Investigators Set Sights on Combinations for Frontline CLL Treatment

Steven Coutre, MD, discusses ongoing efforts to enhance frontline outcomes for patients with CLL.

Steven Coutre, MD

The FDA approvals of ibrutinib (Imbruvica) and obinutuzumab (Gazyva) have revolutionized frontline treatment for patients with chronic lymphocytic leukemia (CLL), says Steven Coutre, MD. Researchers have now set their sights on combinations regimens to further improve frontline outcomes. Additionally, investigators hope that agents approved for later settings, such as venetoclax (Venclexta), will also be successful in the frontline.

In an interview withTargeted Oncology, Coutre, professor of Medicine at the Stanford University Medical Center, discusses ongoing efforts to enhance frontline outcomes for patients with CLL.

TARGETED ONCOLOGY:Please discuss the role of ibrutinib and other frontline treatments for CLL?


Things have evolved in recent years and we now have drugs like ibrutinib, which are very different from our traditional chemotherapy or chemoimmunotherapy regimens. They allow the use of an oral therapy that’s well tolerated and effective. That’s an important issue, since most patients with CLL are diagnosed when they’re 70 years old. Most patients don’t need treatment right away making them in their mid-70s when they do need treatment.

Tolerability of therapy is quite important. In comparison to ibrutinib, we have our traditional chemoimmunotherapy. Those regimens, although they are well tolerated, are still harder than taking a pill. They do have toxicities and for people who have a lot of comorbidities, that’s a significant issue.

We also have antibody therapies. For example, obinutuzumab with chlorambucil is also approved in frontline. That’s a little more difficult than taking a pill and it’s not as effective or durable for as long as the oral therapies.

On the 1 hand, you have a pill you can take, go about your business, and hopefully have little impact on your daily life or quality of life, but right now you do have to take those continuously. We haven’t explored stopping therapy yet. With our more traditional chemoimmunotherapy regimens or immunotherapy, they’re given for a period of time of 6 months or so, which is the tradeoff.

Of course, the other issue that always comes up is cost, the financial impact.

TARGETED ONCOLOGY:What are the key considerations for an oncologist when selecting the optimal treatment for a patient with CLL?


We have very well-defined guidelines for when to start therapy, but besides following those, there isn’t an exact algorithm. I always like to think of it as you're looking at each patient as an individual. There might be medical comorbidities that have a significant impact on your decisions, perhaps somebody is too frail and can’t tolerate these chemotherapy regimens. In that case, oral therapy, like the TKIs, might be most appropriate.

On the flipside, some patients, due to financial constraints, find it better to have a defined course of therapy that might be reimbursed, as opposed to an expensive oral therapy, which might not be fully covered by their insurance. It’s not as simple as just making a medical decision, it’s important to look at the whole picture and have that discussion with your patient to decide what’s best for that individual.

TARGETED ONCOLOGY:Are there any emerging agents in frontline CLL trials?


We had idelalisib, another B-cell receptor pathway inhibitor, but because of safety issues, particularly recent ones with infections, it’s not likely to ever get an approval for upfront therapy.

We have venetoclax, which is a BCL-2 inhibitor and an oral therapy. This is approved now but just for relapsed 17p deleted patients, but I am sure that with more trials, a drug like that may make its way into the frontline.

More importantly, where we’re going is combining some of these drugs, to see if we can get a better response and begin to address the issue of stopping therapy.

An oral, well-tolerated therapy could have added advantages at the time a patient receives therapy. That’s what we’re most interested in.

TARGETED ONCOLOGY:Are there specific combination trials that you are interested in?


Many of them will start with a combination of an antibody, and 1 of these drugs. For example, there are trials with ibrutinib and obinutuzumab as well as venetoclax and obinutuzumab, which the German CLL Study Group has moved ahead quite aggressively.

There are also trials that use a combination of 3 drugs. For example, you might use obinutuzumab and ibrutinib initially, reduce the lymph nodes, reduce the circulating lymphocytes, and then add in venetoclax after several months to get a better overall depth of response. I think there will be many creative ways of doing this and we’ll see what turns out to be the best.

TARGETED ONCOLOGY:You mentioned 17p deletion, in terms of selecting between chemoimmunotherapy and ibrutinib. Is there a patient population that should always have ibrutinib or is that not the case?


Since our chemoimmunotherapy is largely ineffective or has very poor efficacy even if patients initially respond, anyone who has that abnormality should receive one of these novel agents. Fortunately, that abnormality is quite uncommon at the time of diagnosis, experienced by 5% of patients. You should at the very least do a FISH test to see if that's present because it’s a predictive factor. It’s something that will influence what you choose to treat that patient with. All patients should receive 1 of these drugs, but right now, the only 1 that has an indication for initial therapy is ibrutinib.

TARGETED ONCOLOGY:Can you talk about the RESONATE-2 trial and what impact that had?


The RESONATE-2 trial was a randomized trial for previously untreated patients. Patients had to be over the age of 65, which is a typical CLL patient. They were randomized to chlorambucil versus ibrutnib, monotherapy and were allowed to crossover if they didn't respond or responded and then progressed with one of the regimens.

Many of the patients did eventually cross over from chlorambucil and it showed a significant benefit to the use of ibrutinib both in terms of progression-free survival and even overall survival with a short follow-up. There was a survival advantage and many will say that it is because it was compared to chlorambucil alone since we have already been combining chloambucil to rituximab or obinutuzumab.