Infectious complications in patients with chronic lymphocytic leukemia treated with bruton’s tyrosine kinase inhibitors

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

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.

Full Text

Restricted Access

About the authors

Yulia S. Torshina

Institute of Experimental Medicine

Email: torshina.doc18@yandex.ru
ORCID iD: 0000-0002-2387-2712
SPIN-code: 1676-5162

Postgraduate student of Department of Immunology

Russian Federation, Saint Petersburg

Natalia B. Serebryanaya

Institute of Experimental Medicine; North-Western State Medical University named after I.I. Mechnikov

Author for correspondence.
Email: nbvma@mail.ru
ORCID iD: 0000-0002-2418-9368
SPIN-code: 2240-1277
ResearcherId: G-1663-2015

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

Russian Federation, Saint Petersburg

References

  1. 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: 10.1080/10428194.2017.1349905
  2. Morton 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-2005-06-2508
  3. Watson 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.x
  4. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007;57(1):43–66. doi: 10.3322/canjclin.57.1.43
  5. Dores 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.x
  6. Zlokachestvennye novoobrazovaniya v Rossii v 2017 godu (zabolevaemost’ i smertnost’). Ed. by A.D. Kaprin, V.V. Starinski, G.V. Petrova. Moscow; 2018. (In Russ.)
  7. 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.
  8. 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: 10.2174/138161212801227041
  9. Zenz 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.2009.27.8762
  10. Gonzalez 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.2010.32.0838
  11. Malcikova 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-2009-07-234708
  12. Zenz 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-2008-04-154070
  13. Robak P, Robak T. Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017;26(11):1249–1265. doi: 10.1080/13543784.2017.1384814
  14. Chiorazzi 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-2010-07-155663
  15. Klein 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.194.11.1625
  16. Seifert 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.20120833
  17. Griffin 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.20101499
  18. DiLillo 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.2012.165
  19. Muggen AF, Singh SP, Hendriks RW, Langerak AW. Targeting signaling pathways in chronic lymphocytic leukemia. Curr Cancer Drug Targets. 2016;16(8):669–688. doi: 10.2174/1568009616666160408145623
  20. Agathangelidis 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-2011-11-393694
  21. Murray 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-2007-07-099564
  22. Hayakawa 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.2016.61
  23. Chen 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.1300616110
  24. Singh 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.18234
  25. Messmer 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.20040544
  26. Herve 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/JCI24387
  27. Lanemo 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-2007-11-125450
  28. Hoogeboom 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.20121801
  29. Duhren-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/nature11309
  30. Minici 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/ncomms15746
  31. Herman 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-2011-01-328484
  32. Ponader 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-2011-10-386417
  33. Kil 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.
  34. 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-2011-11-390989
  35. Pal 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-z
  36. Byrd 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/NEJMoa1509981
  37. Honigberg 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.1004594107
  38. Herman 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-16-0463
  39. O’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)70513-8
  40. Byrd 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/NEJMoa1215637
  41. Sun 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-2015-04-639203
  42. Lipsky 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.2015.126672
  43. Kamel 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.2014.247
  44. McMullen 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-2014-10-604272
  45. Rogers 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.2015.273
  46. Woyach 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/NEJMoa1400029
  47. Furman 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/NEJMc1402716
  48. Kadri 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.2016003632
  49. Krysiak 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-2016-07-729954
  50. Mato 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.2017.182907
  51. Pleyer 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: 10.1080/10428194.2020.1772477
  52. Tillman 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.13020
  53. Byrd 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/NEJMoa1400376
  54. Barr 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.2018.192328
  55. O’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.2018.06.016
  56. Ghez 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-2017-11-818286
  57. Ruchlemer 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.13001
  58. Rogers 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/s41375-019-0481-1
  59. Woyach J.A. Ibrutinib and Aspergillus: a Btk-targeted risk. Blood. 2018;132(18):1869–1870. doi: 10.1182/blood-2018-08-865659
  60. Ahn 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-2016-06-722991
  61. Hsiehchen D, Arasaratnam R, Raj K, et al. Ibrutinib use complicated by progressive multifocal leukoencephalopathy. Oncology. 2018;95(5):319–322. doi: 10.1159/000490617
  62. Dousa 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/ofy168
  63. Bose 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/10-22
  64. Barf 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.117.242909
  65. Awan 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.2018030007
  66. Yazdy 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-2019-130062
  67. Sharman 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)30262-2

Supplementary files

Supplementary Files
Action
1. Fig. 1. BTK structure. Various domains and an autophosphorylation site (Y223), a phosphorylation site (Y551) that activates BTK, and the C481 binding site of ibrutinib are shown. Upon activation, BTK is phosphorylated at tyrosine at position Y551 by kinases of the SYK or SRC family. Phosphorylation of BTK at Y551 promotes its catalytic activity and leads to its autophosphorylation at position Y223 in the SH3 domain. It is believed that phosphorylation at Y223 stabilizes the active conformation and fully activates BTK (adapted from [34])

Download (36KB)
2. Fig. 2. BTK in the BCR signaling pathway. When BCR cross-links, protein kinases of the SRC family (LYN, FYN) interact with intracellular tyrosine activation motifs located on CD79A/B proteins, which leads to the activation of spleen tyrosine kinase (SYK). SYK then recruits a signaling complex bound with plasma membrane, which includes BTK as well as adapter molecules such as B-cell linker protein (BLNK). The complex then activates phospholipase Cã2 (PLCã2), Ras and protein kinase C (PKC). Ras signals down to extracellular regulated kinase (ERK1), while PKC leads to the activation of mitogen-activated protein kinases (MAPK) and transcription factors, including MYC and NF-êB (adapted from [34])

Download (170KB)
3. Fig. 3. Chemical structures of irreversible inhibitors of BTK, bottom right — a model of the binding of acalabrutinib to BTK in the ATP-binding pocket (adapted from [65])

Download (255KB)

Copyright (c) 2021 Torshina Y.S., Serebryanaya N.B.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 74760 от 29.12.2018 г.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies