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

2021 ◽  
Vol 21 (3) ◽  
pp. 15-27
Author(s):  
Yulia S. Torshina ◽  
Natalia B. Serebryanaya
Keyword(s):  
Clinical Practice ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Scientific Literature ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
Lymphoproliferative Diseases ◽  
New Class ◽  
Btk Inhibitors

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 Brutons 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.

scholarly journals Bruton tyrosine kinase inhibitors for the frontline treatment of chronic lymphocytic leukemia

2020 ◽  
Vol 27 (6) ◽  
Author(s):  
V. Banerji ◽  
A. Aw ◽  
S. Robinson ◽  
S. Doucette ◽  
A. Christofides ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Variable Region ◽  
Tp53 Gene ◽  
Cell Receptor ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Btk Inhibitors

Chronic lymphocytic leukemia (CLL) is the most commonly diagnosed adult leukemia in Canada. Biologic heterogeneity of CLL can be observed between patients which results in variable disease trajectory and response to therapy. Notably, patients with high-risk features such as the presence of deletions in chromosome 17p, aberrations in the TP53 gene, or unmutated immunoglobulin heavy chain variable region genes have inferior outcomes and response to standard chemoimmunotherapy compared to patients without these features. Novel agents which target the B cell receptor signalling pathway, such as Bruton’s tyrosine kinase (BTK) inhibitors have demonstrated clinical efficacy and safety in patients with treatment-naïve CLL, particularly in those with high-risk features. However, due to the current lack of head-to-head trials comparing BTK inhibitors, selection of the optimal BTK inhibitor for patients with CLL is unclear and requires the consideration of multiple factors. This review focuses on the efficacy, safety, and pharmacological features of the BTK inhibitors that are approved or are under clinical development and discusses the practical considerations for the use of these agents in the Canadian treatment landscape.

scholarly journals The TKI Era in Chronic Leukemias

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2201
Author(s):  
Danilo De Novellis ◽  
Fabiana Cacace ◽  
Valeria Caprioli ◽  
William G. Wierda ◽  
Kris M. Mahadeo ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Cell Receptor ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Pi3k Inhibitors ◽  
Cell Functions ◽  
Improved Outcomes ◽  
Btk Inhibitor

Tyrosine kinases are proteins involved in physiological cell functions including proliferation, differentiation, and survival. However, the dysregulation of tyrosine kinase pathways occurs in malignancy, including hematological leukemias such as chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Particularly, the fusion oncoprotein BCR-ABL1 in CML and the B-cell receptor (BCR) signaling pathway in CLL are critical for leukemogenesis. Therapeutic management of these two hematological conditions was fundamentally changed in recent years, making the role of conventional chemotherapy nearly obsolete. The first, second, and third generation inhibitors (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) of BCR-ABL1 and the allosteric inhibitor asciminib showed deep genetic and molecular remission rates in CML, leading to the evaluation of treatment discontinuation in prospective trials. The irreversible BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and spebrutinib) covalently bind to the C481 amino acid of BTK. The reversible BTK inhibitor pirtobrutinib has a different binding site, overcoming resistance associated with mutations at C481. The PI3K inhibitors (idelalisib and duvelisib) are also effective in CLL but are currently less used because of their toxicity profiles. These tyrosine kinase inhibitors are well-tolerated, do have some associated in-class side effects that are manageable, and have remarkably improved outcomes for patients with hematologic malignancies.

scholarly journals A Review of the Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Donald C. Moore, PharmD, BCPS, BCOP, DPLA ◽  
Daniel Thompson, PharmD
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase ◽  
Integral Role ◽  
Btk Inhibitors

The B-cell receptor signaling pathway plays an integral role in the proliferation and survival of malignant B cells. Targeting the B-cell receptor pathway via the inhibition of Bruton tyrosine kinase (BTK) has evolved the treatment of a variety of B-cell malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia. Currently, there are three BTK inhibitors approved by the U.S. Food and Drug Administration: ibrutinib, acalabrutinib, and zanubrutinib. This article reviews the pharmacology, clinical efficacy, safety, dosing, drug-drug interactions, and implications for advanced practitioners of BTK inhibitors in the treatment of B-cell malignancies.

