Drug Review: Ibrutinib

Parathan Karunakaran

doi:10.4103/ijmpo.ijmpo_36_20

Indian Journal of Medical and Paediatric Oncology, Inhaltsverzeichnis

CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2020; 41(03): 383-392
DOI: 10.4103/ijmpo.ijmpo_36_20

Drug Review

Drug Review: Ibrutinib

Parathan Karunakaran

Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India

› Institutsangaben

Abstract

Ibrutinib is an irreversible BTK inhibitor, characterized by high selectivity and potency. It has revolutionized the therapy of B-cell lymphomas, especially chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. Importantly, it has expanded the armamentarium for those patients who are refractory to conventional chemoimmunotherapy. This small-molecule inhibitor has shown efficacy in this difficult-to-treat subset – those with del(17p)/TP53-mutated CLL. Its immunomodulatory properties make it an excellent choice for combining with other immunotherapeutic agents such as venetoclax. The drug is not without drawbacks. The need for indefinite therapy and the presence of adverse effects such as infection, bleeding, hypertension, and arrhythmia temper our enthusiasm for this versatile drug. But overall, ibrutinib's favorable risk profile and lack of myelosuppression make it an ideal therapy for the elderly and those with multiple comorbidities.

Keywords

Bruton tyrosine kinase inhibitors - chronic lymphocytic leukemia - ibrutinib

Volltext

Referenzen

References
1 Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S. 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
2 Herman SE, Mustafa RZ, Gyamfi JA, Pittaluga S, Chang S, Chang B. et al. Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood 2014; 123: 3286-95
3 Cheng S, Ma J, Guo A, Lu P, Leonard JP, Coleman M. et al. BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia 2014; 28: 649-57
4 Niemann CU, Herman SE, Maric I, Gomez-Rodriguez J, Biancotto A, Chang BY. 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: 1572-82
5 Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW. et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol 2012; 30: 2820-2
6 US FDA. Imbruvica (Ibrutinib) Capsules: US Prescribing Information; 2016. Available from: http://www.fda.gov. [Last accessed on 2020 Jan 20].
7 European Medicines Agency. Imbruvica (Ibrutinib) Hard Capsules: EU Summary of Product Characteristics; 2016. Available from: http://www.ema.europa.eu/. [Last accessed on 2020 Jan 20].
8 Molica S, Matutes E, Tam C, Polliack A. Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on. Hematol Oncol 2020; 38: 129-36
9 O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K. et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 2018; 131: 1910-9
10 Yin Q, Sivina M, Robins H, Yusko E, Vignali M, O'Brien S. et al. Ibrutinib therapy increases T cell repertoire diversity in patients with chronic lymphocytic leukemia. J Immunol 2017; 198: 1740-7
11 Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M. et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 2015; 125: 2497-506
12 Woyach JA. Ibrutinib and Aspergillus: A Btk-targeted risk. Blood 2018; 132: 1869-70
13 Colado A, Genoula M, Cougoule C, Marín Franco JL, Almejún MB, Risnik D. et al. Effect of the BTK inhibitor ibrutinib on macrophage- and γδ T cell-mediated response against Mycobacterium tuberculosis. Blood Cancer J 2018; 8: 100
14 Iskierka-Jażdżewska E, Robak T. Minimizing and managing treatment-associated complications in patients with chronic lymphocytic leukemia. Expert Rev Hematol 2020; 13: 39-53
15 Brown JR. How I treat CLL patients with ibrutinib. Blood 2018; 131: 379-86
6 Yun S, Vincelette ND, Acharya U, Abraham I. Risk of atrial fibrillation and bleeding diathesis associated with ibrutinib treatment: A systematic review and pooled analysis of four randomized controlled trials. Clin Lymphoma Myeloma Leuk 2017; 17: 31-70
17 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
18 Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood 2019; 133: 1298-307
19 Lad D, Jain A, Varma S. Complications and management of coagulation disorders in leukemia patients. Blood Lymphat Cancer 2017; 7: 61-72
20 Shatzel JJ, Olson SR, Tao DL, McCarty OJT, Danilov AV, DeLoughery TC. Ibrutinib-associated bleeding: Pathogenesis, management and risk reduction strategies. J Thromb Haemost 2017; 15: 835-47
21 Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, Hill B. et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: A real-world analysis. Haematologica 2018; 103: 874-9
22 Alexandre J, Moslehi JJ, Bersell KR, Funck-Brentano C, Roden DM, Salem JE. Anticancer drug-induced cardiac rhythm disorders: Current knowledge and basic underlying mechanisms. Pharmacol Ther 2018; 189: 89-103
23 Iberri DJ, Kwong BY, Stevens LA, Coutre SE, Kim J, Sabile JM. et al. Ibrutinib-associated rash: A single-centre experience of clinicopathological features and management. Br J Haematol 2018; 180: 164-6
