Dr. Shah on Overcoming Resistance to BTK Inhibitors in MCL

Bijal D. Shah, MD, associate member, Department of Malignant Hematology, Moffitt Cancer Center, discusses overcoming resistance to BTK inhibitors in mantle cell lymphoma (MCL).

Ibrutinib (Imbruvica) and acalabrutinib (Calquence) are both FDA approved for patients with relapsed/refractory MCL, but it is not standard practice to give these agents consecutively. This is due in large part to the overlapping mechanisms that drive resistance to these BTK inhibitors, says Shah. Moreover, mutations like p53 tend to create a more aggressive disease, limiting physicians’ ability to salvage with another BTK inhibitor.

Ongoing research is looking at whether an alternative method of blocking the B-cell receptor can overcome resistance to BTK inhibition. For example, an ongoing trial is looking at the combination of duvelisib (Copiktra), a PI3K gamma and delta inhibitor, and the BCL-2 inhibitor venetoclax (Venclexta). The hope is that the combination can attack the B-cell receptor from a different angle, and in doing so indicate whether the downstream mutations are as pivotal in cancer proliferation as believed to be.