Medical academic journalMedical academic journalМедицинский академический журнал1608-41012687-1378Eco-Vector7606010.17816/MAJ76060Analytical reviewsАналитические обзорыReview ArticleInfectious complications in patients with chronic lymphocytic leukemia treated with bruton’s tyrosine kinase inhibitorsИнфекционные осложнения у больных хроническим лимфолейкозом при лечении ингибиторами тирозинкиназы брутонаhttps://orcid.org/0000-0002-2387-27121676-5162TorshinaYulia S.ТоршинаЮлия Сергеевна
Russian Federation

Postgraduate student of Department of Immunology

аспирант отдела иммунологии

torshina.doc18@yandex.ruhttps://orcid.org/0000-0002-2418-9368G-1663-20152240-1277SerebryanayaNatalia B.СеребрянаяНаталья Борисовна
Russian Federation

PhD, MD (Medicine), Professor, Head of the Laboratory of General Immunology, Department of Immunology, Professor of the Department of Clinical Mycology, Allergology and Immunology

д-р мед. наук, профессор, зав. лабораторией общей иммунологии, отдел иммунологии, профессор кафедры клинической микологии, аллергологии и иммунологии

nbvma@mail.ruInstitute of Experimental MedicineИнститут экспериментальной медициныNorth-Western State Medical University named after I.I. MechnikovСеверо-Западный государственный медицинский университет им. И.И. Мечникова080820210612202121315271507202108082021Copyright ©; 2021, Torshina Y.S., Serebryanaya N.B.Copyright ©; 2021, Торшина Ю.С., Серебряная Н.Б.2021Torshina Y.S., Serebryanaya N.B.Торшина Ю.С., Серебряная Н.Б.https://creativecommons.org/licenses/by-nc-nd/4.0https://journals.eco-vector.com/MAJ/article/view/76060

The aim of this study is to analyze the scientific literature data on the frequency and characteristics of infectious complications during the treatment of patients with lymphoproliferative diseases with a new class of drugs, selective inhibitors of Bruton’s tyrosine kinase (BTK). This work describes the indications for appointing these drugs as well as the participation of BTK in the development and activation of B cells. We have studied the main characteristics of BTK inhibitors used in clinical practice and associated disorders in the activity of off-target tyrosine kinases. The work describes the main types of known infectious complications developing during the treatment with the drugs of this group, the period of their appearance, and characteristic pathogens.

Цель — обобщить данные научной литературы о частоте и особенностях инфекционных осложнений, развивающихся при лечении больных лимфопролиферативными заболеваниями новым классом препаратов — селективными ингибиторами тирозинкиназы Брутона. Показаны участие тирозинкиназы Брутона в образовании и активации В-клеток и роль хронической активации В-лимфоцитов при развитии хронического лимфолейкоза. Определены условия, при которых назначение указанных препаратов имеет преимущества перед ранее примененными схемами терапии, так как чаще позволяет добиваться полной или частичной ремиссии. Рассмотрены основные характеристики ингибиторов тирозинкиназы Брутона, используемых в клинической практике, и осложнения, вызванные, как предполагают, нарушениями активности нецелевых тирозинкиназ. Описаны основные типы выявленных инфекционных осложнений, развивающихся при приеме препаратов указанной группы, временные особенности их появления и характерные возбудители.

