PI3-Kinase Inhibitors in Chronic Lymphocytic Leukemia

2014 ◽  
Vol 9 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Julie E. Chang ◽  
Brad S. Kahl
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
Pi3 Kinase ◽  
Lymphocytic Leukemia

THE ROLE OF THE GENETIC ABNORMALITIES, EPIGENETIC AND microRNA IN THE PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA

2018 ◽  
Vol 40 (4) ◽  
pp. 261-267 ◽  
Author(s):  
K Tari ◽  
Z Shamsi ◽  
H Reza Ghafari ◽  
A Atashi ◽  
M Shahjahani ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
Bone Marrow Involvement ◽  
P53 Mutation ◽  
Lymphocytic Leukemia ◽  
Gene Promoters ◽  
Epigenetic Changes ◽  
Genetic Changes ◽  
Trisomy 12

Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

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.

scholarly journals Autoimmune Hemolytic Anemia After Relapse of Chronic Myeloid Leukemia: A Case Report

2019 ◽  
Vol 12 ◽  
pp. 1179545X1989457
Author(s):  
Tahseen Hamamyh ◽  
Mohamed A Yassin
Keyword(s):  
Case Report ◽  
Chronic Myeloid Leukemia ◽  
Chronic Lymphocytic Leukemia ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
Sudden Drop ◽  
Leukemia Relapse

Autoimmune hemolytic anemia is one of the differential diagnoses for anemia in patients with lymphoproliferative neoplasia, such as chronic lymphocytic leukemia, who experience sudden drop in hemoglobin. The association between autoimmune hemolytic anemia and chronic myeloid leukemia on the contrary is unusual. Here we present a patient with a background of chronic myeloid leukemia treated previously with Tyrosine Kinase Inhibitors, then developed autoimmune hemolysis simultaneously with chronic myeloid leukemia relapse. Hemolysis was treated with steroids with good response.

Chronic Lymphocytic Leukemia: State of the Art and Beyond

2014 ◽  
Vol 12 (5S) ◽  
pp. 801-803
Author(s):  
John C. Byrd
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
State Of The Art ◽  
Lymphocytic Leukemia ◽  
Newly Diagnosed ◽  
Treatment Standard ◽  
Genetic Features ◽  
Treatment Paradigm ◽  
Genomic Studies ◽  
Poor Outcomes

In the treatment of chronic lymphocytic leukemia (CLL), select genomic studies can assist in risk stratification of newly diagnosed patients. Chemoimmunotherapy targeting CD20 offers a survival advantage in symptomatic patients both with and without these high-risk genetic features, though patients with del(17p13.1) have poor outcomes and require specific intervention. Obinutuzumab plus chlorambucil is a treatment standard for untreated elderly patients and is superior to rituximab plus chlorambucil. In the setting of relapsed CLL, the new kinase inhibitors have the potential to completely change the treatment paradigm of CLL.

scholarly journals Incorporating Novel Targeted and Immunotherapeutic Agents in Treatment of B-Cell Lymphomas

2021 ◽  
pp. 1-18
Author(s):  
Harsh Shah ◽  
Deborah Stephens ◽  
John Seymour ◽  
Kami Maddocks
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Targeted Agents ◽  
Large B Cell Lymphoma ◽  
Indolent Lymphomas ◽  
Large B Cell

The introduction of novel targeted agents and immunotherapeutic modalities into the treatment of B-cell lymphomas has drastically shifted the treatment landscape. In diffuse large B-cell lymphoma, recent approvals of CAR T-cell therapy, the antibody-drug conjugate polatuzumab, and the anti-CD19 monoclonal antibody tafasitamab have provided efficacious options for patients with relapsed and refractory disease. These immunotherapies attempt to harness power from the patient’s own immune system to eradicate lymphoma. In chronic lymphocytic leukemia, oral targeted kinase inhibitors such as ibrutinib and acalabrutinib (Bruton tyrosine kinase inhibitors) and venetoclax (BCL2 inhibitor) are now favored over chemoimmunotherapy for upfront treatment because of improved progression-free survival across all subgroups (including high-risk subgroups such as unmutated immunoglobulin variable heavy chain and chromosome 17p deletion). In indolent lymphomas, several PI3K inhibitors are approved for treatment of relapsed disease. However, uptake of these agents has been limited because of toxicity concerns. Combination of lenalidomide and rituximab has been a safe and effective immune modality for patients with refractory indolent lymphomas; it is currently being used as a backbone to bring other targeted agents such as tazemetostat (EZH2 inhibitor) into earlier lines of treatment. In this article, we will review novel commercially available agents in the treatment of relapsed/refractory diffuse large B-cell lymphoma, treatment-naïve chronic lymphocytic leukemia, and relapsed/refractory indolent lymphomas. We will evaluate clinical trials that led to their approval and will provide an outlook into the future novel agents currently under investigation in B-cell malignancies.

scholarly journals Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 88-96 ◽  
Author(s):  
Adrian Wiestner
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Absolute Lymphocyte Count ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Trafficking

Abstract Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend on host factors in the tissue microenvironment for survival and proliferation. In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors are provided that support their survival. Signaling pathways activated in the microenvironment in vivo include the B-cell receptor (BCR) and NF-κB pathways. Thus, CLL is a disease “addicted to the host” and is dependent on pathways that promote normal B-cell development, expansion, and survival; this is particularly true in the case of the BCR signaling cascade. Small-molecule inhibitors of kinases that are essential for BCR signal transduction abrogate the stimulating effects of the microenvironment on CLL cells. The orally administered tyrosine kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol 3-kinase inhibitor GS-1101 have induced impressive responses in relapsed and refractory CLL patients, mostly with moderate side effects. Reductions in lymphadenopathy and splenomegaly are seen within weeks and are frequently accompanied by a transient rise in absolute lymphocyte count that is asymptomatic and probably the result of changes in CLL cell trafficking. This review discusses the biologic basis for kinase inhibitors as targeted therapy of CLL and summarizes the exciting early clinical experience with these agents.

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