24 Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L. et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol 2015; 1: 80-7
25 Thompson PA, O'Brien SM, Wierda WG, Ferrajoli A, Stingo F, Smith SC. 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: 3612-21
26 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
27 Burger JA, Landau DA, Taylor-Weiner A, Bozic I, Zhang H, Sarosiek K. et al. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun 2016; 7: 11589
28 Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A. et al. BTK C481S;-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol 2017; 35: 1437-43
29 Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M. et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 2016; 387: 770-8
30 Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)-Then and now. Am J Hematol 2016; 91: 330-40
31 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
32 Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P. et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 2015; 373: 2425-37
33 Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S. 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: 200-11
34 Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z. et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood 2019; 133: 1011-9
35 Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W. et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 2018; 379: 2517-28
36 Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L. et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019; 20: 43-56 Epub 2018 Dec 3
37 Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J. et al. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med 2019; 381: 432-43
38 Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G. et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med 2019; 380: 2095-103
39 Rogers KA, Huang Y, Ruppert AS, Awan FT, Heerema NA, Hoffman C. et al. Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood 2018; 132: 1568-72
40 Barr PM, Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM. et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood 2017; 129: 2612-5
41 UK CLL. Forum Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: A UK and Ireland analysis of outcomes in 315 patients. Haematologica 2016; 101: 1563-72
42 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
43 Lad DP, Malhotra P, Khadwal A, Prakash G, Jain A, Varma S. Reduced dose ibrutinib due to financial toxicity in CLL. Indian J Hematol Blood Transfus 2019; 35: 260-4
44 Mato AR, Timlin C, Ujjani C, Skarbnik A, Howlett C, Banerjee R. et al. Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced-dose ibrutinib: Results from a multi-centre study. Br J Haematol 2018; 181: 259-61
45 Chen LS, Bose P, Cruz ND, Jiang Y, Wu Q, Thompson PA. et al. A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia. Blood 2018; 132: 2249-59
46 von Tresckow J, Cramer P, Bahlo J, Robrecht S, Langerbeins P, Fink AM. et al. CLL2-BIG: Sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia. Leukemia 2019; 33: 1161-72
47 Jain N, Thompson P, Ferrajoli A, Nabhan C, Mato AR, O'Brien S. Approaches to chronic lymphocytic leukemia therapy in the era of new agents: The conundrum of many options. Am Soc Clin Oncol Educ Book 2018; 38: 580-91
48 Jain P, Keating M, Wierda W, Estrov Z, Ferrajoli A, Jain N. et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood 2015; 125: 2062-7
49 Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD. et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: An interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 2018; 19: 65-75
50 Anderson MA, Tam C, Lew TE, Juneja S, Juneja M, Westerman D. et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood 2017; 129: 3362-70
51 Ibrutinib and Obinutuzumab with or without Venetoclax in Treating Patients with Chronic Lymphocytic Leukemia. Available from: https://clinicaltrials.gov/ct2/show/NCT03701282. [Last accessed on 2020 Jan 20]
52 Ibrutinib and Obinutuzumab with or without Venetoclax in Treating Older Patients with Untreated Chronic Lymphocytic Leukemia. Available from: https://clinicaltrials.gov/ct2/show/NCT03737981. [Last accessed on 2020 Jan 20]
53 Nastoupil LJ, Lunning MA, Vose JM, Schreeder MT, Siddiqi T, Flowers CR. et al. Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: A phase 1 dose escalation and expansion trial. Lancet Haematol 2019; 6: e100-9
54 Gauthier J, Hirayama AV, Purushe J, Hay KA, Lymp J, Li DH. et al. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. Blood 2020; 135: 1650-60
55 de Claro RA, McGinn KM, Verdun N, Lee SL, Chiu HJ, Saber H. et al. FDA Approval: Ibrutinib for Patients with Previously Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic Leukemia. Clin Cancer Res 2015; 21: 3586-90
56 Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R. et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med 2015; 372: 1430-40