Bruton’s tyrosine kinaseibrutinibacalabrutinibopportunistic infectionsinvasive mycosesтирозинкиназа Брутонаибрутинибакалабрутинибоппортунистические инфекцииинвазивные микозыИсследование выполнено в рамках темы государственного задания «Иммунологические основы защитных реакций организма» (шифр: 0557-2019-0006).Ammann EM, Shanafelt TD, Wright KB, et al. Updating survival estimates in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) based on treatment-free interval length. Leuk Lymphoma. 2018;59(3):643–649. DOI: 10.1080/10428194.2017.1349905Ammann E.M., Shanafelt T.D., Wright K.B. et al. Updating survival estimates in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) based on treatment-free interval length // Leuk. Lymphoma. 2018. Vol. 59, No. 3. P. 643–649. DOI: 10.1080/10428194.2017.1349905Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107(1):265–276. DOI: 10.1182/blood-2005-06-2508Morton L.M., Wang S.S., Devesa S.S. et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001 // Blood. 2006. Vol. 107, No. 1. P. 265–276. DOI: 10.1182/blood-2005-06-2508Watson L, Wyld P, Catovsky D. Disease burden of chronic lymphocytic leukaemia within the European Union. Eur J Haematol. 2008;81(4):253–258. DOI: 10.1111/j.1600-0609.2008.01114.xWatson L., Wyld P., Catovsky D. Disease burden of chronic lymphocytic leukaemia within the European Union // Eur. J. Haematol. 2008. Vol. 81, No. 4. P. 253–258. DOI: 10.1111/j.1600-0609.2008.01114.xJemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007;57(1):43–66. DOI: 10.3322/canjclin.57.1.43Jemal A., Siegel R., Ward E. et al. Cancer statistics, 2007 // CA Cancer J. Clin. 2007. Vol. 57, No. 1. P. 43–66. DOI: 10.3322/canjclin.57.1.43Dores G.M, Anderson WF, Curtis RE, et al. Chronic lymphocytic leukaemia and small lymphocytic lymphoma: Overview of the descriptive epidemiology. Br J Haematol. 2007;139(5):809–819. DOI: 10.1111/j.1365-2141.2007.06856.xDores G.M., Anderson W.F., Curtis R.E. et al. Chronic lymphocytic leukaemia and small lymphocytic lymphoma: Overview of the descriptive epidemiology // Br. J. Haematol. 2007. Vol. 139, No. 5. P. 809–819. DOI: 10.1111/j.1365-2141.2007.06856.xZlokachestvennye novoobrazovaniya v Rossii v 2017 godu (zabolevaemost’ i smertnost’). Ed. by A.D. Kaprin, V.V. Starinski, G.V. Petrova. Moscow; 2018. (In Russ.)Злокачественные новообразования в России в 2017 году (заболеваемость и смертность) / под ред. А.Д. Каприна, В.В. Старинского, Г.В. Петровой. Москва, 2018.Klinicheskie rekomendatsii “Khronicheskii limfoleikoz, limfoma iz malykh limfotsitov” 2018 [Internet]. Rossiiskoe obshchestvo onkogematologov. (In Russ.). Available from: https://legalacts.ru/doc/klinicheskie-rekomendatsii-khronicheskii-limfoleikoz-limfoma-iz-malykh-limfotsitov-utv/. Accessed: 22.08.2021.Клинические рекомендации «Хронический лимфолейкоз, лимфома из малых лимфоцитов» [Электронный ресурс] // Российское общество онкогематологов. Режим доступа: https://legalacts.ru/doc/klinicheskie-rekomendatsii-khronicheskii-limfoleikoz-limfoma-iz-malykh-limfotsitov-utv/. Дата обращения: 22.08.2021.Kil LP, Yuvaraj S, Langerak AW, Hendriks RW. The role of B cell receptor stimulation in CLL pathogenesis. Curr Pharm Des. 2012;18(23):3335–3355. DOI: 10.2174/138161212801227041Kil L.P., Yuvaraj S., Langerak A.W., Hendriks R.W. The role of B cell receptor stimulation in CLL pathogenesis // Curr. Pharm. Des. 2012. Vol. 18, No. 23. P. 3335–3355. DOI: 10.2174/138161212801227041Zenz T, Eichhorst B, Busch R, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010;28(29):4473–4479. DOI: 10.1200/JCO.2009.27.8762Zenz T., Eichhorst B., Busch R. et al. TP53 mutation and survival in chronic lymphocytic leukemia // J. Clin. Oncol. 2010. Vol. 28, No. 29. P. 4473–4479. DOI: 10.1200/JCO.2009.27.8762Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011;29(16):2223–2229. DOI: 10.1200/JCO.2010.32.0838Gonzalez D., Martinez P., Wade R. et al. