Patient Choice and Treatment Duration

A pivotal aspect of managing chronic lymphocytic leukemia (CLL) centers on whether patients lean towards a fixed-duration therapy, such as the venetoclax and obinutuzumab (VenG) regimen concluding after 12 months, or an indefinite treatment path continuing until disease progression. This decision substantially impacts a patient’s lifestyle and overall well-being. Dr. Arun Bhandari emphasizes that “patient choice is very important, whether thay want to have a fixed duration therapy with VenG where after 12 months you are done, or whether they are willing to go for indefinite [treatment] until progression.” This underscores the critical role of shared decision-making, where patients actively engage in selecting a treatment plan that aligns with their individual lifestyles and preferences.

For instance, a retired teacher who enjoys traveling might prefer a fixed-duration therapy to minimize long-term disruptions to their plans. Conversely, a younger professional focused on career advancement might opt for continuous therapy to aggressively control the disease and maintain a high quality of life. The key is open communication between the oncologist and the patient, ensuring a fully informed decision.

For patients exhibiting high-risk genetic features, including 17p deletion or *TP53* mutation, Bruton tyrosine kinase inhibitors (BTKis) are frequently favored. Dr. Bhandari notes, “With 17p deletion or *TP53* [mutation], I tend to use BTKi more because I think that’s where the data [show benefit] rather than fixed duration.” This preference arises from data indicating that BTKis may provide superior long-term disease control in these specific subgroups. These genetic markers are identified through comprehensive genomic testing, a standard practice in modern CLL management.

BTK Inhibitors: Ibrutinib, Acalabrutinib, and Zanubrutinib

Selecting among the different BTKis – ibrutinib (Imbruvica), acalabrutinib, and zanubrutinib – presents another layer of complexity.Cost considerations often play a significant role, particularly given the high cost associated with venetoclax. Dr. Bhandari explains,”[Considering] how much the cost of venetoclax is,if ibrutinib [Imbruvica] costs [less],then if I’m cost conscious,I will use that one.” This highlights the economic realities of healthcare, where treatment decisions can be influenced by financial factors. Patient assistance programs and insurance coverage options should be thoroughly explored to mitigate these costs.

Beyond cost,the clinical differences between ibrutinib and acalabrutinib are considered minimal by some experts. Dr. Bhandari states, “You can use ibrutinib or acalabrutinib. I don’t think there’s a big difference.” Though, individual patient profiles and potential side effects should always be carefully considered when choosing a BTKi.For example, a patient with a history of cardiac issues might be steered away from ibrutinib due to its potential cardiovascular side effects.

zanubrutinib is increasingly recognized as a strong contender in the BTKi landscape. Recent data from the SEQUOIA study demonstrated sustained superiority of zanubrutinib versus bendamustine plus rituximab in treatment-naive CLL/SLL patients after five years of follow-up. This reinforces the potential of zanubrutinib as a frist-line treatment option. The SEQUOIA study’s findings are particularly relevant for older adults with CLL who may not tolerate more intensive therapies.

The Role of Continuous Therapy vs. Fixed-Duration Approaches

The debate between continuous BTKi therapy and fixed-duration approaches like VenG remains a central theme in CLL treatment.Dr. Huzefa Bahrain raises a critical question: “Those with the 17p deletion do better with a btki. Do you think that’s as of the mechanism of action, or do you think because it is indeed continuous therapy?” This question probes the underlying reasons for the observed efficacy of BTKis in patients with specific genetic mutations.

Dr. Allan suggests that it’s a combination of both factors. BTKis rapidly halt proliferation and effectively control the disease long-term. He explains, “to answer your question, it is a bit about the mechanism of action, because BTKis shut down proliferation very quickly and very potently. They control the disease very well in the long term, and stop doubling and proliferation, which then translates into controlling the disease for longer. So, it’s a little bit of both. It’s the biology of the disease itself, and whether we have continuous antiproliferative pressure onto the cells—which is why CLL17 [NCT04608318] will be critically important.” This highlights the complex interplay between the drug’s mechanism of action and the disease’s biological characteristics.

the CLL17 study is eagerly anticipated, as it may provide crucial insights into whether continuous therapy leads to improved overall survival (OS) compared to fixed-duration approaches, particularly in patients with deletion 17p.Dr.Allan notes, “We’ve never shown patients with deletion 17p have necessarily an inferior OS compared with those without deletion 17p in any fixed-duration approach, but if we start to see an OS difference in CLL17 and the fixed duration approaches compared with those with BTKi, I think that will answer a big question for us and highlight the need for continuous therapy for these patients.” The results of CLL17 could potentially reshape treatment guidelines for this high-risk patient population.

