The Evolving Role of BTK Inhibitors in Treating Chronic Lymphocytic Leukemia - Episode 6

Time-Limited Therapy Options for BTK Inhibitors

April 16, 2020

Ian Flinn, MD: Do we need to keep people on BTK [Bruton tyrosine kinase] inhibitors indefinitely? If someone is in a great remission—unfortunately it’s rarely a complete remission, at least not as a single agent, but has a great remission—can we take them off? We know anecdotally that there are patients you take off for adverse events and they do fine for a few years. With that said, I personally have been reluctant to stop BTK inhibition in someone who’s tolerating the treatment well because we know that there’s still disease there. They’re not getting into MRD [minimal residual disease] negative, at least very rarely. They are not even into complete remission, and it’s just a matter of time. Maybe I am too conservative. Jan, what’s your approach?

Jan A. Burger, MD, PhD: I share this view in a way, but we’re also lacking data because we’re currently using ibrutinib as we use kinase inhibitors: for treating CML [chronic myeloid leukemia], even though the disease kinetics are quite different. I think you could make the point to say, “Well, you could also treat to best response with a BTK inhibitor and then stop treatment in a patient who’s low risk and who has disease kinetics, so maybe it took the patient several years to need treatment.” If you have a patient who’s low risk, with long lymphocyte doubling time, and maybe several years until needing treatment, if you treat that patient 1 or 2 years with a BTK inhibitor with or without CD20 antibody, those patients could be in a relatively good remission which obviously wouldn’t be an MRD-negative remission. I would imagine those patients could have quite a durable remission and could have a treatment-free interval of several years.

We are doing clinical trials now to ask that question: if that’s an alternative to long-term kinase inhibitor therapy. Because truly that’s the unsolved problem. The BTK inhibitors are great drugs, but many patients eventually drop off because of more or less problematic adverse effects. In reality, many patients, over the years, do not like to be on treatment or have adverse effects, so they have to come off. So there’s a good rationale to look a little deeper into whether there may be a rationale, in certain select patients, to go for shorter exposure and maybe treating them for a certain period of time and then taking them off and treating them again.

We’re going to try to look into that. I think single-agent BTK inhibitor therapy really takes a long time to get patients into something that’s close to a CR [complete response]. What we are doing with clinical trials now is to combine it with a CD20 antibody, expose patients approximately for 2 years with that. Half of the patients may be in a complete remission. And we’re going to take them off and see how that goes. Are you pursuing anything similar to that?

Ian Flinn, MD: No. Most of our efforts have been along some of these other combination studies—time-limited therapies based on combinations with venetoclax and trying to get people off trial or off drug, based on getting them to a really deep remission. But I’m interested to learn about your study and how that goes. I suspect you’re using a low-risk patient population, is that right? So people with low-risk cytogenetics and that kind of thing.

Jan A. Burger, MD, PhD: Yes, that’s true, 17p-deleted patients, for example, wouldn’t qualify for that study. Otherwise we kept it pretty open, but we have an alternative frontline study, which is a venetoclax–BTK inhibitor combination study with obinutuzumab. We want to prioritize that other 1 for higher-risk patients, this 1 for lower-risk patients. I anticipate that maybe lymphocyte doubling time is going to come in as something that we always use to assess our patients. Somebody has a very low lymphocyte doubling time, I think then these time-limited approaches with BTK inhibitors could become an alternative to this very long-term treatment with BTK inhibitors.

But yeah, we are just opening these studies, so I can’t really tell you about any experience. And all these trials are going to take us quite a long time to really have a reasonable readout. I don’t expect to have any data for another 2 or 3 years because we are just starting. Patients are going to be treated for 2 years and then come off, and then it’s going to take us awhile to generate all this data.

Transcript edited for clarity.