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Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies
Open accessAbstract
Purpose: Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients and Methods: Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Results: Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Conclusion: Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.
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“The rapid clearance of ibrutinib (which has a half-life of 2–3 h) could also enable kinase selectivity; ibrutinib should maintain activity against BTK owing to prolonged covalent engagement, while the reversible inhibition of off-targets is minimized65.”
From Advances in covalent drug discovery (2022) · cites this paper as [65]
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BackgroundInfluentialHCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib
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“2%), and overall response (OR) rate was 60%, with responses observed in patients with MCL, follicular lymphoma (FL), DLCL, marginal zone lymphoma (MZL), and Waldenstrom macroglobulinemia.(3) Median progression-free survival (PFS) was 13.”
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“The initial development at Celera and subsequently at Pharmacyclics was focused on RA and, consequently, ibrutinib initially was tested in RA using in vivo models.9,72 The in vivo activity of ibrutinib in B-cell lymphoma was first demonstrated in spontaneous canine B-cell lymphomas.9 The most mature clinical data abou…”
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“5 INTRODUCTION 76 Ibrutinib is an oral, once-daily inhibitor of Bruton’s tyrosine kinase, an essential enzyme in the B-cell 77 receptor signaling pathway [1-3].”
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“A phase I study of ibrutinib in relapsed B-cell malignancies was initiated, where durable clinical activity was noted in nine of 16 patients with CLL or SLL.56 Notable among these patients with CLL receiving ibrutinib was early lymphocytosis, which now is recognized to be a class effect of all BCR antagonists.”
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“Several clinical trials have shown that single-agent ibrutinib is well tolerated and can induce objective clinical responses in CLL; including in patients with high risk disease features (12-14).”
Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies
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B lymphocytes can be activated to act as antigen presenting cells to promote anti-tumor responses
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Bruton’s tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis
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“Prior studies have shown that a single FDA-approved oral dose of ibrutinib or acalabrutinib achieves nearly 100% BTK occupancy in peripheral blood mononuclear cells within just 3–4 hours (14, 35).”
BackgroundZanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up
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“We found that the concentration-dependent component of the inhibition curves covered the range of peak serum concentrations measured clinically in patients receiving 560 mg ibrutinib daily (mean, 300 nmol/L).(12) This suggests that variability in plasma concentration may cause large differences in platelet inhibition…”
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“With up to 45 months of ibrutinib treatment, the safety profile of single-agent ibrutinib remained consistent with observations during the primary analysis of this study and with published data on ibrutinib in previously treated NHL and chronic lymphocytic leukemia.(23,36,37) With an additional 14 months of follow-up…”
ResultSelf-citationZanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma
Tam, C. S. L., Opat, S., Simpson, D., Cull, G., Munoz, J. L., Phillips, T. J., Kim, W. S., Rule, S. A., Atwal, S. K., Wei, R., et al. (2021) · Blood Advances · doi:10.1182/bloodadvances.2020004074 · Cited by 105
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“Antigen stimulation of normal B cells triggers dimerization of BCR initiating a downstream signaling kinase cascade, which in turn regulates multiple cellular processes, including proliferation, differentiation, apoptosis, and survival (Fuentes-Panana et al. 2004; Advani et al. 2013).”
BackgroundSelf-citationKinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib
Wodarz, D., Garg, N., Komarova, N. L., Benjamini, O., Keating, M. J., Wierda, W. G., Kantarjian, H. M., James, D. F., O'Brien, S. M., & Burger, J. A. (2014) · Blood · doi:10.1182/blood-2014-02-554220 · Cited by 107
“Afterweeks tomonths of continuous ibrutinib therapy, normalization of lymphocyte counts and remission is observed in the majority of patients.(3,4,6) Although well-documented, a quantitative understanding of the redistribution phenomenon is still lacking, and it is debated whether the degree of tissue shrinkage accoun…”
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Bruton’s Tyrosine Kinase (BTK) Inhibitors in Clinical Trials
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“Interference with migration and adhesion of CLL and MCL cells appears to be the basis for the characteristic redistribution of tissue-resident leukemia/lymphoma cells typically seen in CLL [19, 43] and MCL [19, 42] patients during the first weeks of treatment.”
