Acalabrutinib Receives FDA Approval for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

On 21 November 2019, the US Food and Drug Administration (FDA) approved acalabrutinib (Calquence, AstraZeneca) for use in adults with chronic lymphocytic leukemia or small lymphocytic lymphoma. The FDA granted this approval on the basis of data from 2 randomized, actively controlled clinical studies in patients with CLL (chronic lymphocytic leukemia), named ELEVATE-TN and ASCEND. In both studies, efficacy was based on independently assessed progression-free survival (PFS). ELEVATE-TN randomized 535 previously untreated patients with CLL into 3 separate arms: acalabrutinib monotherapy (single treatment), acalabrutinib and obinutuzumab, and obinutuzumab and chlorambucil. With a median follow-up of 28.3 months, progression-free survival was observed to increase significantly in the arms containing acalabrutinib. Compared with the obinutuzumab and chlorambucil arm, the hazard ratio for progression-free survival in the acalabrutinib and obinutuzumab arm was 0.10 (95% confidence interval, 0.06, 0.17; p<0.0001), and in the acalabrutinib monotherapy arm it was 0.20 (95% confidence interval, 0.13, 0.30; p<0.0001). ASCEND randomized 310 patients with relapsed or refractory CLL who had previously received at least one systemic treatment into 2 groups. One arm received acalabrutinib, while the other received an investigator-selected treatment regimen (idelalisib and rituximab or bendamustine and rituximab). With a median follow-up of 16.1 months, progression-free survival was significantly longer in the acalabrutinib arm (hazard ratio-HR 0.31; 95% confidence interval, 0.20, 0.49; <0.0001). In neither study had median progression-free survival been reached in the acalabrutinib arm. Nor had median overall survival been reached in any arm of either study (fewer than 15% of patients had experienced an event). The most common (>30%) side effects were anemia (low red blood cell count), neutropenia (low white blood cell count), thrombocytopenia (low platelet count), headache, upper respiratory tract infection and diarrhea. The recommended dose is a capsule taken orally every 12 hours, containing 100 mg, with or without food.

What Is CLL (Chronic Lymphocytic Leukemia)?

CLL is a type of blood and bone marrow cancer characterized by uncontrolled proliferation of mature B cells and their malignant transformation. It is the most common type of leukemia in Western countries. It generally occurs in older patients and is 2 times more common in men than in women. Most cases are diagnosed incidentally on the basis of an abnormally high lymphocyte count detected during a complete blood count. Although there is currently no treatment that provides a complete cure for the disease, Bruton tyrosine kinase inhibitors are among the most effective approaches.

How Does Acalabrutinib Work?

Like zanubrutinib and ibrutinib, acalabrutinib is an inhibitor developed against the Bruton Tyrosine Kinase (BTK) enzyme. BTK forms part of a receptor in a cell signaling pathway that plays an important role in regulating B-cell proliferation. Inhibiting BTK can prevent uncontrolled B-cell proliferation in B-cell malignancies. Acalabrutinib and zanubrutinib have also been approved by the FDA for use in mantle cell lymphoma. Compared with ibrutinib, acalabrutinib is more specific and more potent (effective), and can therefore also be regarded as a 2nd-generation BTK inhibitor.