Optimizing Chronic Lymphocytic Leukemia Treatment Pathways With BTK and BCL-2 Inhibitors

In this interview, Dr Brian T Hill discusses advancements in chronic lymphocytic leukemia treatment, including the impact of targeted therapies like BTK and BCL-2 inhibitors, the role of genetic mutations in treatment decisions, and the evolving use of minimal residual disease testing to optimize patient pathways.

Brian T Hill, MD, PhD: My name is Dr Brian Hill. I'm the director of the Lymphoid Malignancies Program at the Cleveland Clinic Taussig Cancer Institute, where I see patients and do research on novel therapeutics for chronic lymphocytic leukemia (CLL), lymphoma, and related conditions.

What are the most significant advancements in the treatment of CLL in recent years?

Dr Hill: Without a doubt, the biggest advance in the past decade has been the introduction of nontoxic targeted therapies, such as BTK inhibitors, for the treatment of CLL. The first of these was ibrutinib, which was initially FDA approved in 2013 for mantle cell lymphoma, and then approved for CLL not long after that. This agent is highly effective and generally well tolerated. In phase 3 clinical trials, it was shown to be superior to chemotherapy for both newly diagnosed and recently diagnosed patients in need of treatment when compared to standard chemotherapy for older and younger patients.

Although ibrutinib may have some side effects, these have largely been overcome by second-generation oral covalent BTK inhibitors, such as acalabrutinib and zanubrutinib. These agents are equally effective and better tolerated, with lower rates of atrial fibrillation and bleeding, which are common toxicities associated with ibrutinib.

The other big advance has been the introduction of venetoclax-based treatment. Venetoclax is a first-in-class oral BCL-2 inhibitor that has shown remarkable clinical activity in CLL and some other hematologic malignancies. Between BTK inhibitors and the BCL-2 inhibitor venetoclax, we have seen a dramatic change in the treatment landscape for CLL in both frontline and relapsed/refractory settings.

How do genetic mutations, such as TP53 or IGHV status, influence treatment decisions in CLL?

Dr Hill: For IGHV status, patients can be categorized into two major groups: favorable or unfavorable, who have mutated or unmutated IGHV. For most patients who have unfavorable or unmutated IGHV, we aim to avoid chemoimmunotherapy, as these patients tend to have shorter remissions with chemotherapy and really need targeted agents. They tend to have more proliferative CLL and anmore aggressive clinical course.

TP53 mutation can be present in up to 5% of newly diagnosed patients and is higher in the relapsed/refractory setting. It predicts a shorter time therapy initiation and is generally associated with poor outcomes when treated with traditional therapies. In the targeted treatment era, continuous use of oral covalent BTK inhibitors is still associated with favorable outcomes compared with historical data for TP53 mutations.

The use of venetoclax in a time-limited fashion with a monoclonal antibody is effective but tends to have shorter duration of response in patients with TP53 mutations compared to those with wild-type TP53. Many experts favor continuous therapy with a BTK inhibitor for patients with TP53 mutations, although there may be scenarios where venetoclax-based treatment may be appropriate.

Are there emerging tools or tests that could improve the personalization of CLL treatment?

Dr Hill: One of the most significant tools, used both clinically and in research, is testing for minimal residual disease (MRD). These tests, which may either use flow cytometry or DNA-based methods, can detect one CLL cell among 10 000 or, in some cases, one in a million cells. We know that after a time-limited therapy, patients with deeper remissions, characterized by lower disease burden and higher rates of undetectable MRD, tend to have longer remission duration and improved progression-free survival (PFS). Time to the next therapy is longer for patients who achieve an undetectable MRD state in the blood at the conclusion of therapy.

Some studies are examining whether treatment should be extended for patients who don’t achieve certain MRD milestones with various combinations. Those are intriguing options, but not widely used clinically for routine clinical practice.

How has the integration of targeted therapies, such as BTK inhibitors or BCL-2 inhibitors, changed the treatment landscape for CLL?

Dr Hill: As we've moved away from chemotherapy and increasingly utilized frontline BTK inhibitors, many patients have maintained good disease control on these agents for extended periods. There can be intolerances to some of the oral BTK inhibitors, so sometimes switching from one covalent to another covalent BTK inhibitor can be useful. Sometimes patients can develop treatment resistance to covalent BTK inhibitors, in which case we do have a noncovalent oral BTK inhibitor, pirtobrutinib, as well as CAR T-cell therapy as potential options for patients who have been treated with a BTK inhibitor and venetoclax.

As targeted therapies become more widely used and refined, most patients are doing better. However, there is still a small subset of patients who are refractory to both lines of therapy. Developing new and improved strategies for these patients is a key area of ongoing research.

How do you see pathways evolving with the advent of new clinical trial data for CLL treatments?

Dr Hill: New clinical trials are exploring the combination of the two oral targeted agents: BCL-2 and BTK inhibitors. We've seen combination data for ibrutinib with venetoclax and for acalabrutinib with venetoclax. Additionally, there are emerging data on combinations of zanubrutinib and sonrotoclax, which is a next generation oral BCL-2 inhibitor.

These tend to be very effective therapies that can be administered for a time-limited basis, let's say 6 to 12 months. The durability is pretty favorable depending on which combination is used. The rates of undetectable MRD status vary, and as new data emerge, we may find that certain novel combinations are more effective at achieving undetectable MRD. In such cases, these regimens may become more attractive for time-limited treatment strategies.