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.

Novel Tyrosine Kinase Inhibitors Trigger Drug Sensitivity of Primary CLL Cells by Controlling Glucosylation of Ceramides

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3905-3905
Author(s):  
Janine Schwamb ◽  
Valeska Feldhaus ◽  
Michael Baumann ◽  
Michaela Patz ◽  
Susanne Brodesser ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Treatment Options ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Published Data ◽  
The Novel ◽  
Apoptosis Resistance

Abstract Abstract 3905 Background: Apoptosis resistance of chronic lymphocytic leukemia (CLL) cells is mediated by several pro-survival stimuli. In particular, engagement of the B-cell receptor (BCR), CD40-CD40 ligand (CD40L) interaction or stimulation by interleukin-(IL)-4 were identified as major factors to regulate chemoresistance. Sphingolipids are known to be involved in several metabolic pathways involved in chemoresitance. Therefore, we focused on ceramide as pro-apoptotic molecule and its counterpart glucosylceramide, which rather contributes to proliferation and survival. Methods and Results: Applying liquid chromatography electrospray ionization tandem mass spectrometry, we revealed a significant decrease of pro-apoptotic ceramide in BCR/IL-4/CD40L-stimulated primary CLL cells compared to untreated controls (p=0.0258, p=0.0478, p=0.0114). Anti-apoptotic glucosylceramide levels were significantly increased after BCR cross-linking (p=0.0435) while other stimuli caused no relevant change in glucosylceramide expression. We identified BCR engagement to catalyze the crucial modification of ceramide to glucosylceramide via the enzyme UDP-glucose ceramide glucosyltransferase (UGCG) (p=0.0001). Besides specific UGCG inhibitors, we could show for the first time that IgM-mediated UGCG expression was significantly inhibited by the novel and highly effective PI3Kδ and BTK inhibitors CAL-101 and PCI-32765, which were able to revert IgM-induced apoptosis resistance of CLL cells. Recently published data revealed sphingolipids to be essential for mediation of apoptosis via mitochondria. Therefore, we chose ABT-737 – a well-known and also mitochondria-targeting drug – as candidate partner for PI3Kδ and BTK inhibition. When combining each tyrosine kinase inhibitor with ABT-737, a synergistic apoptotic effect could be documented, even under protection by BCR stimulation. Conclusion: In summary, we could demonstrate that sphingolipids are critically involved in CLL pathogenesis. UGCG could be identified as drugable target by the novel kinase inhibitors CAL-101 and PCI-32765 resulting in even synergistic apoptosis following additional application of ABT-737. Sphingolipids seem to offer further targets providing novel treatment options in CLL. C.M.W. and L.P.F. contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.

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.

The Different Faces of Chronic Lymphocytic Leukemia -Two Clinical Cases

2020 ◽  
Vol 13 (1) ◽  
pp. 63-66
Author(s):  
Vanya S. Popova ◽  
Kalina K. Ignatova ◽  
Dobromir D. Nguen ◽  
Pencho T. Tonchev ◽  
Doroteya K. Todorieva ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Age Groups ◽  
Lymphocytic Leukemia ◽  
Inadequate Response ◽  
Tumor Resistance ◽  
Btk Inhibitor ◽  
Indolent Lymphomas ◽  
Clinical Cases

Summary Chronic lymphocytic leukemia is one of the most common types of leukemia affecting adults over 65 years of age [1]. The disease is a part of the so-called indolent lymphomas and has a variable clinical course, defined by many factors. In recent years, knowing better the pathogenetic mechanisms of the disease, significant advances in the treatment have been made [2]. Monoclonal antibodies, immunomodulators, tyrosine kinase inhibitors, anti-apoptotic Bcl-2 protein inhibitors have been approved for clinical practice. Nevertheless, the development of tumor resistance and recurrence of the disease remains a challenge for hematologists, biologists, and pharmacists. We present two clinical cases of patients of both age groups (young adults and adults), in whom treatment was started with a Bruton’s tyrosine kinase (BTK) inhibitor, after inadequate response to immunochemotherapy (CIT).

scholarly journals Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors

2020 ◽  
Vol 1 (3) ◽  
pp. 131-152 ◽  
Author(s):  
Rachael Arthur ◽  
Beatriz Beatriz Valle-Argos ◽  
Andrew J. Steele ◽  
Graham Packham
Keyword(s):  
B Cell ◽  
Kinase Inhibitors ◽  
Early Stage ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Clinical Responses ◽  
B Cell Receptor Signaling ◽  
Btk Inhibitor ◽  
Emergence Of Resistance

Chronic lymphocytic leukemia is a common form of leukemia and is dependent on growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is an important mediator of B-cell receptor signaling and the irreversible BTK inhibitor ibrutinib can trigger dramatic clinical responses in treated patients. However, emergence of resistance and toxicity are major limitations which lead to treatment discontinuation. There remains, therefore, a clear need for new therapeutic options. In this review, we discuss recent progress in the development of BTK-targeted proteolysis targeting chimeras (PROTACs) describing how such agents may provide advantages over ibrutinib and highlighting features of PROTACs that are important for the development of effective BTK degrading agents. Overall, PROTACs appear to be an exciting new approach to target BTK. However, development is at a very early stage and considerable progress is required to refine these agents and optimize their drug-like properties before progression to clinical testing.

