Dr Khan on the Development of Second-Generation BTK Inhibitors in CLL

“The idea [behind] the development of the second-generation [BTK] drugs is that they are more tightly inhibiting the BTK site with [fewer] off-target effects, and that is why, preclinically, we thought that would lead to fewer [adverse] effects. Now we’ve proven that this is the case.”

Cyrus M. Khan, MD, an assistant professor of medicine at the Drexel University School of Medicine and the assistant director of the Stem Cell Transplant Program at the Allegheny Health Network Cancer Institute, detailed the development of BTK inhibitors from first generation to second generation in chronic lymphocytic leukemia (CLL).

The only first-generation BTK inhibitor was ibrutinib (Imbruvica), which was FDA approved in 2014 for the treatment of patients with relapsed/refractory CLL, Khan began. However, with evident advances in science and technology, he noted that newer second-generation BTK inhibitors, including acalabrutinib (Calquence), have demonstrated slightly improved efficacy. Although second-generation BTK inhibitors have demonstrated this improvement in efficacy, the safety profile remains a priority when selecting BTK inhibitors in clinical practice, he explained. For example, with ibrutinib, some patients experienced atrial fibrillation and atrial flutter, along with ventricular arrhythmias, and long-term hypertension, all of which should be carefully considered, he stated. Additionally, other types of adverse effects (AEs), such as myalgia and arthralgia, among others, were observed, he asserted.

When second-generation BTK inhibitors were developed, the aim was to have the drugs tightly inhibit the BTK site with fewer off-target effects compared with ibrutinib, Khan emphasized. He noted that in preclinical studies, investigators hypothesized that these second-generation BTKs would also lead to fewer AEs, which was determined to be true.

In clinical practice, when patients are treated with second-generation BTK inhibitors, they often experience fewer toxicities, according to Khan. Even when patients experience AEs, including atrial flutter, arthralgias, myalgias, and have a bleeding risk, they can continue receiving second-generation BTK inhibitors, and therefore continue receiving the benefit of BTK inhibition for CLL, he said.