Amid Explosion of Targeted Agents, FCR Retains a Role in CLL Paradigm

Mitchell R. Smith, MD, PhD

Chemoimmunotherapy has previously been a frontline standard of care for patients with chronic lymphocytic leukemia (CLL), but the emergence of targeted agents has led to a deeper understanding of how to optimally use these impactful drugs upfront and create practice-changing combinations, explained Mitchell R. Smith, MD, PhD.

“It's been a quite an exciting year in CLL. For a long time, we have had these new agents but didn’t know how to use them,” said Smith. “This year, we've had several studies comparing novel agents such as ibrutinib (Imbruvica) with real-world chemotherapy—fludarabine/cyclophosphamide/rituximab (Rituxan; FCR) in younger patients and bendamustine/rituximab (BR) in older patients. We now have solid, randomized phase III data that is changing the landscape of frontline therapy for CLL.”

In an interview during the 2019 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Smith, a professor of medicine and associate center director for Clinical Investigations in the Division of Hematology & Oncology and the George Washington Cancer Center, discussed the use of chemotherapy versus targeted therapy in patients with newly diagnosed and relapsed/refractory CLL.

OncLive: What combinations are being explored in CLL treatment?

Smith: The idea of [some of these recent studies] in the United States was to take younger patients and compare FCR with an ibrutinib-based regimen [in younger patients] and BR with ibrutinib, or ibrutinib plus rituximab in older patients. These were both large, phase III randomized trials and the progression-free survival (PFS) was prolonged with the ibrutinib-based regimens.

The addition of rituximab, however, to ibrutinib [was not statistically significant]. Therefore, we can use single-agent ibrutinib. Rituximab has always made chemotherapy better, but at least in ibrutinib, the mechanism is different enough that the addition of rituximab is not necessary.

What agents are being explored in the relapsed/refractory CLL setting?

The major difference with venetoclax (Venclexta), a BCL-2 inhibitor, compared with ibrutinib is that [venetoclax] kills the cells rather than stops their growth, [which causes them to] eventually die. We're seeing more deeper responses and achieving minimal residual disease (MRD) negativity, which allows patients to try stopping therapy. We'll be interested in seeing what happens in those studies.

Early data suggest that a significant percentage of patients stay in remission for a period of time, showing the cancer doesn't come “roaring” back. This could change everything if we could treat patients for 12, 18, or 24 months and then allow them to be off of treatment for prolonged periods of time.

Acalabrutinib (Calquence) is very active and hits the same target as ibrutinib. There are a number of trials with acalabrutinib that have been completed and others are in the works, which [will show that is] very similar [to ibrutinib] and less toxic. However, until we see the data from head-to-head comparisons, it's a little hard to be sure of that.

The other major class of drugs are the PI3K inhibitors. They work, but they have a bad reputation for toxicity. However, now we have duvelisib (Copiktra) which hits PI3K-delta and -gamma with a slightly different mechanism of action. Umbralisib is another structurally slightly different PI3K-delta inhibitor that also inhibits an enzyme called casein kinase, which seems to be well tolerated and effective. Then, you have copanlisib (Aliqopa), [which is selective for] p110-alpha and delta. They all have different toxicities because they hit different targets, but PI3K-delta is an active target. How we can combine these things and use them are going to be the subjects of additional studies coming in the near future.

CAR T-cell therapy has emerged in hematologic diseases. What are your thoughts on the use of this treatment in CLL?

CAR T cells look exciting in CLL, but we have to learn more about them. It's in the realm as you get further down in the treatment regimen. The rate of durable remissions is not great; but we have these other new drugs coming [down the pipeline].

If you could identify patients who are going to be long-term responders, CAR T-cell therapy would be an option, but that's an area with many questions. Why doesn't everyone respond? Are we using [CAR T-cell therapy] too late? Do we need to add other agents, such as checkpoint inhibitors, to make those T cells work better? We're only in the infancy in CAR T-cell therapy, especially in CLL, making it an option for a small population of patients.

Trials combining ibrutinib and venetoclax look different than trials in the past. What prompted the trial of the fixed duration of ibrutinib/venetoclax?

We had preclinical data that there was synergy between the two agents, which makes sense because one blocks site signaling and one promotes cell death. They are different sides of the coin in terms of proliferation and lack of apoptosis.

There was some trepidation, but the early [studies of this] looked promising enough to be studied formally. It's the depth of response that made researchers think we could begin to ask this question. In chronic myeloid leukemia (CML), you can stop TKI treatment but only in certain patients who reach MRD for a couple of years. Even then, you do it carefully. In CML, we had evidence that you could stop it during pregnancy and the response would be regained. There was accumulating sense that these TKIs and small molecule inhibitors might be different than chemotherapy.

In the frontline setting, how are you choosing between chemotherapy or one of these targeted therapies?

I have that discussion with patients. FCR might have a niche in treating young, fit patients with IgHV mutations, which is a good-prognosis group. A couple of trials found that a significant number of those patients are 10 years out without the disease coming back after 6 months of intense [FCR] treatment. That group still may get frontline chemotherapy.

Considering cost, adverse events, and toxicity, there is nothing wrong with giving BR, getting several years out of it, and then giving ibrutinib down the line—either alone or in combination. We don't currently know the best strategy. All of these studies show optimal PFS, but that's not what we care about.

There's a lot of work now being done on resistant clones, detecting them early, and maybe adjusting treatments. The idea of personalizing these treatments and coming up with the best strategy for each patient is the dream, which is not that far away. We could follow patients, monitor their blood, see if the clones have the mutation that makes PI3K upregulate and makes BTK resistant to ibrutinib. These are all strategies that are coming.

Aside from the combination of ibrutinib and venetoclax, are there any emerging combinations that you are keeping an eye on?

The big question with that combination is, “Do you need the anti-CD20 agent?” With those three drugs, you're talking about $500,000 each year. With ibrutinib, it does not appear that [the anti-CD20 agent] adds anything. We don't know yet with venetoclax, and there are some conflicting thoughts in the area.

We'll see what resistance develops and work on preventing that resistance by adding other drugs to the combination. Right now, we are learning how to combine [all of these agents] through clinical trials, but we don't currently know what combination is going to be best.

Lenalidomide (Revlimid) used to play a large role in CLL treatment. What is the role of lenalidomide now?

You'll hear a lot about lenalidomide in myeloma and now low-grade lymphoma, but it was an active CLL drug, so much so that we got tumor flare and tumor lysis. [Lenalidomide] has fallen by the wayside, but we shouldn't forget it, especially in patients who are now in their second or third line of treatment. What are you going to do after ibrutinib/venetoclax? Lenalidomide is out there. There's one trial that was a United States intergroup trial that compared fludarabine/rituximab, fludarabine/rituximab plus lenalidomide, and FCR that finally was reported about 1 year ago. It showed that 6 months of [the lenalidomide arm] prolonged overall survival and PFS after chemoimmunotherapy. That's an area that we should keep an eye on.