Dr. Davids on Rationale for Ibrutinib/Umbralisib Combo in R/R CLL and MCL

Matthew S. Davids, MD, MMSc, an associate director with the Center for Chronic Lymphocytic Leukemia; director of clinical research, Lyphoma Program; and medical oncologist, Dana-Farber Cancer Institute and an assistant professor of medicine with Harvard Medical School, discusses the rationale for examining ibrutinib (Imbruvica) in combination with umbralisib in relapsed/refractory chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL).

With the advent of the BTK inhibitor, ibrutinib, the outlook for patients with relapsed/refractory CLL and MCL has improved quite a bit, says Davids. The drug is very active; however, particularly for high-risk patients with CLL, particularly those with TP53 dysfunction, the durability of the responses achieved with the agent is relatively short. In the high-risk population, the median progression-free survival (PFS) is only about 2 to 3 years with ibrutinib monotherapy in the relapsed setting, says Davids. In MCL, even though the response rates with ibrutinib monotherapy are high, the PFS is only a little over 1 year.

That provided a rationale to try and develop combination approaches for this patient population, adds Davids. Several approaches are being evaluated right now. In a recent analysis, investigators examined dual-blockade of the B-cell receptor pathway. It is known that the leukemia cells and mantle cells depend heavily on this B-cell receptor pathway for survival; another arm of the pathway is PI3K, says Davids. In this analysis, investigators go after this other arm of the PI3K pathway to see whether resistance to ibrutinib as a monotherapy agent can be prevented, concludes Davids.