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 Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies

2014 ◽  
Vol 32 (17) ◽  
pp. 1830-1839 ◽  
Author(s):  
Sabine Ponader ◽  
Jan A. Burger
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Btk Inhibitor

Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy.

scholarly journals Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4353-4358 ◽  
Author(s):  
Dushyant Verma ◽  
Hagop Kantarjian ◽  
Sara S. Strom ◽  
Mary Beth Rios ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Myeloproliferative Neoplasm ◽  
Disease Free Survival ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Second Cancers

Abstract Success of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has given patients hope for a long disease-free-survival. A longer survival raises the question of late effects, including development of another malignancy. Records of 1445 patients with CML/myeloproliferative neoplasm or other hematologic malignancies treated with TKIs were reviewed to investigate frequency and characteristics of second malignancies (other than acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic syndrome). The number of second cancers was compared with the number expected from the Surveillance, Epidemiology, and End Results database. After a median follow-up of 107 months (range, 13-362 months) after CML/myeloproliferative neoplasm diagnosis, 66 patients (4.6%) developed 80 second cancers, including skin (31%), prostate (15%), melanoma (13%), digestive system (10%), kidney (4%), thyroid (4%), breast (3%), chronic lymphocytic leukemia (3%), hepatobiliary (3%), and other cancers (14%). Excluding nonmelanoma skin cancers, 55 second cancers were seen in 51 (3.5%) of all patients treated. The risk of second cancer was lower than expected (observed-to-expected ratio, 0.6; 95% confidence interval, 0.44-0.81). Second cancers occur in a small percentage of patients receiving therapy with TKIs for hematologic malignancies, mostly CML. No evidence at the moment suggests that exposure to TKIs increases the risk of developing second cancers.

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.

ZAP-70 Expression in Chronic Lymphocytic Leukemia Is Associated with Altered Signal Transduction.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4702-4702
Author(s):  
Kristy L. Wolniak ◽  
James Marvin ◽  
Charles Goolsby
Keyword(s):  
Signal Transduction ◽  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Cell Receptor ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
Prognostic Information

Abstract B-cell chronic lymphocytic leukemia (CLL) is a malignancy of mature B-cells with a variable clinical course. Given the heterogeneity of disease course, identification of prognostic factors is imperative. One recently identified negative prognostic indicator in CLL is the T-cell tyrosine kinase ZAP70. ZAP70 is analogous to, and can functionally substitute for, the B-cell tyrosine kinase Syk and is activated following B cell receptor (BCR) crosslinking in CLL cells. However, the role of ZAP70 expression in CLL remains elusive. Utilizing flow cytometric analyses of signal transduction molecules, this study examined if ZAP70 expression affects signal transduction in CLL. Peripheral blood samples from ZAP70+ and ZAP70− CLL patients were analyzed. The levels of phosphorylated ERK, STAT5, and S6 (p-ERK, p-STAT5, p-S6) were measured by flow cytometry with and without BCR stimulation. Kinase inhibitors were used to verify the measured phosphorlyated protein levels. Increased constitutive levels of p-ERK, p-STAT5, and p-S6 were seen in ZAP70+ CLL cells as compared to ZAP70− CLL cells. BCR crosslinking gave variable responses in both ZAP70+ and ZAP70− CLL. The majority of ZAP70− cases showed no significant activation or a predominant activation of ERK with rare p-S6 activation. ZAP70+ cells showed activation of either, or both, ERK and S6 pathways and fewer showing no activation. In summary, though the role of ZAP70 in B cell signaling is poorly understood, expression of ZAP70 in CLL correlates with a constitutively active phenotype. Additionally, differential response in ZAP70+ versus ZAP70− cases following BCR crosslinking suggests a possible modulatory role of the BCR pathway. Current studies are underway to determine if these measures carry prognostic information and if the varying signal responses to BCR stimulation correlate with reported differences in apoptotic versus proliferative response.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery

2020 ◽  
Vol 17 (5) ◽  
pp. 585-615 ◽  
Author(s):  
Nikhil S. Sakle ◽  
Shweta A. More ◽  
Sachin A. Dhawale ◽  
Santosh N. Mokale
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Cell Functions ◽  
Anaplastic Lymphoma

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

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