57 Treon SP, Gustine J, Meid K, Yang G, Xu L, Liu X. et al. Ibrutinib monotherapy in symptomatic, treatment-naïve patients with Waldenström macroglobulinemia. J Clin Oncol 2018; 36: 2755-61
58 Noy A, de Vos S, Thieblemont C, Martin P, Flowers CR, Morschhauser F. et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 2017; 129: 2224-32
59 Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I. et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood 2017; 130: 2243-50
60 Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS. et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: Updated safety and efficacy results. Blood 2015; 126: 739-45
61 Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS. et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369: 507-16
62 Wang ML, Goy A, Martin P, Ramchandren R, Alexeeva J, Popat R. et al. Efficacy and safety of single agent ibrutinib in patients with mantle cell lymphoma who progressed after bortezomib therapy. Blood 2014; 124: 4471
63 Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P. et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov 2014; 4: 1022-35
64 Tucker DL, Naylor G, Kruger A, Hamilton MS, Follows G, Rule SA. Ibrutinib is a safe and effective therapy for systemic mantle cell lymphoma with central nervous system involvement A multi-centre case series from the United Kingdom. Br J Haematol 2017; 178: 327-9
65 Tam CS, Anderson MA, Pott C, Agarwal R, Handunnetti S, Hicks RJ. et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med 2018; 378: 1211-23
66 Ahmed R, Kapoor J, Agrawal N, Verma P, Bhurani D. Ibrutinib to allogenic stem cell transplant in a case of refractory mantle cell lymphoma. Indian J Hematol Blood Transfus 2018; 34: 360-1
67 Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C. et al. iNNOVATE Study Group and the European Consortium for Waldenström's Macroglobulinemia. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): An open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol 2017; 18: 241-50
68 Papanota AM, Ntanasis-Stathopoulos I, Kastritis E, Dimopoulos MA, Gavriatopoulou M. Evaluating ibrutinib in the treatment of symptomatic Waldenstrom's macroglobulinemia. J Blood Med 2019; 10: 291-300
69 Gustine JN, Meid K, Dubeau T, Severns P, Hunter ZR, Guang Y. et al. Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound. Am J Hematol 2018; 93: 511-7
70 Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J. et al. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol 2019; 37: 1285-95
71 Goy A, Ramchandren R, Ghosh N, Munoz J, Morgan DS, Dang NH. et al. Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non-germinal center B-cell-like DLBCL. Blood 2019; 134: 1024-36
72 Moore J, Baran AM, Meacham PJ, Evans AG, Barr PM, Zent CS. Initial treatment of B-cell prolymphocytic leukemia with ibrutinib. Am J Hematol 2020; 95: E108-10
73 Jones J, Andritsos L, Kreitman RJ, Ravandi F, Schiffer C, Call TG. et al. Efficacy and safety of the Bruton tyrosine kinase inhibitor ibrutinib in patients with hairy cell leukemia: Stage 1 results of a phase 2 study. Blood 2016; 128: 1215
74 Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, Schartz D. et al. Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov 2017; 7: 1018-29
75 Hajek R, Pour L, Ozcan M, Martin Sánchez J, García Sanz R, Anagnostopoulos A. et al. A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Eur J Haematol 2020; 104: 435-42
76 Bartlett NL, Costello BA, LaPlant BR, Ansell SM, Kuruvilla JG, Reeder CB. et al. Single-agent ibrutinib in relapsed or refractory follicular lymphoma: A phase 2 consortium trial. Blood 2018; 131: 182-90
77 Chen J, Kinoshita T, Sukbuntherng J, Chang BY, Elias L. Ibrutinib inhibits ERBB receptor tyrosine kinases and HER2-amplified breast cancer cell growth. Mol Cancer Ther 2016; 15: 2835-44
78 Kokabee L, Wang X, Sevinsky CJ, Wang WL, Cheu L, Chittur SV. et al. Bruton's tyrosine kinase is a potential therapeutic target in prostate cancer. Cancer Biol Ther 2015; 16: 1604-15
79 Wang J, Liu X, Hong Y, Wang S, Chen P, Gu A. et al. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma. J Exp Clin Cancer Res 2017; 36: 96
80 Zucha MA, Wu AT, Lee WH, Wang LS, Lin WW, Yuan CC. et al. Bruton's tyrosine kinase (Btk) inhibitor ibrutinib suppresses stem-like traits in ovarian cancer. Oncotarget 2015; 6: 13255-68
81 Dreger P, Michallet M, Bosman P, Dietrich S, Sobh M, Boumendil A. et al. Ibrutinib for bridging to allogeneic hematopoietic cell transplantation in patients with chronic lymphocytic leukemia or mantle cell lymphoma: A study by the EBMT Chronic Malignancies and Lymphoma Working Parties. Bone Marrow Transplant 2019; 54: 44-52
82 Michallet M, Dreger P, Sobh M, Koster L, Hoek J, Boumendil A. et al. French Cooperative Group for CLL, SFGM-TC, and the EBMT Chronic Malignancy and Lymphoma Working Parties. Ibrutinib as a salvage therapy after allogeneic HCT for chronic lymphocytic leukemia. Bone Marrow Transplant 2020; 55: 884-90