ISSN: 2329-6917
Journal of Leukemia
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Burton's Tyrosine Kinase Inhibition by Ibrutinib: Current Status

Rohit Mathur*
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
Corresponding Author : Rohit Mathur
Department of Lymphoma and Myeloma
The University of Texas MD Anderson Cancer Center, 7455 Fannin St., Houston, TX 77054 , USA
Tel: 713 563-3412
Fax: 713 563-7314
E-mail: rmathur@mdanderson.org
Received March 30, 2015; Accepted April 01, 2015; Published April 18, 2015
Citation: Mathur (2015) Burton’s Tyrosine Kinase Inhibition by Ibrutinib: Current Status. J Leuk 3:e113. doi: 10.4172/2329-6917.1000e113
Copyright: © 2015 Mathur R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Editorial
Burton’s tyrosine kinase (BTK) is a nonreceptor/cytoplasmic tyrosine kinase that modulates the downstream signaling pathway of B-cell receptor (BCR) [1]. Aberrant BCR signaling including upregulation of tyrosine kinases i.e. Lyn, Syk and Btk is a common feature in lymphoid malignancies such as Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL) and other Non-Hodgkin’s Lymphoma (NHL) [2]. Therefore, inhibition of tyrosine kinases is an attractive treatment option in these lymphoid malignancies. Ibrutinib (formerly PCI-32765) is a first-in-human, orally bioavailable small molecule inhibitor of BTK that has shown potent clinical activity in majority of CD20 positive B-cell malignancies. Based on high response rate, tolerability and safety data, Imbruvica/Ibrutinib has recently been approved by Food and Drug Administration (FDA) for the treatment of MCL (in November 2013) and CLL (in February 2014) with at least one prior therapy. It is now under evaluation as front line therapy in other subtypes of NHL and is explored for combination with other drugs.
Ibrutinib showed a response rate of 68% (75 patients) with a complete response rate of 21% and a partial response rate of 47% in a phase II study of 111 patients with relapsed or refractory mantle cell lymphoma [3]. Previous therapy to these patients had no effect on overall survival. Updated results presented in American society of hematology (Ash) meeting 2014 demonstrated the durability of response and sustained single agent activity of ibrutinib in an international multicenter phase II study of refractory MCL [4]. In another study on previously treated CLL, ibrutinib showed an 71% overall response rate and updated results after 3 years of follow up verify the durability of responses, probably on account of lower toxicity of ibrutinib in CLL and SLL [5]. Results from other recent studies also supports ibrutinib as first line or second treatment option in refractory cases [6]. A survival benefit with ibrutinib, together with sustained improvements in hematologic endpoints and PRO suggest that it enhances quality of life, while prolonging survival in CLL including with p17 deletion [7].
Further, treatment of ibrutinib is under evaluation for other tumors such as Follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and Multiple myeloma (MM). Early results of various studies showed promise of using it as a single agent treatment in relapsed/refractory lymphomas and myeloma. Although, ibrutinib appears less active in FL than in MCL and CLL but it may be a good option for refractory FL [8]. Recent study with multiple myeloma in heavily pre-treated patient population also showed evidence of antitumor activity with treatment of ibrutinib, as a single agent and in combination with dexamethasone, as the treatment was well tolerated with manageable toxicities [9]. In addition, several drug combinations of ibrutinib with other drugs are under evaluation. Initial results from recent studies have also shown that ibrutinib can be successfully combined with rituximab, bortezomib, bendamustine, lenalidomide, ABT-199, ofatumumab or newly developed anti-CD20 antibodies Ublituximab (UTX) or Obinutuzumab (GA101) in different clinical protocols for MCL and CLL [10-14]. The success of ibrutinib also come from its ability to target tumor microenvironment, chemokines SDF1/ CXCR4 mediated migration. Ibrutinib inhibits concomitant TLR and BCR- driven proliferation of CLL cells and overrides the supportive survival-promoting effects of microenvironmental signals [15].
 
Inspite of a broad clinical activity of ibrutinib, several of patients with B-cell malignancies progressed after treatment with ibrutinib. Few studies undertaken so far, attributes the resistance to ibrutinib with mutations in B-cell receptor (BCR) signaling proteins such as BTK C481S, PLCg2 [16,17]. In addition, mutations in MLL2, CREBBP, PIM1 and ERBB4 kinase were also attributed to resistance mechanisms to ibrutinib [18]. Interestingly, treatment with ibrutinib, vincristine, or doxorubicin could induce cell death in MCL cells, but could not reduce the percentage of MCL-initiating cells (MCL-ICs) in a co-culture MCL model [19]. Therefore, it is important to understand the mechanisms underlying the activity of ibrutinib. However, advanced studies have shown that treatment with other targeting agents such as inhibitors of SYK, another downstream mediator of BCR signaling or ABT-199, a Bcl2 inhibitor have potential to sensitize ibrutinib resistant MCL and CLL cells [20]. Pretreatment of DLBCL cells with SYK inhibitors (e.g. R406) re-sensitized resistant B-lymphoma cells with either C481S BTK or R665W PLCG2 mutations to ibrutinib. Ibrutinib in combination with BCL-2 or SYK inhibitors, inhibiting cell growth, IgM-induced calcium flux, cell adhesion or migration in mutation containing cells [21]. Further, other drugs such as Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor or RP6530, a Dual PI3Kδ/γ Inhibitor and newer generation HSP90 inhibitors (AUY922) have been shown to have clinical activity in patients progressed after ibrutinib treatment [22-24].
Pre-clinical reports suggests that ibrutinib antagonizes rituximabdependent NK-cell mediated cytotoxicity (ADCC) due to its secondary irreversible binding to interleukin-2 inducible tyrosine kinase (ITK), which is required for FcR-stimulated NK cell function including calcium mobilization, granule release, and overall ADCC [25]. Therefore, new BTK inhibitors, BTK-InhA (ACP-196), BTK-InhB (BGB-3111), and CGI-1746 (GDC-0834) [26,27] have been synthesized with lower ITK binding, which may preserve NK cell function and therefore synergize rather than antagonize rituximab. Preclinical studies showed that the efficacy of therapeutics which do not inhibit NK cell function, including three novel BTK inhibitors, is superior to ibrutinib [26,28]. Further, clinical investigation with newer inhibitors is needed to determine the impact of this finding on patients with lymphoma receiving rituximab.
In conclusion, ibrutinib has a broad clinical activity in all B-cell malignancies and provided a good treatment option for chemorefractory MCL, and CLL. More mechanistic insights into its function, resistance mechanisms will clearly help understand its clinical activity and its possible use in other leukemia, indolent and other types of lymphomas.
References
  1. Mohamed AJ, Nore BF, Christensson B, Smith CI (1999) Signalling of Bruton's tyrosine kinase, Btk. Scandinavian journal of immunology 2: 113-118.

  2. Shaffer AL, Rosenwald A, Staudt LM (2002) Lymphoid malignancies: the dark side of B-cell differentiation. Nature reviews Immunology 2: 920-932.

  3. Wang ML, Rule S, Martin P, Goy A, Auer R, et al. (2013) Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. The New England journal of medicine 6: 507-516.

  4. Wang M, Goy A, Martin P, Ramchandren R, Alexeeva J, et al. (2014) Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy. Blood 21: 4471-4475

  5. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M et al. (2015) Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib.

  6. Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, et al. (2015) Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. The Lancet Oncology 2: 169-176.

  7. Barrientos JC, O'Brien S, Brown JR, Kay NE, Reddy NM, et al. (2014) Hematologic and Immunologic Function and Patient Well-Being for the Phase III RESONATETM Study of Ibrutinib Vs Ofatumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Blood 21:4696-4705

  8. Bartlett NL, LaPlant BR, Qi J, Ansell SM, Kuruvilla JG, et al. (2014) Ibrutinib Monotherapy in Relapsed/Refractory Follicular Lymphoma (FL): Preliminary Results of a Phase 2 Consortium (P2C) Trial. Blood 21: 800-803

  9. Vij R, Huff CA, Bensinger WI, Siegel DS, Jagannath S, Berdeja J, et al. (2014) Ibrutinib, Single Agent or in Combination with Dexamethasone, in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Phase 2 Results. Blood 21: 31-39

  10. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, et al. (2014) Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. The Lancet Oncology 10: 1090-1099.

  11. Maddocks K, Christian B, Jaglowski S, Flynn J, Jones JA, Porcu P et al. (2015) A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma. Blood 2: 242-248.

  12. Younes A, Thieblemont C, Morschhauser F, Flinn I, Friedberg JW, et al. (2014) Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. The Lancet Oncology 9: 1019-1026.

  13. Sharman JP, Farber CM, Mahadevan D, Schreeder MT, Brooks HD, et al. (2014) Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination with Ibrutinib Is Highly Active in Patients with Relapsed and/or Refractory CLL and MCL; Results of a Phase II Trial. Blood 21 : 4679-4685

  14. Herter S, Sagiv-Barfi I, Chester C, Sadaram M, Hebb J, et al. (2014) Obinutuzumab (GA101) Is Less Prone to Antagonism of Immune Effector Function By Ibrutinib Than Rituximab in Vitro and in Vivo. Blood 21: 1765-1772

  15. Temburni S, Barrientos JC, Kolitz JE, Allen SL, Rai KR, et al. (2014) Ibrutinib Inhibits Concomitant TLR and BCR- Driven Proliferation of Chronic Lymphocytic Leukemia Cells and Overrides the Supportive Survival-Promoting Effects of Microenvironmental Signals. Blood 21: 3310-3312

  16. Furman RR, Cheng S, Lu P, Setty M, Perez AR, et al. (2014) Ibrutinib resistance in chronic lymphocytic leukemia. The New England journal of medicine 24: 2352-2354.

