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 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.

Evaluation of the novel Bruton′s tyrosine kinase (BTK) inhibitor GDC-0853 in chronic lymphocytic leukemia (CLL) with wild type or C481S mutated BTK.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 7530-7530 ◽  
Author(s):  
Sean David Reiff ◽  
Daphne Guinn ◽  
Rose Mantel ◽  
Lisa Smith ◽  
Carolyn Cheney ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Lymphocytic Leukemia ◽  
The Novel ◽  
Wild Type ◽  
Btk Inhibitor

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 BCR pathway inhibition as therapy for chronic lymphocytic leukemia and lymphoplasmacytic lymphoma

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Adrian Wiestner
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Adaptor Protein ◽  
Lymphocytic Leukemia ◽  
Lymphoplasmacytic Lymphoma ◽  
Functional Studies ◽  
Bcr Signaling ◽  
Clinical Responses ◽  
Pathway Inhibition

Abstract Chronic lymphocytic leukemia (CLL) and lymphoplasmacytic lymphoma (LPL) are malignancies of mature B cells. In LPL, mutations of the adaptor protein MYD88 (L265P) in the Toll-like receptor pathway have been recognized recently as being a hallmark of the disease and indicate a dependence of the tumor on this pathway. In CLL, functional studies have implicated BCR activation in the tissue microenvironment as a pivotal pathway in the pathogenesis. Bruton's tyrosine kinase (BTK) and the PI3Kδ isoform are essential for BCR signaling and also seem to be required for signal transduction in LPL cells, even if the role of BCR signaling in this disease remains less well defined. Ibrutinib, a covalent inhibitor of BTK approved by the Food and Drug Administration as a second-line treatment for CLL, and idelalisib, a selective inhibitor of PI3Kδ, achieve excellent clinical responses in both diseases irrespective of classic markers indicating high-risk disease. Several additional inhibitors targeting BTK and PI3Kδ, as well as the spleen tyrosine kinase, have entered clinical trials. This review discusses the biologic basis for kinase inhibitors as targeted therapy for CLL and LPL and summarizes the clinical experience with these agents.

scholarly journals The role of second generation Bruton tyrosine kinase inhibitors in the treatment of chronic lymphocytic leukemia. Resolution

2020 ◽  
Vol 21 (4) ◽  
pp. 45-47
Author(s):  
Irina V. Poddubnaya ◽  
Tatyana E. Bialik ◽  
Natalya N. Glonina ◽  
Olga B. Kalashnikova ◽  
Kamil D. Kaplanov ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Important Place ◽  
First Line Therapy ◽  
Line Therapy ◽  
Bruton Tyrosine Kinase ◽  
Adult Leukemia

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, with incidence rate of 4: 100 thousand per year, according to European data. CLL remains an incurable disease, with most patients over 60 years old. Immunochemotherapy schemes today remain the standard treatment approach for CLL. The advent of novel molecules expands possibilities of treating this disease. Targeted therapy with small molecule inhibitors of Bruton tyrosine kinase (BTK) occupies an important place in the treatment of patients with CLL, both for first-line therapy and for treatment of relapses. The drug acalabrutinib as a highly selective new generation of BTK inhibitor can be considered as an efficient and safe option for first-line therapy and for treatment of the disease relapse in patients with CLL, especially in patients with comorbidity, including cardiovascular diseases (CDV) or risk factors for CVD.

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.

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