Benefits of BCL-2 Targeting Treatment for Patients With Chronic Lymphocytic Leukemia

At the 2023 Lymphoma, Leukemia & Myeloma (LL&M) Congress in New York, New York, Asher Chanan-Khan, MD, Mayo Clinic, Jacksonville, Florida, argued in favor of treatments targeting BCL-2 for patients with chronic lymphocytic leukemia (CLL). 

 

Transcript:

Hi, I am Professor Asher Chanan-Khan from Mayo Clinic in Jacksonville, Florida. I'm here at the [Lymphoma, Leukemia, and Myeloma] Congress debating in favor of targeting BCL-2 in patients with chronic lymphocytic leukemia (CLL). Today there were phenomenal speakers. A lot of data presented on both BCL-2 as a target and [Bruton Kinase Inhibitors] (BTKi). 

My position today was to advocate that BCL-2 is an important and perhaps primary target that we should be thinking about when initiating a treatment in patients with CLL. In my arguments, based on several points that were made already by various speakers, the 2 important aspects of my debate were first, CLL is an incurable disease, and because it's an incurable disease, we still [must] be very careful as to what [treatment] we select. And in that context, whatever treatment options we have, we want to maximize their effect, their impact on patients. And that impact can then translate into progression-free, and perhaps overall survival benefit.

My position therefore was in favor of treatment regimens that [can] deliver deeper responses, such as minimal residual disease, also known as [minimal residual disease] (MRD) negative state. There's data presented by my colleagues [and] clinical trials that were presented that I used to show that MRD, that is undetectable level of disease, is possible in the frontline setting if you use a BCL-2 inhibitor. And in present time we only have 1, which is venetoclax. So venetoclax-based therapies in randomized studies have shown that not only do they deliver high response rate, longer progression-free survival, but also, they go and deliver deeper remissions.

My opponent took the place of a BTKi to be the primary way of therapy and my argument against that was that if you use the BTKi, yes, you do get progression-free survival benefit. You do get patients in a response rates, of overall response rates of 90% or so in the frontline setting, but the complete remission rates are very low. And MRD negative status in these patients is so low, in the ballpark of 10%, versus if you use a BCL-2 targeting agent such as venetoclax, your MRD level varies from anywhere from 50 to 70% depending on technology, depending on where you're testing, but definitely north of 50%.

And in the present time, as we look forward in future, most of the clinical trials are asking the question: Can we achieve MRD negativity in patients with CLL? And that translates into benefit. The second point that I argued today was that the benefit that we see with BTK inhibitors is at the back of a continuous therapy. You have to treat patients for years to control their disease, but you don't get them into an undetectable state. And these years of treatment to patients are costly economically as well as clinically or physically costly. They suffer side effects. They have cumulative toxicities, some BTK inhibitors give you headaches, others give you arrhythmias of the heart and you have to be on other therapies for that, [and] some gives you diarrhea. And so, there's a significant compromised lifestyle if you are on chronic therapy to control your disease.

Whereas if you use a BCL-2 inhibitor-based therapy, you can be done with your treatment in a defined period of time, anywhere from 6 months or a year. And in some relapse trials, up to 2 years. But the bottom line is, you can control the amount of treatment and then you leave patients alone. There's a significant benefit to patients off treatment. Their quality of life is better, their [mental health], they feel better because they're not on therapy. And the ability to tell a patient that, "Your disease cannot be detected at this point" is so reassuring to them in the clinic versus, "Hey, I can still see your disease, you just have to be on this treatment for leukemia indefinitely." 

I think there is a big difference in these narratives. So today, in present time with the availability of treatments that we have, I believe, and that's what I argued, that time-defined treatment with the ability to deliver high degree of MRDs can be achieved only through a BCL-2 based regimen versus BTKi, where you have to be on a continuous therapy and still no control of disease at an MRD negative level.

Source:

Chanan-Khan A. Debate: BTKi vs BCL2i: Round 2. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-21, 2023. New York, NY