BackgroundInfluentialA pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia
Chen, L. S., Bose, P., Cruz, N. D., Jiang, Y., Wu, Q., Thompson, P. A., Feng, S., Kroll, M. H., Qiao, W., Huang, X., et al. (2018) · Blood · doi:10.1182/blood-2018-06-860593 · Cited by 105
Selective Antitumor Activity of Ibrutinib in EGFR-Mutant Non–Small Cell Lung Cancer Cells
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“In addition, constitutive activation of BTK is an essential feature of B cell proliferation in chronic lymphocytic leukemia (CLL), and this characteristic of CLL has been successfully used in the treatment of this B cell leukemia with anti-BTK agents such as ibrutinib (22, 35).”
BackgroundYun, S., Vincelette, N. D., Acharya, U. H., & Abraham, I. L. (2016) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2016.09.010 · Cited by 100
Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease
von Hundelshausen, P., & Siess, W. (2021) · Cancers · doi:10.3390/cancers13051103 · Cited by 100
“Due to its low bioavailability, high doses (420 mg/560 mg daily) of ibrutinib are required to achieve effective Btk target occupancy [75].”
BackgroundMethodInfluentialProteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors
Niessen, S., Dix, M. M., Barbas, S., Potter, Z. E., Lu, S., Brodsky, O., Planken, S., Behenna, D. C., Almaden, C., Gajiwala, K. S., et al. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.08.017 · Cited by 99
“…have been used, for instance, to: i) provide target engagement assays for measuring the fraction of inhibited kinase in native biological systems (Advani et al., 2013), ii) identify targets and off-targets of covalent kinase inhibitors in human cells and to correlate these profiles with…”
MethodThe tumor microenvironment shapes hallmarks of mature B-cell malignancies
Shain, K. H., Dalton, W. S., & Tao, J. (2015) · Oncogene · doi:10.1038/onc.2014.403 · Cited by 104
Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)
Komarova, N. L., Burger, J. A., & Wodarz, D. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409362111 · Cited by 98
“Early-stage clinical trials found ibrutinib to be particularly active in patients with CLL (6, 7) and mantle cell lymphoma (8), and the drug recently has been Food and Drug Administration-approved for patients with relapsed CLL and mantle cell lymphoma.”
BackgroundX-Linked Immunodeficient Mice Exhibit Enhanced Susceptibility to Cryptococcus neoformans Infection
Szymczak, W. A., Davis, M. J., Lundy, S. K., Dufaud, C. R., Olszewski, M. A., & Pirofski, L. (2013) · mBio · doi:10.1128/mbio.00265-13 · Cited by 98
Owen, C., Berinstein, N. L., Christofides, A., & Sehn, L. H. (2019) · Current Oncology · doi:10.3747/co.26.4345 · Cited by 101
Chao, M. P. (2013) · Cancer Management and Research · doi:10.2147/cmar.s34273 · Cited by 97
“Interestingly, CLL and MCL patients had a strong response rate (79% and 75%, respectively), while FL and DLBCL patients had a poor response (23% and 17%, respectively) (Table 2).(77) Additionally, CLL patients noted rapid shrinkage of lymph nodes and marked lymphocytosis, which is thought to mark malignant cell egress…”
Keaney, J., Gasser, J., Gillet, G., Scholz, D., & Kadiu, I. (2019) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-019-09839-0 · Cited by 98
“ibrutinib has also shown therapeutic efficacy in B cell malignancies associated with dysfunctional BCR signaling including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) (Advani et al. 2013; Hendriks et al. 2014).”
