CLL Paradigm Continues to Be Refined

Erlene Seymour, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Erlene Seymour, MD

The chronic lymphocytic leukemia (CLL) landscape has grown with a number of novel FDA-approved therapies in recent years, which has led to combination studies as well as questions surrounding how to best use these agents in practice, explained Erlene Seymour, MD.

“There are multiple combinations that are going to give us a little bit more direction on what the next step will be,” said Seymour, an oncologist at Barbara Ann Karmanos Cancer Institute, Wayne State University.

The BTK inhibitor ibrutinib (Imbruvica) has demonstrated impressive responses as a single agent, but combinations of ibrutinib with venetoclax (Venclexta), fludarabine-cyclophosphamide-rituximab (FCR), and a triplet regimen with obinutuzumab (Gazyva) and venetoclax are anticipated.

For example, the phase II trial of FCR combined with ibrutinib showed a 100% objective response rate as well as a 40% complete response rate with or without hematologic recovery. Notably, 83% of younger, fit patients with CLL achieved minimal residual disease (MRD) negativity in bone marrow.

Additionally, the BTK inhibitor acalabrutinib (Calquence) will be compared in a head-to-head phase III trial with ibrutinib (NCT02477696; ACE-CL-006) in patients with previously treated CLL. The trial is expected to read out in 2019 and may provide an alternative for those who cannot tolerate ibrutinib.

Most recently, in September 2018, the FDA added MRD data from the phase III MURANO trial to the label for venetoclax for its approved use in combination with rituximab (Rituxan) for previously treated patients with CLL.

Beyond BTK, PI3K , and BCL-2 inhibitors, trials defining a set course of treatment or with strong comparator arms are the ones to anticipate, she said.

OncLive: What are the available therapies for patients and how do you decide who should receive them?

Does the future of ibrutinib lie in combination?

What are some promising combinations we have data for?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Seymour discussed these novel therapies as well as their potential applications in the treatment paradigm of CLL.Seymour: Fluorescence in situ hybridization (FISH) testing used to be a prognostic test. About a decade ago, we had been using it for research purposes to show differences in overall survival (OS). It wasn't necessarily guiding how we would treat patients. Now, we have several therapies that are showing improved OS in patients with 17p deletion del(17p). Doing that testing before therapy is more important than it was previously. There is more testing that will be more important in the future, but is not currently mainstream.We have the 5-year data on ibrutinib. As a monotherapy, it's very remarkable, particularly in patients with del(17p). We talk about the future, but it's been about 4 years since it was approved. It is very mainstream now. The future is in combination with other novel therapies. We're seeing some promising results in some ongoing trials showing that, if we combine ibrutinib with other therapies, we may get a very robust response [that may lead to] MRD and cure. We don't have those answers yet, but that's where the future is going.Some of the more promising data, which were presented at the 2017 ASH Annual Meeting and some at the 2018 ASCO Annual Meeting, come from combinations with venetoclax. There is also a trial looking at the combination of obinutuzumab, venetoclax, and ibrutinib in a 14-month course. That is shorter than some other courses that are out there. The results of that phase I trial have already been published.

The FDA just updated the venetoclax label with MRD data. How important is MRD as an endpoint in patients with CLL?

How does acalabrutinib differ from ibrutinib?

What are your thoughts on the available and emerging PI3K inhibitors, such as idelalisib (Zydelig) and duvelisib?

What is the potential with (CAR) T-cell therapy in CLL?

What are some of the remaining challenges?

Is there any rationale to look at checkpoint inhibitors in CLL?

Are there any ongoing trials that you are really excited to see the results of?

Certainly, [there will be] combinations with venetoclax [and likely] combinations with obinutuzumab. The nice thing about those combinations with venetoclax is that we're seeing less tumor lysis syndrome.It's an important endpoint in trials; it hasn't gotten into guidelines yet. We are seeing a hint that MRD translates to better clinical outcomes. The answer that I would like to see with some of these trials is whether it’s a marker to discontinue therapy, or whether it’s a marker for cure. I'm not sure where the answer lies. It's not something that I routinely do, but that may be different in the future.We need to have more than 1 BTK inhibitor. We see this with our tyrosine kinase inhibitors in chronic myeloid leukemia. They're going to have different toxicity profiles. There are going to be patients who do fine on ibrutinib and some patients who don't tolerate ibrutinib, but can tolerate acalabrutinib and vice versa. There needs to be more BTK inhibitors out there, particularly for toxicity profiles.We started with ibrutinib and idelalisib. Idelalisib seems to have a worse toxicity profile compared with the BTK inhibitors, so the timing was not the best for idelalisib. That being said, we do still see responses. There is still a future for PI3K inhibitors. I'm interested to see the differences in toxicity with duvelisib. Umbralisib (TGR-1202) is also coming down the pipeline. As with the BTK inhibitors, there should be other PI3K inhibitors out there.I'm very excited about CAR T-cell therapy in CLL. We are seeing some good responses in patients who have been treated with multiple therapies, including BTK inhibitors. That will be in the future of CLL also.Some of the available drugs are those that patients have to take forever. I really like the focus of these new trials that are trying to set a course; chemoimmunotherapy always had a course. You have to think about financial toxicity for patients. Even though these drugs are working, everyone needs to consider financial toxicity. That is one challenge that is being addressed.[Researchers] have looked at some checkpoint inhibitors in CLL, but nivolumab (Opdivo) [combined with] ibrutinib didn’t show as robust of a response as we wanted to see.If you had to ask me what the most important trial out there is, it’s FCR versus ibrutinib. That is going to change the paradigm. We already saw the results from the phase II trial comparing venetoclax/rituximab with bendamustine and rituximab. I'm more excited to see trials with really good comparator arms, particularly novel therapies that are compared with strong chemoimmunotherapy. Those are the trials that we need to get answers from.

Davids MS, Kim HT, Brander DM, et al. A multicenter, phase II study of ibrutinib plus FCR (iFCR) as frontline therapy for younger CLL patients. In: Proceedings from the 2018 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 496.