CLL Research Update, Comparative Efficacy of Combination Treatments

In part one of this podcast series, Adam Kittai, MD, hematologist and assistant professor of medicine, Ohio State University, provides an overview of current research being conducted on chronic lymphocytic leukemia and discusses the results of the GLOW study comparing ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab. 

Listen to part two here.

Read the full transcript:

Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

In part one of this podcast series, we are joined by Dr Adam Kittai, hematologist and assistant professor of medicine at the Ohio State University. He provides an overview of current research being conducted on chronic lymphocytic leukemia and discusses the results of the GLOW study, comparing ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab. Dr Kittai?

My name is Dr Adam Kittai. I am from the Ohio State University. I am an assistant professor of medicine here.

I am an expert in chronic lymphocytic leukemia, and specifically, my research involves bringing novel clinical trials to this space and also finding novel therapies for high-risk disease, as well as studying cellular therapies and looking at the Richter's syndrome in CLL.

Can you give us an overview of the current research being conducted on ibrutinib?

Ibrutinib is the first BTK inhibitor to be approved for the treatment of CLL. Recently, there is more and more research being done about ibrutinib that is really exciting.

I think that, predominantly, the area of interest is combining ibrutinib with venetoclax, which is a BCL-2 inhibitor, along with other medications like anti-CD20 monoclonal antibodies in order to treat the chronic lymphocytic leukemia to a level that is undetectable.

There are a couple of recently published studies as well as ongoing studies that are looking at exactly this, which include the CAPTIVATE study that was recently published, the registrational trial, GLOW, which hopefully we will get an approval for ibrutinib plus venetoclax in the front-line setting.

Then there are large, cooperative group studies such as EA9161 and the ALLIANCE study that are comparing ibrutinib plus venetoclax plus obinutuzumab versus ibrutinib plus obinutuzumab in the front-line setting for young and old patients.

Then there's going to be the definitive trial that I think we're all looking forward to that won't come out for a few years. That's the CLL17 trial by the German group, which is ibrutinib versus venetoclax plus obinutuzumab versus ibrutinib plus obinutuzumab.

We also have some exciting studies that are comparing ibrutinib to the second-generation BTK inhibitors such as zanubrutinib and acalabrutinib with the ALPINE study and the ELEVATE-RR study.

Lastly, there was one recently published study that I think we all found super interesting but we're waiting for survival data to come out on, is the CLL12 study out of the German group that compared ibrutinib versus placebo for patients with early-stage CLL who otherwise would not have an indication to treat.

A lot going on in the world of ibrutinib. I think that the most interesting ones are the combination studies.

Can you tell us a little bit about the GLOW and CAPTIVATE studies, and how those data build previous data?

Let's start off with the GLOW study. The GLOW study is the registration study. What I mean by registration study is it's a study designed in order to get a new indication for the drug.

It's ibrutinib plus venetoclax, and it's a phase 3 randomized trial that compares this combination to chlorambucil plus obinutuzumab.

I think the biggest dig on this study, which I do have to mention upfront, is that we do view the combination of chlorambucil plus obinutuzumab as a not great comparator at this time, because we have many, many studies that show superiority of ibrutinib by itself to chlorambucil plus obinutuzumab.

I think that's the biggest thing that people harp on with this study, but it is still interesting to see the outcomes for patients who are treated with this combination.

It was an older population. It's designed for patients who are older than 65. The median age was 71. They did not have high-risk disease, so there was no deletion 17p, TP53, and they also had to have a high comorbidity score if they were less than 65.

They designed the trials that patients received 3 cycles of ibrutinib and then 12 cycles of ibrutinib plus venetoclax. After a median followup of 27.7 months, the median progression-free survival was not reached for the combination arm, versus 21 months for the chemoimmunotherapy arm of chlorambucil plus obinutuzumab.

I think one of the interesting things to look at here is the MRD rates. They saw high rates of minimal residual disease negativity in the bone marrow and peripheral blood that were about 50%-60%.

Another interesting thing that I want to comment on here is that undetectable minimal residual disease attained by the ibrutinib plus venetoclax arm was not the same as those who attained undetectable minimal residual disease in the chlorambucil/obinutuzumab arm. One of the interesting studies was just released at ASH 2021.

We'll be excited to see the push on oral presentation on this, that minimal residual disease attained by the combination arm of ibrutinib/venetoclax was not equal to the minimal residual disease attained by chlorambucil and obinutuzumab.

Meaning that patients who attained the undetectable minimal residual disease with the ibrutinib/venetoclax had a longer time of disease remission than the chlorambucil/obinutuzumab arm, suggesting that there is deeper remissions with the combination small-molecule inhibitors.

Something to note, too, that we are all going to be paying closer attention to, is when the study comes out, I think we're all eagerly waiting to see the adverse event profile. It was noted that there were seven deaths that occurred in the combination ibrutinib/venetoclax arm, and only two deaths that occurred in the chlorambucil/obinutuzumab arm.

I think that's going to be something that we're highly waiting for when we see the final publication.

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