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial // J. Clin. Oncol. 2011. Vol. 29, No. 16. P. 2223–2229. DOI: 10.1200/JCO.2010.32.0838Malcikova J, Smardova J, Rocnova L, et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood. 2009;114(26):5307–5314. DOI: 10.1182/blood-2009-07-234708Malcikova J., Smardova J., Rocnova L. et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage // Blood. 2009. Vol. 114, No. 26. P. 5307–5314. DOI: 10.1182/blood-2009-07-234708Zenz T, Krober A, Scherer K, et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008;112(8):3322–3329. DOI: 10.1182/blood-2008-04-154070Zenz T., Krober A., Scherer K. et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up // Blood. 2008. Vol. 112, No. 8. P. 3322–3329. DOI: 10.1182/blood-2008-04-154070Robak P, Robak T. Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017;26(11):1249–1265. DOI: 10.1080/13543784.2017.1384814Robak P., Robak T. Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia // Expert. Opin. Investig. Drugs. 2017. Vol. 26, No. 11. P. 1249–1265. DOI: 10.1080/13543784.2017.1384814Chiorazzi N, Ferrarini M. Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities. Blood. 2011;117(6):1781–1791. DOI: 10.1182/blood-2010-07-155663Chiorazzi N., Ferrarini M. Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities // Blood. 2011. Vol. 117, No. 6. P. 1781–1791. DOI: 10.1182/blood-2010-07-155663Klein U, Tu Y, Stolovitzky GA, et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med. 2001;194(11):1625–1638. DOI: 10.1084/jem.194.11.1625Klein U., Tu Y., Stolovitzky G.A. et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells // J. Exp. Med. 2001. Vol. 194, No. 11. P. 1625–1638. DOI: 10.1084/jem.194.11.1625Seifert M, Sellmann L, Bloehdorn J, et al. Cellular origin and pathophysiology of chronic lymphocytic leukemia. J Exp Med. 2012;209(12):2183–2198. DOI: 10.1084/jem.20120833Seifert M., Sellmann L., Bloehdorn J. et al. Cellular origin and pathophysiology of chronic lymphocytic leukemia // J. Exp. Med. 2012. Vol. 209, No. 12. P. 2183–2198. DOI: 10.1084/jem.20120833Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70–. J Exp Med. 2011;208(1):67–80. DOI: 10.1084/jem.20101499Griffin D.O., Holodick N.E., Rothstein T.L. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70– // J. Exp. Med. 2011. Vol. 208, No. 1. P. 67–80. DOI: 10.1084/jem.20101499DiLillo DJ, Weinberg JB, Yoshizaki A, et al. Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function. Leukemia. 2013;27(1):170–182. DOI: 10.1038/leu.2012.165DiLillo D.J., Weinberg J.B., Yoshizaki A. et al. Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function // Leukemia. 2013. Vol. 27, No. 1. P. 170–182. DOI: 10.1038/leu.2012.165Muggen AF, Singh SP, Hendriks RW, Langerak AW. Targeting signaling pathways in chronic lymphocytic leukemia. Curr Cancer Drug Targets. 2016;16(8):669–688. DOI: 10.2174/1568009616666160408145623Muggen A.F., Singh S.P., Hendriks R.W., Langerak A.W. Targeting signaling pathways in chronic lymphocytic leukemia // Curr. Cancer Drug Targets. 2016. Vol. 16, No. 8. P. 669–688. DOI: 10.2174/1568009616666160408145623Agathangelidis A, Darzentas N, Hadzidimitriou A, et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. Blood. 2012;119(19):4467–4475. DOI: 10.1182/blood-2011-11-393694Agathangelidis A., Darzentas N., Hadzidimitriou A. et al. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies // Blood. 2012. Vol. 119, No. 19. P. 4467–4475. DOI: 10.1182/blood-2011-11-393694Murray F, Darzentas N, Hadzidimitriou A, et al. Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood. 2008;111(3):1524–1533. DOI: 10.1182/blood-2007-07-099564Murray F., Darzentas N., Hadzidimitriou A. et al. Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis // Blood. 