Wierda Discusses Novel Combinations, Sequencing in CLL

William G. Wierda, MD, PhD

Although ibrutinib (Imbruvica) remains the go-to drug for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), new drugs and novel combinations are showing potential. With this progress, questions regarding sequencing continue to pose a challenge.

The BCL-2 inhibitor venetoclax (Venclexta) as monotherapy has demonstrated a high rate of objective response and is well tolerated in patients with 17p deletion, but is also showing promise outside of that indication, says William G. Wierda, MD, PhD.

Another novel combination in this space is ibrutinib, cyclophosphamide, fludarabine, and obinutuzumab (Gazyva)—referred to as IFCG—that is undergoing investigation as a frontline treatment for young fit patients who have been determined to do well on fludarabine, cyclophosphamide, and rituximab (FCR)-based treatment.

OncLive: What has led to the need for this discussion on sequencing in CLL?

During an interview with OncLive at the National Comprehensive Cancer Network (NCCN) 12th Annual Congress on Hematologic Malignancies, Wierda, executive medical director of the Leukemia Center at The University of Texas MD Anderson Cancer Center, discussed the continued importance of ibrutinib, the promise for novel combinations, and the impact this progress has had on sequencing for CLL.Wierda: It is because we have so many agents now, and most of the agents approved as monotherapy. Ibrutinib was approved as monotherapy, venetoclax was approved as monotherapy—so the early trials were looking at the activity of those single agents and patients have been treated based on what was available. For example, ibrutinib was the first drug that was available, so most of the patients who were treated in the community initially had gone on ibrutinib. Now, we have venetoclax, so that is another option.

Speaking of combinations, are there any that are looking particularly promising?

There is a lot of work and research devoted to identifying good combinations. Perhaps [the next successes will be] combinations of the agents that I have mentioned, or combinations of these agents with a CD20 antibody or other drugs to get better remission. And then there are also considerations about what is the right sequence to give them in, and do you expect to have a response to one thing if patients have developed resistance to another. For example, responses in ibrutinib-refractory patients with venetoclax.We have a couple trials with new novel combinations in the frontline setting with previously untreated patients. We have a trial of a combination based on an FCR regimen that Dr Michael Keating developed at MD Anderson. So, it is the next generation of treatment combination with IFCG—4 drugs for patients that we know do the best with FCR-based treatment. These are patients who are young and have a mutated immunoglobulin heavy chain variable gene (VG), and we know that these patients, over 50% of them, can get a good remission that lasts more than 10 years with FCR.

This 4-drug combination trial is now intended to achieve the same thing or better but, what we are doing is a little bit different. In addition to modifying some of the drugs, we are just giving 3 cycles of the chemotherapy part. So, not only are we working on making a more potent regimen and combination to treat patients, but we are trying to reduce or pull back on the amount of chemotherapy that they are exposed to in order to reduce their risk for other malignancies in the bone marrow, as well as Richter's Transformation. We are excited and interested in that new combination for young, fit patients with a mutated VG.

With all of these newer agents, what importance do older agents such as ibrutinib hold in CLL?

Another combination that we are excited about, which is generating some data, is ibrutinib plus venetoclax. In this trial, patients receive 3 months of ibrutinib by itself, and then up to 2 years of the combination. There are 2 patient cohorts for that trial, an untreated patient population and a previously-treated patient population. We are generating some data in that trial, which, along with the IFCG data will be presented at American Society of Hematology (ASH) this year. We are seeing good, deep, minimal residual disease (MRD)-negative remission already in that trial.Ibrutinib is an extremely effective drug. It is effective in the frontline setting—so we see the patients who initially receive it have very long periods of disease control. The more common reason for frontline patients to come off of treatment is because of tolerability and toxicities.

What would your advice be to community oncologists about how to sequence therapies in CLL?

The work that we are doing now and the focus with ibrutinib is looking at the dosage closely. We have a couple clinical trials at MD Anderson looking at dose and trying to determine whether patients need to be on 420 mg, or if a lower dose may be as effective and better tolerated. The other aspect we are working on with ibrutinib is that in exploring these combinations, we want to focus on patients getting into a deep remission so that we can give them a treatment-free period. Right now, patients stay on ibrutinib until it does not work anymore.Right now, there are a couple things that drive sequencing of therapies. One of them is the amount of data that we have on a given treatment of drug. Since ibrutinib was available first, we have the best view on how the remissions look, and how long remission and disease control lasts. For venetoclax—another oral drug that is very effective—we have an idea of how active it is and the depth of remission, but we don't yet have a great look at how long those remissions last. That aspect drives the fact that in the salvage setting, and in the frontline setting, we use ibrutinib first because we know it will control the disease and we know that the remissions will last a significant period of time.

So, right now, ibrutinib is probably the first go-to drug among the small molecule inhibitors because of those factors. Now, we will be getting more data on venetoclax, and we will have a better idea about the length of remission, not just in the patients with a 17p deletion, but also in patients who don’t have a 17p deletion.

The other small molecular inhibitor that is commercially available is idelalisib (Zydelig). That drug has had less usage, probably because of its toxicity profile. It is a little bit harder to give and a little less well tolerated—so the usage of that drug is really driven by the toxicity and the fact that we have other drugs that have lower incidence of toxicity.

How do you think newer agents and approaches such as CAR T-cell therapy are going to fit into the future treatment of this disease?

Another aspect that may drive what people are using and how they are using it is the tumor lysis that has been associated with venetoclax. That has been a little more challenging to initiate because you have to start at a low dose and escalate gradually over a month and monitor patients very closely.We are starting to see patients who are refractory to ibrutinib as one group of patients. We know that ibrutinib is very effective, but responses don’t last forever. Venetoclax is another option, but it is only approved for patients with relapsed disease and 17p deletion, even though it is getting used outside of the FDA-approved indication.

Although we have these very effective agents, we do have patients who are developing resistance, and there is a strong need for additional treatment and new drugs that work by different mechanisms of action. We are sort of moving away from chemotherapy, and I think we will see more patients being treated frontline with the small molecular inhibitors, and if they fail those, they will still be chemotherapy-näive. So, it may be that we can use chemotherapy later on—we don’t know yet.

Is there anything else that you’d like to highlight?

But, again, the push has been to identify drugs that are active, that work by a new mechanism of action, and that aren’t chemotherapy, like the CAR T-cell therapies. The durable responses that have been seen with CAR T-cell therapies in acute lymphoblastic leukemia have led us to speculate that it may be a cell-based therapy that can induce long durable remissions. We entertain the concept of cure with that type of treatment. I mentioned the 2 trials that we have [at MD Anderson] that we are excited about—the IFCG trial and the ibrutinib plus venetoclax trial. We have some other trials with novel agents. For example, there is a drug called SNS-062, which we are looking at for patients who are ibrutinib-refractory. SNS-062 is a small molecule inhibitor of Bruton’s tyrosine kinase, and it potentially can have activity in patients who have developed a mutation that has resulted in their resistance to ibrutinib.

We have several other new trials with novel agents that we are excited about, and are working on getting access to others like MCL-1 inhibitors. There is a lot of activity going on and a lot of interesting things. It is still a very exciting time in CLL.