Breakthroughs and Challenges in BCL-2 Inhibitor Therapy for CLL Treatment

John Seymour, MD

BCL-2 inhibitors like venetoclax (Venclexta) work by targeting the BCL-2 protein, which plays a key role in preventing apoptosis, or programmed cell death. According to John Seymour, MD, overexpression of BCL-2 allows cancer cells to evade apoptosis, leading to uncontrolled growth.

By binding to BCL-2, venetoclax displaces apoptotic activators like BIM and BID, which leads to triggering of the cell death pathway. However, the complexity does not only lie in the presence of BCL-2, but also in the interaction with other factors like MCL-1. These may influence the effectiveness of the drug, showing the need for careful patient selection and a further understanding of individual tumor biology.

Seymour, director of hematology at the Peter MacCallum Cancer Center and the Royal Melbourne Hospital in Melbourne, Australia, also addressed why BCL-2 was considered an undruggable target for so long. Unlike other cancer therapies that target enzymatic activity, BCL-2 inhibitors interfere with protein-protein interactions, which present unique challenges in drug design. It took years to develop a compound that could selectively bind to BCL-2 without affecting related proteins like BCL-XL. The breakthrough came with venetoclax, which demonstrated efficacy as well as a high level of specificity for BCL-2.

Additionally, Seymour highlighted the emergence of combination therapies, which pair BCL-2 inhibitors with agents like Bruton tyrosine kinase (BTK) inhibitors or anti-CD20 antibodies to enhance outcomes and reduce the likelihood of resistance. These advances have expanded the treatment landscape for chronic lymphocytic leukemia (CLL), offering both time-limited and continuous therapy options tailored to the needs of individual patients.

In an interview with Targeted Oncology^TM, Seymour discussed the mechanisms, challenges, and advancements in BCL-2 inhibitor therapy, specifically focusing on venetoclax for the treatment of CLL.

Microscopic image of CLL cells - Generated with Google Gemini AI

Targeted Oncology: Can you explain the mechanism of action of BCL-2 inhibitors?

Seymour: BCL-2 inhibitors work by binding to and preventing the action of BCL-2. In the normal cell death pathway, as cells age, they should die by apoptosis. Overexpression of BCL-2 prevents activation of that pathway. Delivering a BCL-2 inhibitor [like] venetoclax binds to BCL-2 and then displaces those apoptotic activators, such as BIM and BID that then bind to and activate that pathway.

Understanding that it is not solely what level of BCL-2 is present that determines sensitivity, but what are the apoptotic activators that are bound to BCL-2? How will they be displaced? Are there other factors present, such as MCL-1, that can potentially quench those factors, or will they go on to trigger apoptosis? So, it is understanding the dynamic balance between those regulators that determines the sensitivity to venetoclax. But the potency and the rapidity of induction of apoptosis is what leads to the need for that gradual dose ramp-up and cytoreduction and avoid those biochemical issues that can lead to significant patient morbidity.

Why was BCL-2 considered an undruggable target for so long? What led to the development of effective BCL-2 inhibitors?

The vast majority of drugs that were developed work by binding to a catalytic or an enzymatic issue. Drugs like tyrosine kinase inhibitors in [chronic myeloid leukemia], imatinib [Gleevec], dasatinib [Sprycel], ponatinib [Iclusig], or the BTK inhibitors in other lymphoid malignancies, all prevent an enzymatic action.

The issue with BCL-2 is that it is not phosphorylating or modifying its binding partner, but it is leading to occupation of a binding site that then prevents binding with another protein. It is this protein-protein interaction that we need to interfere with, and because there is a large family of these proteins, the specificity to be unique for BCL-2 without inhibiting BCL-XL, for example, that leads to reduction in platelet number. It is that combination, the protein-protein interaction, rather than being a catalytic inhibition, and the very minimal differences between the structure of those family of proteins needed a unique structure and one that had exquisite specificity.

What were the key findings from the trials that demonstrated the efficacy of BCL-2 inhibitors in CLL?

Firstly, the potency and effectiveness, but the flip side of that was the risk of tumor lysis syndrome of biochemical changes with rapid introduction. The analogy I use is that this is a powerful weapon, like a power tool or a chainsaw. One needs to use it with care and skill to ensure that you ramp up safely.

Another key finding was that with continued single-agent therapy, there is a significant risk of induction of resistance mutations that lead to outgrowth of resistant clones. That was the impetus to use combination therapy, either with BTK inhibitors or with an anti-CD20 antibody, to achieve deeper reductions but enable time-limited therapy.

The third paradigm that emerged was, if we use this time-limited therapy, it then retains disease sensitivity, so at progression, we can retreat with that same combination.

How do these BCL-2 inhibitors compare with other standard-of-care treatments for CLL?

It is hard. Do you prefer Coke or do you prefer Pepsi? Both have their characteristics. People will have a preference for one or the other. For us as prescribers, it gives us a great choice, and depending upon the patient profile, and that is both their host profile, so my personal preference for younger patients is, I prefer a time-limited treatment that, at the moment, based on US approvals, is a venetoclax and anti-CD20 combination, whereas for older or frailer patients, I prefer continuous outpatient BTK inhibitor therapy. Then, based on disease biology, with IGHV-mutated disease, we get very long remissions after venetoclax-based therapy, whereas with IGHV-unmutated disease, they tend to relapse earlier, so I prefer BTK therapy. Both tools are good, and like Coke or Pepsi, they are both useful to have in the fridge. We can then choose which best fits the biologic profile of the disease and the host characteristic, their age, their comorbidities, their cardiovascular risk profile, to make the right choice for the right patient.

What are your key takeaways from this for a community oncologist?

My key takeaways for a community oncologist are that we have a great repertoire of tools of available to treat CLL, but understanding and getting a clear profile of the biology of that disease, TP53 mutational status, IGHV mutational status, is useful information to then make an informed choice and involve the patient in that dialog, because what is involved in terms of the number of visits, inpatient, outpatient, frequency of blood testing is quite different between the 2 approaches. So, ensuring that the patient is aware of what is involved in the pathway and make sure that they are an active partner in that choice is a takeaway.