2008. Vol. 111, No. 3. P. 1524–1533. DOI: 10.1182/blood-2007-07-099564Hayakawa K, Formica AM, Colombo MJ, et al. Loss of a chromosomal region with synteny to human 13q14 occurs in mouse chronic lymphocytic leukemia that originates from early-generated B-1 B cells. Leukemia. 2016;30(7):1510–1519. DOI: 10.1038/leu.2016.61Hayakawa K., Formica A.M., Colombo M.J. et al. Loss of a chromosomal region with synteny to human 13q14 occurs in mouse chronic lymphocytic leukemia that originates from early-generated B-1 B cells // Leukemia. 2016. Vol. 30, No. 7. P. 1510–1519. DOI: 10.1038/leu.2016.61Chen SS, Batliwalla F, Holodick NE, et al. Autoantigen can promote progression to a more aggressive TCL1 leukemia by selecting variants with enhanced B-cell receptor signaling. Proc Natl Acad Sci USA. 2013;110(16):E1500–1507. DOI: 10.1073/pnas.1300616110Chen S.S., Batliwalla F., Holodick N.E. et al. Autoantigen can promote progression to a more aggressive TCL1 leukemia by selecting variants with enhanced B-cell receptor signaling // Proc. Natl. Acad. Sci. USA. 2013. Vol. 110, No. 16. P. E1500–1507. DOI: 10.1073/pnas.1300616110Singh SP, Pillai SY, de Bruijn MJW, et al. Cell lines generated from a chronic lymphocytic leukemia mouse model exhibit constitutive Btk and Akt signaling. Oncotarget. 2017;8(42):71981–71995. DOI: 10.18632/oncotarget.18234Singh S.P., Pillai S.Y., de Bruijn M.J.W. et al. Cell lines generated from a chronic lymphocytic leukemia mouse model exhibit constitutive Btk and Akt signaling // Oncotarget. 2017. Vol. 8, No. 42. P. 71981–71995. DOI: 10.18632/oncotarget.18234Messmer BT, Albesiano E, Efremov DG, et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia. J Exp Med. 2004;200(4):519–525. DOI: 10.1084/jem.20040544Messmer B.T., Albesiano E., Efremov D.G. et al. Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia // J. Exp. Med. 2004. Vol. 200, No. 4. P. 519–525. DOI: 10.1084/jem.20040544Herve M, Xu K, Ng YS, et al. Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J Clin Invest. 2005;115(6):1636–1643. DOI: 10.1172/JCI24387Herve M., Xu K., Ng Y.S. et al. Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity // J. Clin. Invest. 2005. Vol. 115, No. 6. P. 1636–1643. DOI: 10.1172/JCI24387Lanemo Myhrinder A, Hellqvist E, Sidorova E, et al. A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies. Blood. 2008;111(7):3838–3348. DOI: 10.1182/blood-2007-11-125450Lanemo Myhrinder A., Hellqvist E., Sidorova E. et al. A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies // Blood. 2008. Vol. 111, No. 7. P. 3838–3348. DOI: 10.1182/blood-2007-11-125450Hoogeboom R, van Kessel KP, Hochstenbach F, et al. A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi. J Exp Med. 2013;210(1):59–70. DOI: 10.1084/jem.20121801Hoogeboom R., van Kessel K.P., Hochstenbach F. et al. A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi // J. Exp. Med. 2013. Vol. 210, No. 1. P. 59–70. DOI: 10.1084/jem.20121801Duhren-von Minden M, Ubelhart R, Schneider D, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature. 2012;489(7415):309–312. DOI: 10.1038/nature11309Duhren-von Minden M., Ubelhart R., Schneider D. et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signaling // Nature. 2012. Vol. 489, No. 7415. P. 309–312. DOI: 10.1038/nature11309Minici C, Gounari M, Ubelhart R, et al. Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia. Nat Commun. 2017;8:15746. DOI: 10.1038/ncomms15746Minici C., Gounari M., Ubelhart R. et al. Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia // Nat. Commun. 2017. No. 8. P. 15746. DOI: 10.1038/ncomms15746Herman 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(23):6287–6296. DOI: 10.1182/blood-2011-01-328484Herman S.E., Gordon A.L., 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. Vol. 117, No. 23. P. 6287–6296. DOI: 10.1182/blood-2011-01-328484Ponader 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(5):1182–1189. DOI: 10.1182/blood-2011-10-386417Ponader S., Chen S.S., Buggy J.J. 