Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia among adults. It is also one of the most commonly relapsing types of cancer. While chemotherapy and traditional forms of cancer treatment do prolong remission and overall survival rates, relapse occurs in practically all patients. The commonality of relapse in patients with CLL has prompted the discovery of novel drug targets in hopes of stopping the proliferation of leukemia cells in the body. Bruton’s tyrosine kinase (BTK) is a downstream signal proliferator in several pathways that are relevant to both tumor-cell survival and the ability for the tumor-cells to adhere to one another.
However, the inhibition of BTK results in the loss of immunoglobulins in blood serum which results in an increased risk of infection for those affected by BTK inhibitors. In addition, because the structure of BTK is vastly different from other tyrosine kinases it is a perfect therapeutic target. Ibrutinib is a first-in-class, small molecule drug that covalently binds to and inhibits the action of BTK, specifically its cysteine (C481) site. Ibrutinib is, however, not a very selective inhibitor as it also inhibits the action of many other protein kinases and causes severe side-effects. Second generation BTK inhibitor, acalabrutinib, is highly selective to BTK C481 and therefore has a lower side-effect profile than ibrutinib.
The response to acalabrutinib in early clinical testing was overwhelming with 98% of patients having reduction in lymphadenopathy (swollen lymph nodes) and 61% having concomitant lymphocytosis (elevation in blood-lymphocytes). Additionally, most adverses effects of the medication were not considered dangerous or life-threatening with most being mild headaches and diarrhea. Only two events of progression were reported in the study. All in all, acalabrutinib shows major steps in the reduction of relapses for CLL patients, and a new string of hope for those diagnosed with CLL.
Do you think this drug has the potential to become a first like treatment for leukemias? Could drugs like this lead to the end of chemotherapy?
Byrd JC, Harrington B, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374:323-332