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

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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.

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

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2. 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])

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3. 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])

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4. 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])

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

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