Targeting Bruton’s Tyrosine Kinase Across B-Cell Malignancies
- 220 Downloads
Bruton’s tyrosine kinase (BTK) is crucial in B-cell development and survival. The role of BTK as a downstream kinase in the B-cell receptor (BCR) signaling pathway is well described. As a key player in the pathogenesis of B-cell malignancies, targeting of dysregulated BCR signaling has been explored by development of inhibitors of downstream mediators. Discovery of the biological function of BTK and the development of covalent inhibitors for clinical use, ibrutinib as the lead agent and acalabrutinib as the second clinically approved BTK inhibitor, have revolutionized the treatment options for B-cell malignancies. Currently, ibrutinib is approved for mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma and chronic graft versus host disease, while acalabrutinib is approved for mantle cell lymphoma. Potential expansion of indications in other diseases is under investigation in several clinical trials, while combination of BTK inhibitors with either chemoimmunotherapy or other targeted agents is being systematically explored in B-cell malignancies.
Compliance with Ethical Standards
This study was funded by The Danish Cancer Society (Grant number R-130-A8217-15-S38) and The Novo Nordisk Foundation (Grant number NNF16OC0019302).
Conflict of interest
Carsten Utoft Niemann has received grants from Janssen and Abbvie; consulting fees from Roche, Gilead, Janssen, Abbvie, AstraZeneca, and CSL Behring; and travel support to meetings from Roche, Gilead, Janssen, and Abbvie. Caspar da Cunha-Bang declares no conflicts of interest that might be relevant to the contents of this article.
- 3.Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–54.Google Scholar
- 4.Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. In: Presented in part at the 40th annual meeting of the american society of hematology, held in Miami Beach, FL, December 4–8, 1998, 1999, vol. 94, pp. 1840–7.Google Scholar
- 36.Palma M, Krstic A, Berglöf A, et al. Very early effects of ibrutinib on tumor and immune cells in blood and lymph nodes in relapsed or refractory chronic lymphocytic leukemia (CLL) patients. Blood. 2016;128:3235.Google Scholar
- 43.Hansson L, Winqvist M, Asklid A, et al. Real-world results on ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL): data from 97 Swedish patients treated in a compassionate use program. Blood. 2015;126:1745.Google Scholar
- 44.von Tresckow J BJ, Niemann CU, Kater AP, Fink AM, et al. The GAIA (CLL13) trial—an international, randomized, four-arm study for first line treatment of physically fit CLL patients without del17p or TP53 mutation. Integr Cancer Sci Therap 2017;4.Google Scholar
- 45.Elevate CLL R/R: study of acalabrutinib (ACP-196) versus ibrutinib in previously treated subjects with high risk chronic lymphocytic leukemia. 2015. 2018, https://clinicaltrials.gov/ct2/show/study/NCT02477696?term=acalabrutinib&recrs=de&phase=2&rank=1. Accessed 14 Sept 2018.
- 46.Elevate CLL TN: study of obinutuzumab + chlorambucil, acalabrutinib (ACP-196) + obinutuzumab, and acalabrutinib in subjects with previously untreated CLL. 2015. 2018, https://clinicaltrials.gov/ct2/show/study/NCT02475681?term=acalabrutinib&recrs=de&phase=2&rank=2. Accessed 14 Sept 2018.
- 56.Carsten U, Niemann M-DL, Nasserinejad K, Janssens AMH, Enggaard L, Kersting S, Veldhuis GJ, Mous R, Melink CHM, Dobber JA, Schjødt I, Dompeling EC, Poulsen CB, Tran HTT, Salmi T, Mattsson M, Kater AP. Safety analysis of venetoclax and ibrutinib for previously treated patients with chronic lymphocytic leukemia (CLL): first interim analysis from the phase ii vision ho141 trial. 23rd European In: Hematology association congress. Stockholm, 2018.Google Scholar
- 57.Hillmen P, Munir T, Rawstron A, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (bloodwise TAP CLARITY study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy. Blood. 2017;130:428.Google Scholar
- 61.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;17:200–11.CrossRefGoogle Scholar
- 62.Davids MS, Kim HT, Brander DM, et al. Initial results of a multicenter, phase II study of ibrutinib plus FCR (iFCR) as frontline therapy for younger CLL patients. Blood. 2016;128:3243.Google Scholar
- 63.Valentin R, Deng J, Ten Hacken E, et al. Dynamic BH3 profiling to assess the effects of novel agents on anti-apoptotic protein dependence of CLL cells. Blood. 2017;130:4289.Google Scholar
- 74.Younes A, Thieblemont C, Morschhauser F, et al. 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. Lancet Oncol. 2014;15:1019–26.CrossRefGoogle Scholar
- 81.Neuman LL, Ward R, Arnold D, et al. First-in-human phase 1a study of the safety, pharmacokinetics, and pharmacodynamics of the noncovalent bruton tyrosine kinase (BTK) inhibitor SNS-062 in healthy subjects. Blood. 2016;128:2032.Google Scholar