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. Vol. 119, No. 5. P. 1182–1189. DOI: 10.1182/blood-2011-10-386417Kil LP, de Bruijn MJ, van Hulst JA, et al. Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res. 2013;3(1):71–83.Kil L.P., de Bruijn M.J., van Hulst J.A. et al. Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia // Am. J. Blood Res. 2013. Vol. 3, No. 1. P. 71–83.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(11):2590–2594. DOI: 10.1182/blood-2011-11-390989de Rooij M.F., Kuil A., Geest C.R. 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. Vol. 119, No. 11. P. 2590–2594. DOI: 10.1182/blood-2011-11-390989Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57. DOI: 10.1186/s12943-018-0779-zPal Singh S., Dammeijer F., Hendriks R.W. Role of Bruton’s tyrosine kinase in B cells and malignancies // Mol. Cancer. 2018. Vol. 17, No. 1. P. 57. DOI: 10.1186/s12943-018-0779-zByrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323–332. DOI: 10.1056/NEJMoa1509981Byrd J.C., Harrington B., O’Brien S. et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia // N. Engl. J. Med. 2016. Vol. 374, No. 4. P. 323–332. DOI: 10.1056/NEJMoa1509981Honigberg 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 USA. 2010;107(29):13075–13080. DOI: 10.1073/pnas.1004594107Honigberg L.A., Smith A.M., 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. USA. 2010. Vol. 107, No. 29. P. 13075–13080. DOI: 10.1073/pnas.1004594107Herman SEM, Montraveta A, Niemann CU, et al. The Bruton tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia. Clin Cancer Res. 2017;23(11):2831–2841. DOI: 10.1158/1078-0432.CCR-16-0463Gordon M.J., Danilov A.V. The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia // Ther. Adv. Hematol. 2021. No. 12. P. 2040620721989588. DOI: 10.1177/2040620721989588O’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(1):48–58. DOI: 10.1016/S1470-2045(13)70513-8Herman S.E.M., Montraveta A., Niemann C.U. et al. The Bruton tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia // Clin. Cancer Res. 2017. Vol. 23, No. 11. P. 2831–2841. DOI: 10.1158/1078-0432.CCR-16-0463Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. DOI: 10.1056/NEJMoa1215637O’Brien S., Furman R.R., Coutre S.E. 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. Vol. 15, No. 1. P. 48–58. DOI: 10.1016/S1470-2045(13)70513-8Sun 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(19):2213–2219. DOI: 10.1182/blood-2015-04-639203Byrd J.C., Furman R.R., Coutre S.E. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia // N. Engl. J. Med. 2013. Vol. 369, No. 1. P. 32–42. DOI: 10.1056/NEJMoa1215637Lipsky 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(12):1571–1578. DOI: 10.3324/haematol.2015.126672Lipsky A.H., Farooqui M.Z., Tian X. et al. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib // Haematologica. 2015. Vol. 100, No. 12. P. 1571–1578. DOI: 10.3324/haematol.2015.126672Kamel S, Horton L, Ysebaert L, et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation. Leukemia. 2015;29(4):783–787. DOI: 10.1038/leu.2014.247Kamel S., Horton L., Ysebaert L. et al. Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation // Leukemia. 2015. Vol. 29, No. 4. P. 783–787. DOI: 10.1038/leu.2014.247McMullen 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(25):3829–3830. DOI: 10.1182/blood-2014-10-604272McMullen J.R., Boey E.J., Ooi J.Y. et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling // Blood. 2014. Vol. 124, No. 25. P. 3829–3830. DOI: 10.1182/blood-2014-10-604272Rogers KA, Ruppert AS, Bingman A, et al. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia. Leukemia. 2016;30(2):346–350. DOI: 10.1038/leu.2015.273Rogers K.A., Ruppert A.S., Bingman A. et al. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia // Leukemia. 