BCL2 Inhibition in Leukemia - Episode 2

Venetoclax's Role in Frontline CLL Management

June 25, 2019

Harry Erba, MD, PhD:We’re going to focus our attention on BCL2 inhibition, but do you want to comment on some of the still-unmet needs and challenges in taking care of these patients?

Matthew Davids, MD, MMSc:I always like to say that CLL [chronic lymphocytic leukemia] is still considered to be an incurable disease for most patients. I think that’s a major unmet need in and of itself, that we need to develop therapies that can be curative for this disease, particularly for younger patients who have higher-risk forms of CLL. For older patients, we might not need to cure the disease. If we can get them on a good therapy that they can stay on chronically for a few years, it’s possible they would die of something else. I think that the goals of care really depend on the type of patient.

But certainly, we have many different treatment options available to us now, going back to chemotherapy and chemoimmunotherapy, and many different novel agents. I think increasingly, we’re finding that we’re needing to use multiple novel agents together to really get durable benefits for the high-risk patients. Of the unmet needs, probably those high-risk deletion 17p,TP53patients are where we’re going to need combination strategies. We might actually do quite well for the patients with low-risk disease, even just using sequential novel agent monotherapy.

Harry Erba, MD, PhD:There are a number of options now for our patient with CLL in terms of BTK inhibition and PI3-kinase-delta inhibition. But in this discussion, let’s focus on BCL2 inhibition. What’s BCL2, and how does it play into the pathogenesis of CLL?

Matthew Davids, MD, MMSc:BCL2 is an anti-apoptotic protein. It causes the cells to basically be prevented from undergoing cell death. And BCL2 is a ubiquitous protein, so it’s present in all of our cells, but it’s present at very high levels in CLL cells and very high levels relative to the other pro-apoptotic proteins as well. And so CLL cells really functionally depend on BCL2 for their survival. And disrupting that BCL2 homeostasis is very disruptive to a CLL cell. When we work with venetoclax in the laboratory, we can target BCL2 and we can see cells dying within an hour of drug exposure. And when the drug was taken into the first CLL patients, this was also seen with tumor lysis syndrome occurring very quickly with this drug. So it’s a very, very potent mechanism. It really works right at the level of the mitochondria of the cell. It’s such a fundamental mechanism of the cell that it can kill cells very quickly.

Harry Erba, MD, PhD:And venetoclax is an inhibitor of BCL2. It was first approved in the relapsed-refractory setting for CLL, but recently the FDA has expanded the labeled indication for previously untreated patients with CLL, given in combination with obinutuzumab.

Matthew Davids, MD, MMSc:That’s right.

Harry Erba, MD, PhD:You want to tell us more about that combination and the data that led to that approval?

Matthew Davids, MD, MMSc:Sure. Let me start with some of the data that led to the development of a frontline study. Venetoclax as a single agent was approved as an accelerated approval back in 2016. It’s effective as a single agent, but like the B-cell receptor kinase inhibitors, it tends to need to be used as a continuous drug in that sense. We don’t have a time-limited strategy using venetoclax as a monotherapy. A major innovation was combining venetoclax with rituximab. This was the MURANO study that was published last year in theNew England Journal of Medicine, and it’s designed as a 2-year time-limited regimen for relapsed-refractory CLL patients. That led to the full FDA approval of venetoclax with rituximab in the relapsed setting.

That’s the background out of which this new study, CLL14, grew. CLL14 targets the frontline CLL population, and instead of doing 2 years of therapy, the theory was that as a previously untreated group, they might need less treatment. So it was designed as a 1-year time-limited therapy. Instead of using rituximab, they opted to use obinutuzumab, which is the type 2 CD22 antibody, which has already been shown to be more potent at killing CLL cells than rituximab, not just in vitro.

But actually, in the CLL11 study that the German CLL Study Group conducted, there was an overall survival benefit when chlorambucil was combined with obinutuzumab, compared with chlorambucil with rituximab. I think it was a very logical choice to use the best CD20 antibody for CLL patients, to use venetoclax together as a time-limited regimen, and that formed the generation of this CLL14 study, which was conducted by the German CLL Study Group in collaboration with a number of different centers around Europe and really around the world.

This was designed as 1 year of time-limited therapy. It starts with the obinutuzumab given first, the idea being to try to cytoreduce—reduce the risk of tumor lysis syndrome from the venetoclax. And then on day 22 of that first cycle, the venetoclax is started with the usual ramp-up, starting at 20 mg and then week by week slowly going up slowly to 400 mg, again to mitigate the risk of tumor lysis syndrome. And then patients complete 6 months of that combination therapy, of venetoclax with obinutuzumab. And they go on to get 6 additional months of venetoclax as a monotherapy. And then all patients stop after 1 total year of therapy.

Harry Erba, MD, PhD:This is in all CLL patients who require therapy, not just deletion 17p, is that correct?

Matthew Davids, MD, MMSc:Correct. It’s a study that was open to patients with all different prognostic markers, but it was a study that was restricted to patients with medical comorbidities. And to do this they used the CIRS score, the Cumulative Illness Rating Scale, and patients had to have a certain level of other comorbidities in order to qualify for the study. The reason for that was that the comparator in this study is chlorambucil with obinutuzumab. This is a regimen that is reasonably active for CLL patients. I think the advantage of that chlorambucil regimen is that it tends to be very well tolerated, and so I think it’s a legitimate comparator for that older, frailer population. It’s not a regimen that we use as commonly in younger, fit CLL patients. That kind of raises the question of how much the CLL14 study may or may not apply to that population. But nonetheless, I think it’s a reasonable comparator. Interestingly, they did a full 12 months of chlorambucil in that study compared with the usual 6 months in order to make it equivalent to the venetoclax regimen.

Transcript edited for clarity.