BackgroundMethodInfluentialBurger, J. A., Li, K. W., Keating, M. J., Sivina, M., Amer, A. M., Garg, N., Ferrajoli, A., Huang, X., Kantarjian, H. M., Wierda, W. G., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.89904 · Cited by 98
“In addition, the significant transient increase in CLL cell counts in the peripheral blood (1) can be reversed by treatment interruption (8).”
BackgroundCortelazzo, S., Ponzoni, M., Ferreri, A. J. M., & Dreyling, M. H. (2011) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2011.05.001 · Cited by 97
Ibrutinib: A Review in Chronic Lymphocytic Leukaemia
Deeks, E. D. (2017) · Drugs · doi:10.1007/s40265-017-0695-3 · Cited by 96
“Lymphocytosis is usually accompanied by reductions in lymphadenopathy [12] and is likely a reflection of tumour cells moving from infiltrated tissues to the blood [7, 14, 35].”
BackgroundMedicinal attributes of pyridine scaffold as anticancer targeting agents
Mohamed, E. A., Ismail, N. S. M., Hagras, M., & Refaat, H. M. (2021) · Future Journal of Pharmaceutical Sciences · doi:10.1186/s43094-020-00165-4 · Cited by 93
“For AEE-788, an association between hydrogen bonds between N- and Thr854, bridged water was observed through water molecules [26].”
BackgroundIbrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth
Chen, J., Kinoshita, T., Sukbuntherng, J., Chang, B. Y., & Elias, L. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0923 · Cited by 93
“Pharmacokinetics in humans has been well studied (3, 29), and our results in these tumor models compare well with the ranges noted clinically: in the phase I study, a MTD was not established, but the highest well-tolerated dose tested was 12.”
BackgroundMethodResultInfluentialSelf-citationWiestner, A. U. (2015) · Haematologica · doi:10.3324/haematol.2014.119123 · Cited by 92
Characterization of ibrutinib-sensitive and -resistant mantle lymphoma cells
Ma, J., Lu, P., Guo, A., Cheng, S., Zong, H., Martin, P., Coleman, M., & Wang, Y. L. (2014) · British Journal of Haematology · doi:10.1111/bjh.12974 · Cited by 90
Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non‐Hodgkin lymphoma
Zhang, S. Y., Smith, S. M., Zhang, S. Y., & Wang, Y. L. (2015) · British Journal of Haematology · doi:10.1111/bjh.13427 · Cited by 91
“…I DE 16 9 PR, 2 CR (69) – – Byrd et al 2013 Ib/II Ibrutinib 420 mg/d PO 51 34 PR, 2 CR (71) 75% (26) 83% (26) Ibrutinib 840 mg/d PO 34 24 PR (71) MCL Advani et al 2013 I DE 9 4 PR, 3 CR (78) – – Wang et al 2013 II Ibrutinib 560 mg/d PO 111 52 PR, 23 CR (68) – 58% (18) DLCBL Advani et al 2013 I…”
InfluentialSelf-citationHow we manage follicular lymphoma
Hiddemann, W., & Cheson, B. D. (2014) · Leukemia · doi:10.1038/leu.2014.91 · Cited by 90
Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK
Kim, E., Hurtz, C., Koehrer, S., Wang, Z., Balasubramanian, S., Chang, B. Y., Müschen, M., Davis, R. E., & Burger, J. A. (2016) · Blood · doi:10.1182/blood-2016-06-722900 · Cited by 88
Self-citationO'Brien, S. M., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Sharman, J. P., Wierda, W. G., Jones, J. A., Zhao, W., et al. (2016) · Blood · doi:10.1182/blood.v128.22.233.233 · Cited by 88
Self-citationYu, J., Chen, L., Cui, B., Wu, C. C. N., Choi, M. Y., Chen, Y., Zhang, L., Rassenti, L. Z., Widhopf, G. F., & Kipps, T. J. (2016) · Leukemia · doi:10.1038/leu.2016.368 · Cited by 88
ten Hacken, E., & Burger, J. A. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0226 · Cited by 93
“Similar to patients receiving ibrutinib therapy (51, 61), patients receiving idelalisib show early lymphocytosis after treatment start, due to CLL cell redistribution from tissues into the blood.”
