Acalabrutinib in treatment of patients with chronic lymphocytic leukemia including those at high genetic risk

Acalabrutinib belongs to a class of Bruton’s tyrosine kinase inhibitors (BTKis) which have become one of the most widely used drugs for the treatment of B-cell malignancies including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma, Waldeström’s macroglobulinemia, and marginal zone lymphoma. Chronic lymphocytic leukemia is the most frequently diagnosed hematological malignancy in the Western world, with a median age of 72 at diagnosis. BTK inhibitors are recommended in monotherapy until disease progression or unacceptable toxicity. Acalabrutinib shows high specificity towards its target, with minimal off-target activity regarding other kinases. This leads to fewer treatment-related adverse events compared to the first-class BTK inhibitor, ibrutinib. Moreover, acalabrutinib has proven its efficacy in numerous clinical trials i.e. ACE-Ly-004, STELLAR, ASCEND, ELEVATE-TN, and ELEVATE-RR, including in high-risk patients. The most clinically relevant high-risk feature of chronic lymphocytic leukemia is a disruption of TP53 signaling via either 17p deletion or TP53 mutation. Another significant adverse genetic marker is unmutated IGHV. Recent trials have aimed at studying novel combination regimens that lead to a negative measurable residual disease status and allow for time-limited highly-active chemotherapy-free treatment, with acalabrutinib as one of the key players.