The Changing Treatment Paradigm in CLL

Steven Coutre, MD: The treatment landscape in CLL is obviously changing dramatically, largely because of the introduction of the new oral therapies. And so, it’s really a transformative time in managing CLL. I think everyone is interested in whether or not we need to use chemotherapy or chemoimmunotherapy. There are some subgroups of patients who still may benefit from that, and the jury is still out there. We’ll learn more about it, but clearly we are able to better treat this disease for a longer period of time with drugs that are better tolerated for many of our patients. And that’s largely because of drugs like ibrutinib; these oral, highly effective, well-tolerated therapies.

It really expands our options for patients. Maybe it’s an older patient who is unfit, where one would give some chlorambucil to. It’s not a particularly good drug, it has some side-effect limitations—but it was a therapy you could give. Or, in this country, single-agent rituximab was very widely used in that setting. It’s not very effective as a single agent, but it’s easy to understand why it was used. It’s easy to give. You get a response. It’s not chemotherapy. Everyone leaves happy, but, unfortunately, it pushes the issue down the road a little bit because you’re going to address the need for treatment again in that patient. You just don’t get a durable response. And I think with drugs like ibrutinib, we’re really just fundamentally changing that. It’s really an interesting era that we’re just starting to enter.

Now, as first combination therapy, of course, everyone likes to combine active agents. But, in my view, there has to be a reason for that. It can’t just be, “Well, this active drug works by this mechanism of action and this one works by a different one, and so let’s use the two together.” We have to demonstrate that there’s added value to our patients. You might say, “Well, let’s take two of these oral drugs and use them.” That’s two very expensive drugs instead of one drug, and there’s no reason to do that unless there’s true benefit from it. That benefit is not likely to be efficacy. You see responses with, say, single-agent ibrutinib.

Really, the issue to me going forward is if we’re going to use combination therapy, can we do it so we can use time-limited therapy, so we can actually stop therapy even if it’s for a period of time and it’s not indefinitely, even if we’re not curing patients? But, can we use a combination in a rational way and a time limited way to deliver effective, well-tolerated therapy and get a good durable response? I think that’s really where the next wave of clinical trials are going with these agents. To the extent of participating in clinical trials, absolutely, that’s why we are using combinations; not because we’re just interested in looking at two new drugs together. But we really want to answer questions that hopefully will translate into benefits for everybody.

Right now, of course, ibrutinib has a broad approval in CLL for up-front therapy for patients who have had prior therapy. So, that’s everyone except those who are in the watch-and-wait period who don’t need therapy at this point. That remains the same. We’re not advocating treating patients earlier; we’re still advocating using traditional criteria for when somebody might need to initiate therapy. But having said that, there’s no reason not to consider ibrutinib for the treatment of any patient with CLL; a patient who needs treatment whether it be frontline, whether they’re fit, unfit, whatever their age, or whether they’ve had prior treatment. It really should be part of the equation when you’re considering a treatment for a given patient. There really shouldn’t be reasons not to consider it. There may be a reason to choose a different therapy for a specific patient. Certainly, we have many other active drugs, but ibrutinib is something that likely would be part of the discussion.

BTK (Bruton's tyrosine kinase) inhibitors like ibrutinib, of course, have come in to our treatment regimens for CLL. I think this trend is going to continue not only with newer drugs, as well, but also across all stages of treatment. I think frontline therapy is going to become dominated by drugs like ibrutinib which have demonstrated clear efficacy, demonstrated tolerability. And when we compare them to our chemoimmunotherapy regimens, I think they’ll come out favorably. Of course, we’d like to see direct comparisons, and we are getting that data. But even today, we have enough information and have enough experience to know that using a drug like ibrutinib as initial therapy is a very good option for many of our patients.

Chemoimmunotherapy has become the standard approach for many patients with CLL from an era of single-agent drugs to combinations with monoclonal antibodies. FCR (fludarabine/cyclophosphamide/rituximab) and BR, for example, are perhaps the most dominant regimens, and fortunately, we’ve been guided by very high-quality clinical trials showing the benefit of this combination therapy. And now, of course, we have newer oral targeted agents. I think that, in the future, we’re likely going to replace the chemoimmunotherapy regimens for most, if not the vast majority, of patients. I think it’s still early in the game there, but certainly from what we’ve seen so far, there’s no reason to think that this won’t be the case going forward, that we’ll be able to choose these oral therapies for the majority of our patients.