P1 expression promote leukemic cell infiltration of lymph nodes in chronic lymphocytic leukemia. Cancer Res. 2015;75:4153–4163.
   PubMed Web of Science ®Google Scholar
• 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;119:2590–2594.
   PubMed Web of Science ®Google Scholar
• ten Hacken E, Burger JA. Molecular pathways: targeting the microenvironment in chronic lymphocytic leukemia–focus on the B-cell receptor. Clin Cancer Res. 2014;20:548–556.
   PubMed Web of Science ®Google Scholar
• Herman SE, Mustafa RZ, Jones J, et al. Treatment with ibrutinib inhibits BTK- and VLA-4-dependent adhesion of chronic lymphocytic leukemia cells in vivo. Clin Cancer Res. 2015;21:4642–4651.
   PubMed Web of Science ®Google Scholar
• Chen SS, Chang BY, Chang S, et al. BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia.. Leukemia. 2016;30(4):833–843.
   Web of Science ®Google Scholar
• Burger JA, Buggy JJ. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765). Leuk Lymphoma. 2013;54:2385–2391.
   PubMed Web of Science ®Google Scholar
• 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;28:2188–2196.
   PubMed Web of Science ®Google Scholar
• Wodarz D, Garg N, Komarova NL, et al. Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib. Blood. 2014;123:4132–4135.
   PubMed Web of Science ®Google Scholar
• 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;123:1810–1817.
   PubMed Web of Science ®Google Scholar
• Sagiv-Barfi I, Kohrt HE, Czerwinski DK, et al. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U S A. 2015;112:E966–72.
   PubMed Web of Science ®Google Scholar
• Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123:1957–1960.
   PubMed Web of Science ®Google Scholar
• Duong MN, Matera EL, Mathe D, et al. Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies. MAbs. 2015;7:192–198.
   PubMed Web of Science ®Google Scholar
• Borge M, Belen Almejun M, Podaza E, et al. Ibrutinib impairs the phagocytosis of rituximab-coated leukemic cells from chronic lymphocytic leukemia patients by human macrophages. Haematologica. 2015;100:e140–2.
   PubMed Web of Science ®Google Scholar
• Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014;15:1090–1099.
   PubMed Web of Science ®Google Scholar
• Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015;126:842–850.
   PubMed Web of Science ®Google Scholar
• Skarzynski M, Niemann CU, Lee YS, et al. Interactions between ibrutinib and anti-CD20 antibodies: competing effects on the outcome of combination therapy. Clin Cancer Res. 2016;22(1):86–95.
   PubMed Web of Science ®Google Scholar
• Niemann CU, Herman SE, Maric I, et al. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib - findings from an investigator-initiated phase II study. Clin Cancer Res. 2016;22:1572–1582.
   PubMed Web of Science ®Google Scholar
• IMBRUVICA prescribing information. U.S. Food and Drug Administration [Internet]. 2016 [2016 5]. Available from: http://www.imbruvica.com/docs/librariesprovider3/default-document-library/prescribing_information.pdf?sfvrsn=14
   Google Scholar
• de Jong J, Sukbuntherng J, Skee D, et al. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia. Cancer Chemother Pharmacol. 2015;75:907–916.
   PubMed Web of Science ®Google Scholar
• 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;75:111–121.
   PubMed Web of Science ®Google Scholar
• de Jong J, Skee D, Murphy J, et al. Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants. Pharmacol Res Perspect. 2015;3:e00156.
   PubMed Web of Science ®Google Scholar
• Scheers E, Leclercq L, de Jong J, et al. Absorption, metabolism, and excretion of oral 14C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men. Drug Metab Dispos. 2015;43:289–297.
   PubMed Web of Science ®Google Scholar
• Tobinai K, Ogura M, Ishizawa K, et al. Safety and tolerability of ibrutinib monotherapy in japanese patients with relapsed/refractory B cell malignancies. Int J Hematol. 2016;103:86–94.
   PubMed Web of Science ®Google Scholar
• Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125:2062–2067.
   PubMed Web of Science ®Google Scholar
• Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80–87.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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;17:200–211.
   PubMed Web of Science ®Google Scholar
• Sun C, Tian X, Lee YS, et al. Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood. 2015;126:2213–2219.
   PubMed Web of Science ®Google Scholar
• Oda A, Ikeda Y, Ochs HD, et al. Rapid tyrosine phosphorylation and activation of bruton’s tyrosine/Tec kinases in platelets induced by collagen binding or CD32 cross-linking. Blood. 2000;95:1663–1670.
