CLL Landscape to Change Dramatically Over Next Decade

Jose Leis, MD

Standard treatment approaches for patients with chronic lymphocytic leukemia (CLL) will continue to include fludarabine, cyclophosphamide, and rituximab (FCR) and allogeneic stem cell transplantation.

However, recent approvals of novel agents and ongoing developments of combination regimens are advancing the field into a realm of new, improved, and individualized possibilities for patients, explains Jose Leis, MD.

One clinical opportunity is a phase II study of ibrutinib (Imbruvica)—which was first approved as a treatment for patients with previously treated CLL in September 2014 and later as a frontline therapy in March 2016—plus venetoclax (Venclexta) in patients with relapsed/refractory disease or high-risk untreated patients (NCT02756897). Venetoclax was approved by the FDA in April 2016 in pretreated patients who have a 17p deletion (del[17p]).

Leis lectured on this shifting landscape of CLL during the 2016 OncLive State of the Science Summit on the Treatment of Hematologic Malignancies.

“To be aware of your patient and really understand them is really going to be pivotal to what therapy you recommend for that patient,” said Leis. “It’s very clear that 1 medication—1 therapy—does not fit all.”

OncLive: How have we seen the field of CLL evolve?

In an interview, Leis, a professor of Medicine and head of the Chronic Lymphocytic Leukemia Program at Mayo Clinic, spoke on the current state of the disease and pivotal clinical trial findings in CLL to be presented at the 2016 ASH Annual Meeting. Additionally, he provided insight into the potential of chimeric antigen receptor (CAR) T-cell therapies in CLL and how the treatment paradigm will look in the coming years.Leis: The world of CLL therapy has just really dramatically changed in the last 20 years. I got interested in CLL because my father-in-law called while I was a young faculty member at Harvard and told me he had been diagnosed with CLL. In 1995, we didn’t know about prognostic factors; we didn’t really know anything about the clinical course of aggressive CLL. Unfortunately, within 3 years, he passed from his disease.

What we knew at that time really didn’t tell us what the basis of the disease was. The first major advance was that our understanding that cytogenetics made a difference. In a German study published in The New England Journal of Medicine in 2000, it showed that it’s really not 1 disease; it’s a broad spectrum of B-cell aggressiveness from the 17p deletion patients who literally have 6 months before they progress to needing treatment, to 13q deletion (del[13q]) patients who will go for a decade before they might progress. There is also the finding about the mutational status in immunoglobulin genes. That’s going to be a really important thing in the next 20 years.

The big advances started with the combination of chemoimmunotherapy, the FCR regimen by Dr. Michael Keating of The University of Texas MD Anderson Cancer Center in the early 2000s. That really improved the responses and the complete remission rates.

What is the state of the disease now?

The second thing that really happened in the late 2000s was the understanding that the B-cell—receptor pathway plays a major role. Once that became known, then targeted therapies could be developed. We went from chlorambucil as single therapy, lymphoma-type regimens with fludarabine and purine analogs, and then combination therapy. In the 2010s, the era has become that of targeted therapies.It is depending on each individual patient. The University of Texas MD Anderson Cancer Center group and the Germans who collaborated on this mutational status study are playing a major role. Twenty percent to 40% and more of patients treated with FCR who had the mutated subtype immunoglobulin genes had favorable cytogenetics. At a 13-year follow-up, they don’t have any evidence of disease.

Therefore, MRD status is playing a role here. However, the important thing is that, potentially, chemoimmunotherapy can cure some patients. That is really very different than we used to think—that nobody could be cured. For favorable-risk patients who are young and fit, FCR may cure a subset of those patients.

For the high-risk patients, you need targeted therapies, which have been nothing but phenomenal. The response rates seen with single agents have been at more than 80%. Results with ibrutinib have been dramatic in the high-risk 17p deletion patients. It looks like upfront therapy with ibrutinib is better than in the relapsed/refractory setting; we know that patients with 17p deletion who have had other therapies will relapse at a median of 28 months. However, that has been much better with upfront therapy.

