Use of PI3K Inhibitors in B-cell Malignancies - Episode 3

PI3K Inhibitors in Management of CLL


Ian Flinn, MD, PhD: The role of PI3-kinase inhibitors in the management of CLL [chronic lymphocytic leukemia] is becoming clearer. Frankly, we have great new therapies, frontline therapies, for patients with CLL, whether that is 1 of the BTK inhibitors or now venetoclax in combination. I think many physicians treating patients with chronic lymphocytic leukemia would likely start with ibrutinib or venetoclax. If they haven’t had that, when someone progresses, perhaps switch to the other agent.

But we have a real need for patients who have had at least 2 prior therapies in CLL. This is where the PI3-kinase inhibitors come in, specifically idelalisib and duvelisib, in this patient population. That’s the group that probably has the biggest need and where the efficacy is best. For the toxicity, the adverse-event profile supports using these agents in that setting. The question comes up whether you use the single-agent duvelisib or you use a combination of idelalisib and rituximab in that setting. It’s really an unknown question, to be honest with you. I think either is an appropriate approach.

We do know that duvelisib is a single agent. It is administered orally, and it’s certainly easier for patients than combining with rituximab. But you could also ask the question if rituximab really adds anything to idelalisib. Some investigators and some clinicians might say, “Well, maybe just use single-agent idelalisib.” Regardless, I think this is the patient population who have had 2 prior therapies, and this is really where the PI3-kinase inhibitors are most used.

In chronic lymphocytic leukemia, duvelisib has been approved for patients with 2 prior therapies with CLL. This is based on the DUO trial. The DUO trial was a large randomized international phase III trial in which patients with 1 prior therapy were randomized to receive either duvelisib or ofatumumab. In a subset analysis with patients with 2 prior therapies, the duvelisib improved response rates. It nearly doubled the overall response rate compared with single-agent ofatumumab and substantially improved progression-free survival from a little over 16 months to approximately 9 months in that subset of patients. It also had an improved safety profile when used for patients with 2 prior therapies. It is a very important addition to our armamentarium for patients with chronic lymphocytic leukemia.

In a similar fashion, idelalisib was also tested in a large randomized international trial. The design was for patients with at least 1 prior therapy and who are basically unfit for more aggressive treatment. Patients were randomized to receive either single-agent rituximab or the combination with rituximab and idelalisib. In a recent update to our initial publication, we’ve seen that progression-free survival is now in advance of 20 months for patients treated with a combination of idelalisib and rituximab.

Transcript Edited for Clarity