   PubMed Web of Science ®Google Scholar
• Atkinson BT, Ellmeier W, Watson SP. Tec regulates platelet activation by GPVI in the absence of btk. Blood. 2003;102:3592–3599.
   PubMed Web of Science ®Google Scholar
• Liu J, Fitzgerald ME, Berndt MC, et al. Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo. Blood. 2006;108:2596–2603.
   PubMed Web of Science ®Google Scholar
• Lipsky AH, Farooqui MZ, Tian X, et al. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib. Haematologica. 2015;100:1571–1578.
   PubMed Web of Science ®Google Scholar
• Shinohara M, Koga T, Okamoto K, et al. Tyrosine kinases btk and tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell. 2008;132:794–806.
   PubMed Web of Science ®Google Scholar
• Fabbro SK, Smith SM, Dubovsky JA, et al. Panniculitis in patients undergoing treatment with the bruton tyrosine kinase inhibitor ibrutinib for lymphoid leukemias. JAMA Oncol. 2015;1:684–686.
   PubMedGoogle Scholar
• Mulvey JJ, Nuovo GJ, Magro CM. Cutaneous, purpuric painful nodules upon addition of ibrutinib to RCVP therapy in a CLL patient: A distinctive reaction pattern reflecting iatrogenic Th2 to Th1 milieu reversal. Am J Dermatopathol. 2016;38:492–498.
   PubMed Web of Science ®Google Scholar
• Bitar C, Farooqui MZ, Valdez J, et al. Hair and nail changes during long-term therapy with ibrutinib for chronic lymphocytic leukemia. JAMA Dermatol. 2016;152:698.
   PubMed Web of Science ®Google Scholar
• Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: Working toward cure for patients with CLL. Blood. 2016;127:279–286.
   PubMed Web of Science ®Google Scholar
• Davids MS. Boldly targeting kinases without mutations. Blood. 2014;123:1119–1121.
   PubMed Web of Science ®Google Scholar
• Lamothe B, Cervantes-Gomez F, Sivina M, et al. Proteasome inhibitor carfilzomib complements ibrutinib’s action in chronic lymphocytic leukemia. Blood. 2015;125:407–410.
   PubMed Web of Science ®Google Scholar
• Woyach JA, Johnson AJ. Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood. 2015;126:471–477.
   PubMed Web of Science ®Google Scholar
• Hing ZA, Mantel R, Beckwith KA, et al. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Blood. 2015;125:3128–3132.
   PubMed Web of Science ®Google Scholar
• Patel V, Keating MJ, Wierda WG, et al. Preclinical combination of TP-0903, an AXL inhibitor and B-PAC-1, a procaspase-activating compound with ibrutinib in chronic lymphocytic leukemia. Leuk Lymphoma. 2016;57:1494–1497.
   PubMed Web of Science ®Google Scholar
• Experts in chronic myeloid leukemia. Price of drugs for chronic myeloid leukemia (CML), reflection of the unsustainable cancer drug prices: perspective of CML experts. Blood. 2013;121:4439–4442.
   PubMed Web of Science ®Google Scholar
• Nisitani S, Satterthwaite AB, Akashi K, et al. Posttranscriptional regulation of bruton’s tyrosine kinase expression in antigen receptor-stimulated splenic B cells. Proc Natl Acad Sci U S A. 2000;97:2737–2742.
   PubMed Web of Science ®Google Scholar
• Cervantes-Gomez F, Kumar Patel V, Bose P, et al. Decrease in total protein level of bruton’s tyrosine kinase during ibrutinib therapy in chronic lymphocytic leukemia lymphocytes. Leukemia. 2016;30:1803–1804.
   PubMed Web of Science ®Google Scholar
• Bajpai UD, Zhang K, Teutsch M, et al. Bruton’s tyrosine kinase links the B cell receptor to nuclear factor kappaB activation. J Exp Med. 2000;191:1735–1744.
   PubMed Web of Science ®Google Scholar
• Petro JB, Rahman SM, Ballard DW, et al. Bruton’s tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. J Exp Med. 2000;191:1745–1754.
   PubMed Web of Science ®Google Scholar
• Lee KG, Xu S, Wong ET, et al. Bruton’s tyrosine kinase separately regulates NFkappaB p65RelA activation and cytokine interleukin (IL)-10/IL-12 production in TLR9-stimulated B cells. J Biol Chem. 2008;283:11189–11198.
   PubMed Web of Science ®Google Scholar
• Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–436.
   PubMed Web of Science ®Google Scholar