Ibrutinib Monotherapy and Combinations in CLL

Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, was approved by the FDA for treatment of any patient with relapsed refractory chronic lymphocytic leukemia (CLL) who had at least one prior therapy, as well as in both upfront and relapsed settings for individuals with 17p deletion. Patients with 17p deletion CLL tend to relapse earlier on ibrutinib than other patients, notes Jennifer R. Brown, MD, PhD.

Ibrutinib is not a specific inhibitor of BTK, says Brown, and has the potential to inhibit a number of kinases, such as interleukin-2-inducible T-cell kinase, or ITK. Inhibition of ITK in animal models resulted in the reconstitution of some normal T-cell function and enhanced immune response to the introduction of infections. This has raised the possibility that some of the agent’s activity is not directly related to its inhibition of BTK, explains Brown.

Ibrutinib is typically administered continuously until progression. Clinical studies evaluating ibrutinib in combination with other novel agents are being initiated that could provide a deeper response, says Brown. Complete remissions would allow for the possibility of time-delimited therapy, which is likely to limit toxicity, and potentially reduce costs, states Brown.

The HELIOS trial evaluated whether the addition of ibrutinib to bendamustine and rituximab provided benefit over the regimen of bendamustine and rituximab in patients with relapsed and refractory CLL. This clinical trial showed that chemotherapy can be combined safely with ibrutinib, states Robert R. Furman, MD. If a patient has not received ibrutinib or idelalisib, a phosphoinositide 3-kinase inhibitor, by the time of relapse, it is important to use these agents at that point in time, adds Furman.