2016. Vol. 30, No. 2. P. 346–350. DOI: 10.1038/leu.2015.273Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286–2294. DOI: 10.1056/NEJMoa1400029Woyach J.A., Furman R.R., Liu T.M. et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib // N. Engl. J. Med. 2014. Vol. 370, No. 24. P. 2286–2294. DOI: 10.1056/NEJMoa1400029Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370(24):2352–2354. DOI: 10.1056/NEJMc1402716Furman R.R., Cheng S., Lu P. et al. Ibrutinib resistance in chronic lymphocytic leukemia // N. Engl. J. Med. 2014. Vol. 370, No. 24. P. 2352–2354. DOI: 10.1056/NEJMc1402716Kadri S, Lee J, Fitzpatrick C, et al. Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL. Blood Adv. 2017;1(12):715–727. DOI: 10.1182/bloodadvances.2016003632Kadri S., Lee J., Fitzpatrick C. et al. Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL // Blood Adv. 2017. Vol. 1, No. 12. P. 715–727. DOI: 10.1182/bloodadvances.2016003632Krysiak K, Gomez F, White BS, et al. Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma. Blood. 2017;129(4):473–483. DOI: 10.1182/blood-2016-07-729954Krysiak K., Gomez F., White B.S. et al. Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma // Blood. 2017. Vol. 129, No. 4. P. 473–483. DOI: 10.1182/blood-2016-07-729954Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874–879. DOI: 10.3324/haematol.2017.182907Mato A.R., Nabhan C., Thompson M.C. et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis // Haematologica. 2018. Vol. 103, No. 5. P. 874–879. DOI: 10.3324/haematol.2017.182907Pleyer C, Sun C, Desai S, et al. Reconstitution of humoral immunity and decreased risk of infections in patients with chronic lymphocytic leukemia treated with Bruton tyrosine kinase inhibitors. Leuk Lymphoma. 2020;61(10):2375–2382. DOI: 10.1080/10428194.2020.1772477Pleyer C., Sun C., Desai S. et al. Reconstitution of humoral immunity and decreased risk of infections in patients with chronic lymphocytic leukemia treated with Bruton tyrosine kinase inhibitors // Leuk. Lymphoma. 2020. Vol. 61, No. 10. P. 2375–2382. DOI: 10.1080/10428194.2020.1772477Tillman BF, Pauff JM, Satyanarayana G, et al. Systematic review of infectious events with the BTK inhibitor ibrutinib in the treatment of haematologic malignancies. Eur J Haematol. 2018;100(4):325–334. DOI: 10.1111/ejh.13020Tillman B.F., Pauff J.M., Satyanarayana G. et al. Systematic review of infectious events with the BTK inhibitor ibrutinib in the treatment of haematologic malignancies // Eur. J. Haematol. 2018. Vol. 100, No. 4. P. 325–334. DOI: 10.1111/ejh.13020Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–223. DOI: 10.1056/NEJMoa1400376Byrd J.C., Brown J.R., O’Brien S. et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia // N. Engl. J. Med. 2014. Vol. 371, No. 3. P. 213–223. DOI: 10.1056/NEJMoa1400376Barr PM, Robak T, Owen C, et al. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018;103(9):1502–1510. DOI: 10.3324/haematol.2018.192328Barr P.M., Robak T., Owen C. et al. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2 // Haematologica. 2018. Vol. 103, No. 9. P. 1502–1510. DOI: 10.3324/haematol.2018.192328O’Brien S, Hillmen P, Coutre S, et al. Safety analysis of four randomized controlled studies of ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma or mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18(10):648–657. DOI: 10.1016/j.clml.2018.06.016O’Brien S., Hillmen P., Coutre S. et al. Safety analysis of four randomized controlled studies of ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma or mantle cell lymphoma // Clin. Lymphoma Myeloma Leuk. 2018. Vol. 18, No. 10. P. 648–657. DOI: 10.1016/j.clml.2018.06.016Ghez D., Calleja A., Protin C. et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018;131(17):1955–1959. DOI: 10.1182/blood-2017-11-818286Ghez D., Calleja A., Protin C. et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib // Blood. 