ResultHerman, S. E. M., Sun, E. X., McAuley, E. M., Hsieh, M. M., Pittaluga, S., Raffeld, M. A., Liu, D., Keyvanfar, K., Chapman, C. M., Chen, J., et al. (2013) · Leukemia · doi:10.1038/leu.2013.131 · Cited by 84
Self-citationByrd, J. C., Smith, S. D., Wagner‐Johnston, N. D., Sharman, J. P., Chen, A. I., Advani, R. H., Augustson, B. M., Marlton, P. V., Commerford, S. R., Okrah, K., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.24310 · Cited by 84
“The early 1990’s brought forth the first broadly applicable noncytotoxic monoclonal antibody therapy, rituximab, where research over the next decade would demonstrate its value across virtually all B-cell malignancies either as monotherapy or in combination with chemotherapy [1, 2].”
BackgroundSelf-citationPPAR-alpha is a therapeutic target for chronic lymphocytic leukemia
Spaner, D., Lee, E., Shi, Y., Wen, F., Li, Y., Tung, S., McCaw, L., Wong, K. K. W., Gary‐Gouy, H., Dalloul, A. H., et al. (2012) · Leukemia · doi:10.1038/leu.2012.329 · Cited by 85
Skarzynski, M., Niemann, C. U., Lee, Y. S., Martyr, S. E., Marić, I., Salem, D., Stetler‐Stevenson, M., Marti, G. E., Calvo, K. R., Yuan, C. M., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1304 · Cited by 83
“org Clin Cancer Res; 22(1) January 1, 2016 91”
BackgroundInfluentialDrug-Target Residence Time Affects in Vivo Target Occupancy through Multiple Pathways
Lee, K. S. S., Yang, J., Niu, J., Ng, C., Wagner, K. M., Dong, H., Kodani, S. D., Wan, D., Morisseau, C. H. P., & Hammock, B. D. (2019) · ACS Central Science · doi:10.1021/acscentsci.9b00770 · Cited by 81
Myklebust, J. H., Brody, J., Kohrt, H. E. K., Kolstad, A., Czerwinski, D. K., Wälchli, S., Green, M. R., Trøen, G., Liestøl, K., Beiske, K., et al. (2016) · Blood · doi:10.1182/blood-2016-05-718494 · Cited by 84
B cells and their mediators as targets for therapy in solid tumors
Gunderson, A. J., & Coussens, L. M. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.03.005 · Cited by 80
“For example, ibrutinib, a small molecule inhibitor of Btk has shown efficacy in B-CLL/SLL [50] patients as well as in mouse models of cMyc-induced insulinoma [51]; thus, Btk (as well as Syk) inhibitors could also prove tractable for other cancers where B cells (and Btk or Syk signaling) contribute necessary mechanisms…”
Aalipour, A., & Advani, R. H. (2014) · Therapeutic Advances in Hematology · doi:10.1177/2040620714539906 · Cited by 84
Self-citationSivina, M., Kreitman, R. J., Arons, E., Ravandi, F., & Burger, J. A. (2014) · British Journal of Haematology · doi:10.1111/bjh.12867 · Cited by 79
Targeting Bruton’s Tyrosine Kinase in CLL
Ahn, I. E., & Brown, J. R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.687458 · Cited by 82
“Both of these doses achieve sustained and complete BTK occupancy (>95%) (26).”
BackgroundIbrutinib for B cell malignancies
Novero, A., Ravella, P. M., Chen, Y., Dous, G. V., & Liu, D. (2014) · Experimental Hematology and Oncology · doi:10.1186/2162-3619-3-4 · Cited by 80
“Chronic lymphocytic leukemia (CLL) A phase 1 dose escalation study of ibrutinib as a single agent enrolled 56 patients with relapsed/refractory B-cell malignancies, including non-Hodgkin’s lymphoma, CLL, and Waldenstrom’s macroglobulinemia [22,23].”
BackgroundChronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2015
Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N. L., Byrd, J. C., Czuczman, M. S., Fayad, L., et al. (2015) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2015.0045 · Cited by 78
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Self-citationEfremov, D. G., Turkalj, S., & Laurenti, L. (2020) · Cancers · doi:10.3390/cancers12061396 · Cited by 85
Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia.
Parmar, S., Patel, K., & Pinilla-Ibarz, J. A. (2014) · PubMed Central · Cited by 79
Vargas, L., Hamasy, A., Nore, B. F., & Smith, C. I. E. (2013) · Scandinavian Journal of Immunology · doi:10.1111/sji.12069 · Cited by 77
Qin, J., Johnstone, T. G., Baturevych, A., Hause, R. J., Ragan, S. P., Clouser, C. R., Jones, J. C., Ponce, R. A., Krejsa, C. M., Salmon, R. A., et al. (2020) · Journal of Immunotherapy · doi:10.1097/cji.0000000000000307 · Cited by 79
Clinical implications of food–drug interactions with small-molecule kinase inhibitors
Veerman, G., Hussaarts, K. G. A. M., Jansman, F. G. A., Koolen, S. L. W., van Leeuwen, R. W. F., & Mathijssen, R. H. J. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(20)30069-3 · Cited by 83
de Jong, J., Sukbuntherng, J., Skee, D. M., Murphy, J., O'Brien, S. M., Byrd, J. C., James, D. F., Hellemans, P., Loury, D. J., Jiao, J. J., et al. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2708-9 · Cited by 77
“In early studies, ibrutinib as a single agent demonstrated high response rates and durable efficacy in previously treated B cell malignancies [1, 2, 21].”
BackgroundSelf-citationOral administration of Bruton's tyrosine kinase inhibitors impairs GPVI-mediated platelet function
Rigg, R. A., Aslan, J. E., Healy, L. D., Wallisch, M., Thierheimer, M. L. D., Loren, C. P., Pang, J., Hinds, M. T., Gruber, A., & McCarty, O. J. T. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00325.2015 · Cited by 78
“In support of its role in B-cell receptor signaling, Btk has been found to be elevated in B-cell malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), and after several successful clinical trials, the covalent Btk inhibitor ibrutinib was recently approved by the US Food and Drug Admin…”
Background
Metadata
- Authors
- Advani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., Kolibaba, K. S., Furman, R. R., Rodriguez, S., Chang, B. Y., Sukbuntherng, J., Izumi, R., Hamdy, A., Hedrick, E., & Fowler, N. H.
- Affiliations
- University of Vermont (US)
- Corresponding author
- Advani, Ranjana H.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2013-01-01
- Volume
- 31
- Issue
- 1
- Pages
- 88-94
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC5505166
- OpenAlex
- W2171771895
- Cited by
- 1,128
- References
- 32
- Citations by year
- 2026: 17 · 2025: 38 · 2024: 47 · 2023: 44 · 2022: 46 · 2021: 90 · 2020: 79 · 2019: 92 · 2018: 73 · 2017: 117 · 2016: 94 · 2015: 135 · 2014: 134 · 2013: 110
- FWCI
- 58.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Abbott Laboratories
- GlaxoSmithKline
- Gilead Sciences
- Celgene
- Genentech
- Takeda Oncology
- Pharmacyclics
- National Cancer Institute (P30CA016672)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Dermatology › Cutaneous lymphoproliferative disorders research
- Keywords
- ibrutinib, BTK inhibitors, relapsed/refractory B-cell malignancies, B-cell lymphoma, chronic lymphocytic leukemia, B cell receptor signaling, irreversible kinase inhibitors, BTK occupancy, dose-limiting toxicity, pharmacokinetics, progression-free survival
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Administration, Oral, Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Piperidines, Prognosis, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell, Salvage Therapy, Drug Resistance, Neoplasm, Maximum Tolerated Dose, Protein Kinase Inhibitors
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