Wierda Discusses Novel Combinations, Sequencing in CLL

Angelica Welch
Published: Saturday, Oct 07, 2017

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.

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

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. 

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.

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?

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. 

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. 

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

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.

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