Frontline CLL Paradigm Rapidly Evolving to Include Novel Therapies

William G. Wierda, MD, PhD

As more agents are approved in the treatment paradigm of chronic lymphocytic leukemia (CLL), researchers are exploring frontline options—in addition to ibrutinib (Imbruvica) and the regimen of fludarabine, cyclophosphamide, and rituximab (FCR)—in ongoing trials.

As an example, the safety and efficacy of the BCL-2 inhibitor venetoclax (Venclexta) combined with ibrutinib is being tested in an open-label phase II CLL trial that has 2 cohorts: high-risk, untreated patients and relapsed/refractory patients (NCT02756897).

If the results are promising, this could be an exciting first-line treatment option for patients with CLL, explains William G. Wierda, MD, PhD.

OncLive: Please provide an overview of what you presented today.

In an interview with OncLive during the 2016 OncLive State of the Science Summit on Treatment of Hematologic Malignancies, Wierda, professor of Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, provided his expert insight on the frontline treatment of patients with CLL.Wierda: My presentation today was an overview of first-line therapies for patients with CLL. This is an area that has been changing very rapidly over the last 2 to 3 years where, up until then, we were using chemotherapy and chemoimmunotherapy. Over the last couple of years, we have had large randomized trial data available with the small molecule inhibitors—particularly ibrutinib, which, in the RESONATE-2 trial, showed improvement in outcomes over chemotherapy for patients who received the agent in the frontline setting.

What is imperative for community oncologists to learn from this discussion?

The management of patients is obviously changing with this very positive data. The other data that I showed was an update of our FCR experience. The important take-home message from that data is that there is a subgroup of patients who do very well with FCR and are probably cured from it. Those are patients who have a mutated V gene who receive FCR in the frontline setting.What I hope they take away is what should be a rational, reasonable way to manage patients in the frontline setting with CLL. For example, [there are] patients who have a 17p deletion. They shouldn’t be treated unless they have an indication for treatment; when they get treated, they should get ibrutinib as their first treatment. They should not get chemotherapy. We should stay away from chemotherapy for patients who have 17p deletion. For patients who have a mutated V gene, are young and fit and can tolerate FCR, FCR would be the indicated treatment for those patients.

Are there any ongoing studies in this space that you are excited about?

The other group of patients is elderly, over 65 years of age, or younger with an unmutated V gene. For that big group, we are trying to minimize exposure to chemotherapy and use the treatments that are less toxic early on to manage the disease and save chemotherapy and chemoimmunotherapy for later. This is because we like to avoid the side effects that we get with it, as well as the long-term negative effects that we get—such as secondary malignancies and secondary acute myeloid leukemia and risk for Richter’s transformation.We have a study that we are enrolling right now that I’m very excited about. It’s a combination of ibrutinib plus venetoclax. We have 2 cohorts for that trial. We have a previously untreated patient cohort, and we have a cohort for relapsed patients. I’m excited about that combination because, clinically, it makes very good sense. Ibrutinib’s major talent is in controlling the disease and shrinking lymph nodes. It’s less effective at eliminating disease from the bone marrow and from the blood.

What are some of the remaining challenges in CLL?

On the other hand, venetoclax is highly effective at eliminating disease from the blood and the bone marrow. That combination is going to be particularly important and highly effective, and it’s obviously an oral combination. Those 2 drugs are given orally and we will see significant benefit from that combination.Well, 1 challenge is the need for continuous treatment. If patients go on to 1 of the small molecule inhibitors, they have excellent disease control, but they still have measurable disease. Most of them just achieve a partial remission. Now partial remission is good, but they still have measurable disease. Moreover, if you stop the medicines, the disease will just grow. Therefore, you can’t stop the medicine for ibrutinib or idelalisib (Zydelig), etcetera. Patients have to stay on those medicines.

What we are working toward now is sequencing the drugs or combinations that will allow eventually for a treatment-free period, or treatment-free interval. That is a need.

What other agents are in development?

Another big need that we are starting to work on is the fact that these patients have a very dysregulated immune system. They’re at increased risk for infections and for other cancers, and so we need to develop strategies and treatments that correct their immune system and allow it to work properly so they don’t get these infections and second cancers.The CAR [chimeric antigen receptor] T-cell trial is something we are very interested and excited about. There’s a CD19-targeted CAR therapy that has been used and is in development for acute lymphoblastic leukemia, as well as for non-Hodgkin lymphoma. There will be trials hopefully opening soon for CLL. I am excited about that strategy as an immune-based method for patients with CLL.

Then, there are also the checkpoint inhibitors. These are antibodies that activate the immune system. We are doing a trial also with nivolumab (Opdivo) and ibrutinib as a combination to treat the leukemia, and we’re also looking at correction or normalization of the immune system for those patients on that treatment.