scholarly journals Combination of Gatekeeper Mutations and Cysteine 481 Replacement Causes Super Resistance to the Irreversible BTK Inhibitors Ibrutinib, Acalabrutinib and Zanubrutinib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5759-5759
Author(s):  
Hernando Yesid Estupiñan Velasquez ◽  
Yuye Shi ◽  
Dara K. Mohammad ◽  
Qing Wang ◽  
Mauno Vihinen ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Resistance Mutation ◽  
Kinase Domain ◽  
Lymphocytic Leukemia ◽  
Resistance Mutations ◽  
Nucleotide Substitutions ◽  
Single Nucleotide Change ◽  
Btk Inhibitors

Resistance to the irreversible Bruton´s tyrosine kinase (BTK) inhibitors is the main cause of disease progression in patients with Chronic Lymphocytic Leukemia (Quinquenel et. al. Blood 2019). Cysteine to serine substitution at the position 481 in BTK, is the most common resistance mutation. Other less frequent mutations like the constitutively active phospholipase C-gamma 2 (PLCG2) variant also occur (Woyach et. al. J. Clin. Oncology 2017). Different from many other tyrosine kinase inhibitors, BTK mutations less frequently affect the gatekeeper residue in the kinase domain (Maddocks et. al. JAMA Oncology 2015). In this study, we have performed mutation scanning with substitutions replacing the gatekeeper residue. We have generated all the possible amino acid substitutions requiring a single nucleotide change in the gatekeeper and several variants requiring 2 or 3 nucleotide substitutions. Selected variants were also combined with substitutions at the C481, which is the binding site of irreversible BTK inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib. Our results show unexpected, super-resistant variants and demonstrate that concomitant mutations, such as cysteine 481 to serine combined with threonine 474 to isoleucine or methionine, enhanced the resistance to irreversible BTK inhibitors. On the other hand, reversible BTK inhibitors displayed different inhibitory responses against the super-resistant mutants. Binding of the BTK inhibitors was subjected to molecular dynamics predictions, which correlated with the experimental binding data. Based on the available clinical and experimental results, the mechanisms underlying the spectrum of resistance mutations in BTK are presented. Disclosures No relevant conflicts of interest to declare.

scholarly journals Observations on the use of Bruton’s tyrosine kinase inhibitors in SAR-CoV-2 and cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Brooke Benner ◽  
William E. Carson
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Innate Immune ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Process Understanding ◽  
Btk Inhibitors ◽  
Severe Lung Disease ◽  
Pro Inflammatory Cytokines ◽  
Severe Lung

AbstractBruton’s tyrosine kinase (BTK) inhibitors, drugs utilized in cancer, are being repurposed for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (COVID-19). Recently, BTK inhibitors acalabrutinib and ibrutinib have been found to protect against pulmonary injury in a small group of patients infected with SARS-CoV-2. The high levels of pro-inflammatory cytokines found in the circulation of COVID-19 patients with severe lung disease suggest the involvement of the innate immune system in this process. Understanding the potential mechanism of action of BTK inhibition in SARS-CoV-2 is clearly of importance to determine how acalabrutinib, ibrutinib and possibly other BTK inhibitors may provide protection against lung injury.

scholarly journals Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

2021 ◽  
Vol 14 (7) ◽  
pp. 626
Author(s):  
Julie Bolcaen ◽  
Shankari Nair ◽  
Cathryn H. S. Driver ◽  
Tebatso M. G. Boshomane ◽  
Thomas Ebenhan ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Radionuclide Therapy ◽  
Kinase Inhibitors ◽  
Nuclear Imaging ◽  
Therapy Resistance ◽  
Targeted Radionuclide Therapy ◽  
Therapy Strategy ◽  
Dismal Prognosis

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

scholarly journals Discontinuation of tyrosine kinase inhibitors in CML patients in real-world clinical practice at a single institution

BMC Cancer ◽  
2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Nuno Cerveira ◽  
Bruno Loureiro ◽  
Susana Bizarro ◽  
Cecília Correia ◽  
Lurdes Torres ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Real World ◽  
Kinase Inhibitors ◽  
Single Institution

scholarly journals The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

2021 ◽  
Author(s):  
Tadeusz Robak ◽  
Magda Witkowska ◽  
Piotr Smolewski
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Effects ◽  
Kinase Inhibitors ◽  
Clinical History ◽  
Lymphocytic Leukemia ◽  
Current Status ◽  
Covalent Inhibitors ◽  
History Of ◽  
Reduced Toxicity ◽  
Btk Inhibitors

The use of the Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKIs are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib is the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in an early phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, drug-drug interactions associated with the treatment of CLL with BTK inhibitors, and examines its further implications.

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