In an earlier study, very few of those patients, at 3 years, have relapsed or progressed on ibrutinib. We are seeing the same thing with idelalisib (Zydelig) in the upfront setting. The B-cell—receptor pathway inhibition is showing some dramatic responses in the frontline setting, and we will be seeing more of that incorporated into our treatment algorithms.

There will be some really interesting things presented at the ASH Annual Meeting this year. The rescue of ibrutinib failures with venetoclax will be really important. As we continue the 17p deletion patients on ibrutinib and, if they do progress, 70% of those patients potentially can be rescued with the BCL-2 inhibitor venetoclax.

What potential could CAR T-cell therapy have in this disease?

There is potential for maintenance therapy, where 2 studies presented will show that maintenance lenalidomide (Revlimid) after any of the frontline therapies and chemoimmunotherapy dramatically improves progression-free survival. We are really looking at interesting things coming in the future.CAR T-cell therapy, for CLL, is actually having a re-blossom. A lot has been shown in the last few years from acute lymphoblastic leukemia studies in kids. Remember, the first clinical trial of CAR T-cell therapy was in CLL. Now, the first patient who was treated at the University of Pennsylvania is more than a decade out and that patient is completely disease free. There are at least 3 or 4 ongoing clinical trials with different CAR T-cell therapies in CLL. Those are showing improving responses in patients who have had multiple prior lines of therapy.

Some combinations are being studied with venetoclax. What are your thoughts there?

A combination of CAR T-cell therapy plus ibrutinib is going to be presented at ASH. Also, the efficacy of CAR T-cell therapy in ibrutinib failures will also be presented. There is going to be a lot of enhanced interest in CAR T-cell therapy coming after this meeting. More clinical trials will be expanding in this area.Targeting different pathways at the same time is going to definitely increase potential responses. We have to be cautious in doing the clinical trials because not always what we predict will be the result. In this case, we’re targeting BCL-2—which is overexpressed in almost all CLL—but at the same time you’re targeting other pathways. These are going to be very interesting results. We know that they are not very mature; we do know that they’re showing some very good response rates.

If you could envision the future of CLL treatment, what would it look like?

Regarding the trials of venetoclax combined with ibrutinib, I would have predicted a higher response rate than what was seen in the venetoclax plus ibrutinib arm. I do think it has great promise; venetoclax is a very interesting therapy. But, in combination, I do think it will improve over time.Second-generation BTK inhibitors, like acalabrutinib (ACP-196), are being enrolled in phase III trials to be compared with ibrutinib. It looks like it might have less potential side effects. PI3K inhibitors are well into clinical trials and are showing some very good responses. We see a very strong emphasis on targeted therapies over the next couple of years.

Potential combinations with standard chemoimmunotherapy may deepen the responses and get better MRD negativity. If you get that duration of response, the potential for cure is increased. Combinations with the targeted therapies and regimens such as FCR are preliminary data. The study with ibrutinib plus FCR will be presented at ASH, as well. The next 5 to 10 years will show that we are going to be able to figure out what the specific patient needs are, based on the biology of their disease.

What is the main message to get across to community oncologists?

Also, for some patients, these combinations aren’t going to be enough. We will be better able to define the role of both CAR T-cell therapies and in some patients, when to do allogeneic stem cell transplantation. That’s still the only definitively curative therapy, although FCR may cure some of those favorable-risk patients.There is such an excitement about the targeted therapies—that there is an ease of them because they are pills. You write a prescription and the patient goes away. What I want people to understand is that biology makes a difference. There are some people for whom chemoimmunotherapy is still the number 1 therapy. There are others where that has no role whatsoever, or their CLL will not respond to that. You really have to individualize.

You also have to be fair to the patient and tell them that all of these therapies have side effects. A pill sounds great, but pills can have some serious side effects as seen in clinical trials and individual practice. Clinical trials are done in very fit patients who have no other comorbidities and aren’t on a lot of medicines.

In the real world, that is not the patient you give that therapy to. The average patient will have immune systems that are not working properly, they are on aspirin, they’ve got a stent, etc. When you put someone on these new targeted therapies, things happen.