<p>Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data</p>

Abstract

Recently, the treatment landscape for chronic lymphocytic leukemia (CLL) has changed dramatically due to the development of drugs targeting proteins in the B cell antigen receptor (BCR) pathway. Acalabrutinib, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, was recently FDA approved for treatment of treatment naïve and relapsed refractory CLL. Acalabrutinib was designed as a more selective BTK inhibitor as compared to ibrutinib in an attempt to mitigate some of the treatment limiting toxicities seen with ibrutinib such as atrial fibrillation and bleeding. In preclinical studies, acalabrutinib was demonstrated to have efficacy in CLL in both patient blood samples and murine models. A multinational phase 1/2 study demonstrated the efficacy and safety of acalabrutinib monotherapy in treatment naïve, relapsed refractory and ibrutinib-intolerant CLL patients. Subsequent phase 3 studies, ASCEND and ELEVATE-TN, compared acalabrutinib monotherapy or combination acalabrutinib and obinutuzumab to standard of care treatments and demonstrated acalabrutinib's improved efficacy and tolerability. Currently, a phase 3 study is ongoing to compare acalabrutinib to ibrutinib monotherapy (NCT02477696). In the setting of recent FDA approval, real-world evidence will help to elucidate the optimal use of acalabrutinib in the treatment of CLL.

Platelet function and bleeding in chronic lymphocytic leukemia and mantle cell lymphoma patients on ibrutinib

“…The second‐generation inhibitor acalabrutinib is a more specific inhibitor of BTK with much less inhibitory capacity for Tec kinase 9 (although the most recent studies suggest that the picture of specificity could be more complicated 10 ). However, it is not yet clear whether the selectivity of acalabrutinib is sufficient to fully avoid the platelet dysfunction reported for ibrutinib, and use of acalabrutinib is still associated with bleeding 11 …”

Therapeutic Options for Patients with TP53 Deficient Chronic Lymphocytic Leukemia: Narrative Review

“… 54 Constitutive BCR signaling is of great significance for the pathogenesis of CLL, as it enhances the proliferation and survival of B lymphocytes. 69 , 70 Upon stimuli of the BCR, protein tyrosine kinases, such as spleen tyrosine kinase (SYK) and LYN kinase become activated. SYK and LYN activate the Bruton tyrosine kinase (BTK) and phosphoinositol-3-kinases (PI3Ks), which stimulate downstream cascades resulting in activation of protein kinase B (AKT), extracellular signal-regulated kinases ERK1 and 2, nuclear factor (NF)-kB, and nuclear factor of activated T-cells (NFAT).…”

“… 69 Inhibition of kinases, involved in BCR signaling became an attractive potentiality in the treatment of CLL. 70 …”

“…In 2019 the FDA approved acalabrutinib for treatment of TN and relapsed refractory CLL or small lymphocytic lymphoma (SLL). 70 The approval was based on the results of two clinical trials: ELEVATE-TN 82 and ASCEND. 83 In the phase 3 ASCEND trial, conducted on 310 patients with R/R CLL, acalabrutinib monotherapy has been compared to idelalisib+rituximab or bendamustine+rituximab therapies.…”

“…Zanubrutinib (BGB-3111) is another second-generation, irreversible BTK inhibitor. 70 It has greater selectivity compared with ibrutinib and what seems even more important it has a longer half-life in comparison with acalabrutinib and ibrutinib, which results in longer exposure of CLL cells to BTK inhibition. 84 In November, 2019 zanubrutinib received approval for treatment of R/R mantle cell lymphoma.…”