  17. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, et al. (2014) Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. The New England journal of medicine 24: 2286-2294.

  18. Balasubramanian S, Schaffer M, Deraedt W, Davis C, Stepanchick E, et al. (2014) Mutational Analysis of Patients with Primary Resistance to Single-Agent Ibrutinib in Relapsed or Refractory Mantle Cell Lymphoma (MCL). Blood 21: 78-79.

  19. Samaniego F, Sehgal L, Braun FK, Berkova Z, Romaguera JE, et al. (2014) Molecular Signatures of Tumor-Initiating Cells Unveil Wnt Pathway As a Therapeutic Target in Mantle Cell Lymphoma. Blood 21: 2148-2150.

  20. Chiron D, Dousset C, Brosseau C, Touzeau C, Maiga S, et al. (2015) Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. Oncotarget.

  21. Kuo H-P, Crowley R, Xue L, Schweighofer KJ, Cheung LW, et al. (2014) Combination of Ibrutinib and BCL-2 or SYK Inhibitors in Ibrutinib Resistant ABC-Subtype of Diffuse Large B-Cell Lymphoma. 21:505-506.

  22. Porcu P, Flinn I, Kahl BS, Horwitz SM, Oki Y, et al. (2014) Clinical Activity of Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor, in Patients Previously Treated with Ibrutinib. Blood 21: 3335-3336.

  23. Vakkalanka S, Nyayapathy S, Viswanadha S (2014) Addition of RP6530, a Dual PI3Kδ/γ Inhibitor, Overcomes Ibrutinib Resistance in DLBCL Cells in Vitro. Blood 21: 4497-4499.

  24. Kopp N, Tschuri S, Haebe S, van Bodegom D, Bird L, et al. (2014) Newer-Generation HSP90 Inhibitors Can Overcome Ibrutinib Resistance and Suppress Proliferation in Human Mantle Cell Lymphoma in Vitro and in Vivo. Blood 21: 1686-1689.

  25. Kohrt HE, Sagiv-Barfi I, Rafiq S, Herman SE, Butchar JP, et al. (2014) Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 12: 1957-1960.

  26. Rajasekaran N, Sadaram M, Hebb J, Sagiv-Barfi I, Ambulkar S, et al. (2014) Three BTK-Specific Inhibitors, in Contrast to Ibrutinib, Do Not Antagonize Rituximab-Dependent NK-Cell Mediated Cytotoxicity. Blood 21: 3118-3119.

  27. Siernicka M, Bojarczuk K, Bobrowicz M, Dwojak M, Pyrzynska B, et al. (2014) Influence of Btk Inhibitors on Antitumor Activity of Natural Killer Cells. Blood 21: 2742-2745.

  28. Akinleye A, Chen Y, Mukhi N, Song Y, Liu D (2013) Ibrutinib and novel BTK inhibitors in clinical development. Journal of hematology & oncology 6: 59-61.

References

  1. Mohamed AJ, Nore BF, Christensson B, Smith CI (1999) Signalling of Bruton's tyrosine kinase, Btk. Scandinavian journal of immunology 2: 113-118.

  2. Shaffer AL, Rosenwald A, Staudt LM (2002) Lymphoid malignancies: the dark side of B-cell differentiation. Nature reviews Immunology 2: 920-932.

  3. Wang ML, Rule S, Martin P, Goy A, Auer R, et al. (2013) Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. The New England journal of medicine 6: 507-516.

  4. Wang M, Goy A, Martin P, Ramchandren R, Alexeeva J, et al. (2014) Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy. Blood 21: 4471-4475

  5. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M et al. (2015) Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib.

  6. Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, et al. (2015) Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. The Lancet Oncology 2: 169-176.

  7. Barrientos JC, O'Brien S, Brown JR, Kay NE, Reddy NM, et al. (2014) Hematologic and Immunologic Function and Patient Well-Being for the Phase III RESONATETM Study of Ibrutinib Vs Ofatumumab in Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Blood 21:4696-4705

  8. Bartlett NL, LaPlant BR, Qi J, Ansell SM, Kuruvilla JG, et al. (2014) Ibrutinib Monotherapy in Relapsed/Refractory Follicular Lymphoma (FL): Preliminary Results of a Phase 2 Consortium (P2C) Trial. Blood 21: 800-803

  9. Vij R, Huff CA, Bensinger WI, Siegel DS, Jagannath S, Berdeja J, et al. (2014) Ibrutinib, Single Agent or in Combination with Dexamethasone, in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Phase 2 Results. Blood 21: 31-39

  10. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, et al. (2014) Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. The Lancet Oncology 10: 1090-1099.