Doublet Therapies: Ibrutinib/Venetoclax and Acalabrutinib/Venetoclax

Doublet therapies, such as ibrutinib/venetoclax and acalabrutinib/venetoclax, are also under active inquiry. The CAPTIVATE study (NCT02910583),a fixed-duration approach with ibrutinib/venetoclax,demonstrates promising results,tracking historically well with the progression-free survival (PFS) curves from VenG. Dr. Allan comments, “the CAPTIVATE study as a fixed duration approach with ibrutinib/venetoclax seems to be tracking historically well with the PFS curves from VenG. It has some advantages in that it’s an all-oral approach. We don’t have the antibody to deal with and the immunosuppression that comes with it.” The all-oral nature of these regimens offers convenience and reduces the need for intravenous infusions.

While doublet therapies offer the advantage of being entirely oral,their specific role in different patient populations is still being defined. One potential advantage lies in treating patients with bulky disease. Dr. Allan points out, “One thing that was shown is that with VenG, bulky disease greater than 5 cm at study entry was an self-reliant predictor for inferior PFS, and on the CAPTIVATE study, they showed that bulky disease did not identify a patient who is going to have inferior PFS. They got MRD at the same rates, etc. If there is a patient population that might be best for doublet or even triplet, it might be a patient with disease bulk, because it’s so good at getting control of disease, mitigating tumor lysis, and seemingly having very good outcomes, etc.” This suggests that doublet therapies may be particularly effective in rapidly reducing tumor burden and preventing complications like tumor lysis syndrome.

Real-World Considerations: Cost and Access

Cost remains a significant barrier to accessing optimal CLL treatment in the United States. The high price of novel therapies can limit patient choice and potentially impact outcomes. Advocacy groups like the Leukemia & Lymphoma Society (LLS) are actively working to ensure that patients have access to affordable and effective treatments. policy changes, such as those aimed at controlling drug costs for Medicare patients, are crucial in addressing this issue. The Inflation Reduction Act, signed into law in 2022, includes provisions aimed at lowering prescription drug costs for seniors, which could have a positive impact on CLL patients.

Dr. Ligeng Tian highlights the real-world challenges,stating,”I do have patients who end up doing BR simply as they don’t want to take the pills forever,the cost issue,and they want to be done with it after some BR. The fixed duration is shorter than venetoclax, and you’re not worried about tumor lysis.” This underscores the ongoing need for efforts to alleviate the financial burden of CLL treatment on patients and the healthcare system. Bendamustine and rituximab (BR) is an older chemotherapy regimen that, while less expensive, may not be as effective or well-tolerated as newer targeted therapies.

Looking Ahead: The Future of CLL Treatment

The CLL treatment landscape is constantly evolving, with ongoing research exploring novel combinations and targeted therapies. As new data emerge, treatment strategies will continue to adapt, with a growing emphasis on personalized approaches that consider individual patient characteristics, disease biology, and treatment preferences. The ultimate goal is to improve outcomes and quality of life for individuals living with CLL. Clinical trials are continuously evaluating new drugs and treatment strategies, offering hope for even more effective and less toxic therapies in the future.

The integration of minimal residual disease (MRD) assessment into treatment decision-making is also gaining momentum. MRD negativity, indicating the absence of detectable cancer cells after treatment, is associated with longer remission durations. However, the optimal use of MRD in guiding treatment strategies is still under investigation.Studies are exploring whether MRD status can be used to tailor treatment duration or to identify patients who may benefit from additional therapy.