2018. Vol. 131, No. 17. P. 1955–1959. DOI: 10.1182/blood-2017-11-818286Ruchlemer R, Ben-Ami R, Bar-Meir M, et al. Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: An observational study. Mycoses. 2019;62(12):1140–1147. DOI: 10.1111/myc.13001Ruchlemer R., Ben-Ami R., Bar-Meir M. et al. Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: An observational study // Mycoses. 2019. Vol. 62, No. 12. P. 1140–1147. DOI: 10.1111/myc.13001Rogers K.A., Mousa L., Zhao Q. et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies. Leukemia. 2019;33(10):2527–2530. DOI: 10.1038/s41375-019-0481-1Rogers K.A., Mousa L., Zhao Q. et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies // Leukemia. 2019. Vol. 33, No. 10. P. 2527–2530. DOI: 10.1038/s41375-019-0481-1Woyach J.A. Ibrutinib and Aspergillus: a Btk-targeted risk. Blood. 2018;132(18):1869–1870. DOI: 10.1182/blood-2018-08-865659Woyach J.A. Ibrutinib and Aspergillus: a Btk-targeted risk // Blood. 2018. Vol. 132, No. 18. P. 1869–1870. DOI: 10.1182/blood-2018-08-865659Ahn I.E., Jerussi T., Farooqui M. et al. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood. 2016;128(15):1940–1943. DOI: 10.1182/blood-2016-06-722991Ahn I.E., Jerussi T., Farooqui M. et al. Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib // Blood. 2016. Vol. 128, No. 15. P. 1940–1943. DOI: 10.1182/blood-2016-06-722991Hsiehchen D, Arasaratnam R, Raj K, et al. Ibrutinib use complicated by progressive multifocal leukoencephalopathy. Oncology. 2018;95(5):319–322. DOI: 10.1159/000490617Hsiehchen D., Arasaratnam R., Raj K. et al. Ibrutinib use complicated by progressive multifocal leukoencephalopathy // Oncology. 2018. Vol. 95, No. 5. P. 319–322. DOI: 10.1159/000490617Dousa KM, Babiker A, Van Aartsen D, et al. Ibrutinib therapy and mycobacterium chelonae. Skin and soft tissue infection. Open Forum Infect Dis. 2018;5(7):ofy168. DOI:10.1093/ofid/ofy168Dousa K.M., Babiker A., van Aartsen D. et al. Ibrutinib therapy and mycobacterium chelonae. Skin and soft tissue infection // Open Forum Infect. Dis. 2018. Vol. 5, No. 7. P. ofy168. DOI:10.1093/ofid/ofy168Bose P, Gandhi V. Managing chronic lymphocytic leukemia in 2020: an update on recent clinical advances with a focus on BTK and BCL-2 inhibitors. Fac Rev. 2021;10:22. DOI: 10.12703/r/10-22Bose P., Gandhi V. Managing chronic lymphocytic leukemia in 2020: an update on recent clinical advances with a focus on BTK and BCL-2 inhibitors // Fac. Rev. 2021. No. 10. P. 22. DOI: 10.12703/r/10-22Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): A covalent bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240–252. DOI: 10.1124/jpet.117.242909Barf T., Covey T., Izumi R. et al. Acalabrutinib (ACP-196): A covalent bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile // J. Pharmacol. Exp. Ther. 2017. Vol. 363, No. 2. P. 240–252. DOI: 10.1124/jpet.117.242909Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3(9):1553–1562. DOI: 10.1182/bloodadvances.2018030007Awan F.T., Schuh A., Brown J.R. et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib // Blood Adv. 2019. Vol. 3, No. 9. P. 1553–1562. DOI: 10.1182/bloodadvances.2018030007Yazdy M, Mato A, Roeker L, et al. Toxicities and outcomes of acalabrutinib-treated patients with chronic lymphocytic leukemia: a retrospective analysis of real world patients. Blood. 2019;134(Suppl 1):4311. DOI: 10.1182/blood-2019-130062Yazdy M., Mato A., Roeker L. et al. Toxicities and outcomes of acalabrutinib-treated patients with chronic lymphocytic leukemia: a retrospective analysis of real world patients // Blood. 2019. Vol. 134, No. Suppl 1. P. 4311. DOI: 10.1182/blood-2019-130062Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278–1291. DOI: 10.1016/S0140-6736(20)30262-2Sharman J.P., Egyed M., Jurczak W. et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial // Lancet. 2020. Vol. 395, No. 10232. P. 1278–1291. DOI: 10.1016/S0140-6736(20)30262-2