The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable
            in vitro
            activity against chronic lymphocytic leukemia B cells with CD20 antibodies

Chronic lymphocytic leukemia (CLL) treatment landscape has changed dramatically with the recently developed drugs targeting the B-cell receptor (BCR) signalling pathway. Acalabrutinib, a second generation Bruton tyrosine kinase inhibitor, was approved in 2020 in Russia for the treatment of patients with CLL. Acalabrutinib was developed as a more selective Bruton tyrosine kinase inhibitor then ibrutinib. This drug is aimed at reducing the adverse events that limit the use of ibrutinib, such as atrial fibrillation and bleeding. Phase I/II multicenter studies have demonstrated the efficacy and safety of acalabrutinib monotherapy in untreated CLL patients and in patients with relapsed/refractory CLL and ibrutinib intolerance. Phase III trials, ASCEND and ELEVATE-TN, compared acalabrutinib monotherapy and a combination of acalabrutinib and obinutuzumab versus standard therapies and demonstrated improved efficacy and tolerability of acalabrutinib. A phase III trial comparing acalabrutinib and ibrutinib monotherapy (ELEVATE-RR) is ongoing. The results of this study along with real-life clinical data could determine the place of acalabrutinib in CLL treatment.

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Acalabrutinib: a highly selective, potent Bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia

Leukemia & Lymphoma ◽

10.1080/10428194.2020.1864352 ◽

2021 ◽

pp. 1-18

Author(s):

Paolo Ghia ◽

Monika Dlugosz-Danecka ◽

Lydia Scarfò ◽

Wojciech Jurczak

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Lymphocytic Leukemia ◽

Bruton Tyrosine Kinase

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Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765

Blood ◽

10.1182/blood-2011-01-328484 ◽

2011 ◽

Vol 117 (23) ◽

pp. 6287-6296 ◽

Cited By ~ 491

Author(s):

Sarah E. M. Herman ◽

Amber L. Gordon ◽

Erin Hertlein ◽

Asha Ramanunni ◽

Xiaoli Zhang ◽

...

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

Tyrosine Kinase ◽

B Cell ◽

Lymphocytic Leukemia ◽

Cell Contact ◽

Irreversible Inhibitor ◽

Bcr Signaling ◽

Bruton Tyrosine Kinase

Abstract B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell–specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.

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What Influences the Choice of Ibrutinib–Rituximab vs Classic Chemoimmunotherapy for Chronic Lymphocytic Leukemia?

Cell Transplantation ◽

10.1177/0963689720950209 ◽

2020 ◽

Vol 29 ◽

pp. 096368972095020

Author(s):

Sara Bravaccini ◽

Giovanni Martinelli ◽

Claudio Cerchione

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Lymphocytic Leukemia ◽

Western World ◽

Phosphatidylinositol 3 Kinase ◽

Fda Approval ◽

Bruton Tyrosine Kinase ◽

Treatment Naïve

Chronic lymphocytic leukemia (CLL), with an incidence rate between 4 and 6 cases per 100,000 persons per year, is considered the most prevalent leukemia in the western world. Chemoimmunotherapy (such as fludarabine, cyclophosphamide, and rituximab), bendamustine plus rituximab, and, more recently, novel agents such as ibrutinib (Bruton tyrosine kinase inhibitor), idelalisib (phosphatidylinositol-3-kinase δ inhibitor), and venetoclax (BCL-2 inhibitor) have changed the management of CLL. Shanafelt and colleagues compared the efficacy of ibrutinib–rituximab with that of standard chemoimmunotherapy in patients with treatment-naïve CLL. They did not, however, mention that the therapy varies on the basis of where patients live and, given that local guidelines not immediately reflect US Food and Drug Administration (FDA) updates, discrepancies in treatment occur. Important CLL goals are the availability of rapidly reproducible tests, standardization of national and international guidelines, and FDA approval-based treatment reimbursement.

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