  11. Maddocks K, Christian B, Jaglowski S, Flynn J, Jones JA, Porcu P et al. (2015) A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma. Blood 2: 242-248.

  12. Younes A, Thieblemont C, Morschhauser F, Flinn I, Friedberg JW, et al. (2014) Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. The Lancet Oncology 9: 1019-1026.

  13. Sharman JP, Farber CM, Mahadevan D, Schreeder MT, Brooks HD, et al. (2014) Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination with Ibrutinib Is Highly Active in Patients with Relapsed and/or Refractory CLL and MCL; Results of a Phase II Trial. Blood 21 : 4679-4685

  14. Herter S, Sagiv-Barfi I, Chester C, Sadaram M, Hebb J, et al. (2014) Obinutuzumab (GA101) Is Less Prone to Antagonism of Immune Effector Function By Ibrutinib Than Rituximab in Vitro and in Vivo. Blood 21: 1765-1772

  15. Temburni S, Barrientos JC, Kolitz JE, Allen SL, Rai KR, et al. (2014) Ibrutinib Inhibits Concomitant TLR and BCR- Driven Proliferation of Chronic Lymphocytic Leukemia Cells and Overrides the Supportive Survival-Promoting Effects of Microenvironmental Signals. Blood 21: 3310-3312

  16. Furman RR, Cheng S, Lu P, Setty M, Perez AR, et al. (2014) Ibrutinib resistance in chronic lymphocytic leukemia. The New England journal of medicine 24: 2352-2354.

  17. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, et al. (2014) Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. The New England journal of medicine 24: 2286-2294.

  18. Balasubramanian S, Schaffer M, Deraedt W, Davis C, Stepanchick E, et al. (2014) Mutational Analysis of Patients with Primary Resistance to Single-Agent Ibrutinib in Relapsed or Refractory Mantle Cell Lymphoma (MCL). Blood 21: 78-79.

  19. Samaniego F, Sehgal L, Braun FK, Berkova Z, Romaguera JE, et al. (2014) Molecular Signatures of Tumor-Initiating Cells Unveil Wnt Pathway As a Therapeutic Target in Mantle Cell Lymphoma. Blood 21: 2148-2150.

  20. Chiron D, Dousset C, Brosseau C, Touzeau C, Maiga S, et al. (2015) Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. Oncotarget.

  21. Kuo H-P, Crowley R, Xue L, Schweighofer KJ, Cheung LW, et al. (2014) Combination of Ibrutinib and BCL-2 or SYK Inhibitors in Ibrutinib Resistant ABC-Subtype of Diffuse Large B-Cell Lymphoma. 21:505-506.

  22. Porcu P, Flinn I, Kahl BS, Horwitz SM, Oki Y, et al. (2014) Clinical Activity of Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor, in Patients Previously Treated with Ibrutinib. Blood 21: 3335-3336.

  23. Vakkalanka S, Nyayapathy S, Viswanadha S (2014) Addition of RP6530, a Dual PI3Kδ/γ Inhibitor, Overcomes Ibrutinib Resistance in DLBCL Cells in Vitro. Blood 21: 4497-4499.

  24. Kopp N, Tschuri S, Haebe S, van Bodegom D, Bird L, et al. (2014) Newer-Generation HSP90 Inhibitors Can Overcome Ibrutinib Resistance and Suppress Proliferation in Human Mantle Cell Lymphoma in Vitro and in Vivo. Blood 21: 1686-1689.

  25. Kohrt HE, Sagiv-Barfi I, Rafiq S, Herman SE, Butchar JP, et al. (2014) Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 12: 1957-1960.

  26. Rajasekaran N, Sadaram M, Hebb J, Sagiv-Barfi I, Ambulkar S, et al. (2014) Three BTK-Specific Inhibitors, in Contrast to Ibrutinib, Do Not Antagonize Rituximab-Dependent NK-Cell Mediated Cytotoxicity. Blood 21: 3118-3119.

  27. Siernicka M, Bojarczuk K, Bobrowicz M, Dwojak M, Pyrzynska B, et al. (2014) Influence of Btk Inhibitors on Antitumor Activity of Natural Killer Cells. Blood 21: 2742-2745.

  28. Akinleye A, Chen Y, Mukhi N, Song Y, Liu D (2013) Ibrutinib and novel BTK inhibitors in clinical development. Journal of hematology & oncology 6: 59-61.

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