Advances and challenges in BCL-2 inhibitor therapy for CLL treatment

BCL-2 inhibitors, such as 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 avoid apoptosis, leading to uncontrolled growth.

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

Seymour, director of hematology at Peter MacCallum Cancer Center and Royal Melbourne Hospital in Melbourne, Australia, also addressed why BCL-2 was considered an indestructible 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 and also a high level of specificity for BCL-2.

Additionally, Seymour highlighted the emergence of combination therapies, which combine BCL-2 inhibitors with agents such as Bruton tyrosine kinase (BTK) inhibitors or anti-CD20 antibodies to improve outcomes and reduce the likelihood of resistance. These advances have expanded the treatment landscape for chronic lymphocytic leukemia (CLL) by offering continuous and time-limited therapy options tailored to each patient’s needs.

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

Microscopic image of LLC 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 the activation of this pathway. Administration of a BCL-2 inhibitor (similar) to venetoclax binds to BCL-2 and then displaces apoptotic activators such as BIM and BID, which then bind and activate this pathway.

Understanding that it is not just the level of BCL-2 present that determines sensitivity, but what are the apoptotic activators that are linked to BCL-2? How will they be moved? Are there other factors present, such as MCL-1, that can potentially extinguish these factors, or will they trigger apoptosis? Therefore, it is the understanding of the dynamic balance between these regulators that determines sensitivity to venetoclax. But the potency and rapidity of apoptosis induction is what leads to the need for this gradual increase in dose and cytoreduction and avoids the biochemical problems that can lead to significant patient morbidity.

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

The vast majority of medications developed work by binding to a catalytic or enzymatic issue. Drugs such as tyrosine kinase inhibitors in (chronic myeloid leukemia), imatinib (Gleevec), dasatinib (Sprycel), ponatinib (Iclusig) or BTK inhibitors in other lymphoid malignancies all prevent enzymatic action.

The problem with BCL-2 is that it does not phosphorylate or modify its binding partner, but rather leads to the occupancy of a binding site that prevents it from binding to another protein. It is in this protein-protein interaction that we need to interfere, and as there is a large family of these proteins, the specificity is unique for BCL-2 without inhibiting BCL-XL, for example, which leads to a reduction in the number of platelets. It’s this combination, the protein-protein interaction, rather than being a catalytic inhibition, and the minimal differences between the structure of that family of proteins needed a unique structure that had exquisite specificity.

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

Firstly, potency and efficacy, but the flip side of that was the risk of tumor lysis syndrome from biochemical changes with rapid introduction. The analogy I use is that it is a powerful weapon, like a power tool or a chainsaw. You need to use it carefully and skillfully to ensure that you accelerate safely.

Another important finding was that with continuation of single-agent therapy, there is a significant risk of induction of resistance mutations that lead to the growth of resistant clones. This was the impetus to utilize combination therapy, either with BTK inhibitors or an anti-CD20 antibody, to achieve deeper reductions but allow for time-limited therapy.

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

How do these BCL-2 inhibitors compare to other standard treatments for CLL?

It is difficult. Do you prefer Coca-Cola or Pepsi? Both have their characteristics. People will have a preference for one or the other. For us as prescribers, this gives us a lot of choice, and depending on the patient profile, and this is the host profile, so my personal preference for younger patients is, I prefer a time-limited treatment that, at the moment, based in US approvals, it is a combination of venetoclax and anti-CD20, while for older or more frail patients, I prefer continuous outpatient therapy with a BTK inhibitor. So, based on the biology of the disease, with IGHV-mutated disease, we obtain very long remissions after venetoclax-based therapy, while with IGHV-unmutated disease, they tend to relapse earlier, so I prefer BTK therapy. Both tools are good and, like Coca-Cola or Pepsi, are useful to have in the fridge. We can then choose what best adapts to the biological profile of the disease and the characteristics of the host, their age, their comorbidities, their cardiovascular risk profile, to make the right choice for the right patient.

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

My key takeaways for a community oncologist are that we have a large repertoire of tools available to treat CLL, but understanding and gaining a clear profile of the biology of this disease, TP53 mutational status, IGHV mutational status, is useful information to then make an informed choice and involve the patient in this dialogue, because what is involved in terms of number of consultations, inpatient, outpatient, frequency of blood tests is quite different between the 2 approaches. Therefore, ensuring that the patient is aware of what is involved along the way and making sure that they are an active partner in this choice is a lesson.