As treatment paradigms for CLL continue to evolve with new research and emerging therapies, health care providers must stay current through continuous education.
When treating chronic lymphocytic leukemia (CLL), particularly in patients who have already been exposed to standard therapies, providers must prioritize each individual’s unique needs, goals, and quality-of-life preferences. Patient-centered care requires ensuring that therapies align with the patient’s personal values, lifestyle, and long-term health goals. Open and transparent communication among the patient, caregivers, and health care team is essential to establish what the patient wishes to achieve from treatment, whether that means disease stability, achieving remission, or managing symptoms to improve quality of life.
As treatment paradigms for CLL continue to evolve with new research and emerging therapies, health care providers must stay current through continuous education. This ongoing commitment to professional development enables providers to offer the most effective options at each stage of the disease while avoiding repeated use of therapies that may be unlikely to benefit the patient.
The treatment landscape for CLL has undergone significant transformation in recent years. While chemoimmunotherapy was once the standard first-line approach, the advent of covalent Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, and B-cell lymphoma-2 (BCL2) inhibitors, like venetoclax, have offered safer and highly effective alternatives. Despite these advancements, some patients face challenges in treatment due to disease progression or intolerance to these therapies, particularly in those with prior exposure to 1 or both classes of drugs.
With multiple trials demonstrating superior efficacy of covalent BTK inhibitors and venetoclax-based regimens compared to chemoimmunotherapy, the latter is no longer recommended as a first-line treatment. However, in specific situations, such as the need for rapid debulking, chemoimmunotherapy may still be considered.
For patients who respond well to covalent BTK inhibitors, treatment should ideally continue until disease progression or intolerance. When a venetoclax regimen is used as first-line therapy, it follows a fixed 1-year duration, after which time post-treatment observation is recommended until relapse necessitates second-line treatment. Continuous covalent BTK inhibitor therapy may be logistically simpler, as venetoclax regimens carry a risk of tumor lysis syndrome and often require more frequent monitoring and office visits during the first 2 months. However, venetoclax plus obinutuzumab avoids the potentially dose-limiting cardiotoxicities associated with covalent BTK inhibitors, such as atrial fibrillation, hypertension, and bleeding risk. Additionally, patient age can play a role in treatment selection, as younger patients may prefer fixed-duration therapy to maximize time off treatment in the years ahead.
Despite the treatment advancements, most patients will eventually experience disease progression. Once progression occurs, clinicians must carefully evaluate and select the most appropriate subsequent treatment option.
For patients with relapsed or refractory disease following treatment with a covalent BTK inhibitor, the choice of subsequent therapy should prioritize prior treatment history, duration of remission, and potential resistance mechanisms. Venetoclax is an effective option in this setting, achieving an overall response rate of 63% in patients previously treated with a BTK inhibitor. Combination therapy with venetoclax and an anti-CD20 monoclonal antibody is also a viable strategy, particularly for patients who experience disease relapse after a period of remission.
For an outline of treatment options and considerations for treatment selection in later lines of therapy, refer to ACCC’s Double Exposed CLL Treatment Guide.
When considering potential retreatment with covalent BTK inhibitors or BCL2 inhibitors, the clinician must consider the reasons for discontinuing the therapy initially. Patients who have developed resistance to covalent BTK inhibitors are unlikely to have successful retreatment with another BTK inhibitor in the same class. If the discontinuation was due to adverse effects, then the treating provider may consider retreatment with another covalent BTK inhibitor, but response needs to be monitored closely, as cross-resistance may limit the effectiveness of this approach.
Similar to retreatment with covalent BTK inhibitors, venetoclax retreatment could be considered for those who achieved a durable response initially but relapsed after a period with therapy. Again, close monitoring is essential because prior exposure may impact drug sensitivity and may be more suited for patients who do not have a high-risk mutation and who previously were only on venetoclax therapy for a limited time.
Noncovalent BTK inhibitors, such as pirtobrutinib, represent a novel approach to targeting BTK by employing an alternative binding mechanism that has demonstrated efficacy in patients whose disease is refractory to covalent BTK inhibitors. This therapeutic option is particularly valuable for individuals whose disease has progressed despite prior treatment with covalent BTK inhibitors. Clinical trials have shown pirtobrutinib to be both effective and potentially better tolerated for some patients, offering a promising alternative for those requiring continued BTK inhibitor therapy. Among double-exposed CLL patients, pirtobrutinib has achieved a progression-free survival of 16.8 months and an overall response rate of 73%, highlighting its potential to address this challenging clinical scenario.
Ongoing clinical trials are exploring the potential benefits of pirtobrutinib in combination therapy or as a single agent for both relapsed and previously untreated CLL. While these studies aim to determine its effectiveness and safety, it remains uncertain whether pirtobrutinib will be incorporated into earlier lines of therapy, pending the outcomes of the continuing trials.
With numerous ongoing clinical trials evaluating new therapies, it is essential for health care providers to stay updated on the latest research. Several agents and modalities, such as bispecific antibodies, CAR T-cell therapy, next-generation BTK inhibitors, and novel BCL2 inhibitors, are showing promise in clinical trials and may expand treatment options for this patient population.
Clinical trials offer potentially cutting-edge treatments that may not otherwise be available. The way providers discuss clinical trials with patients can significantly influence their likelihood of enrolling. Providers should address fears about receiving placebo treatments, uncertainty about adverse effects, and engage in clear yet compassionate conversations with their patients.
Discussing the possibility of clinical trial enrollment throughout a patient’s treatment journey, rather than only when other treatments fail, can help patients become more open to the idea. Numerous resources are available to support patients in understanding clinical trials, including the Leukemia & Lymphoma Society’s Clinical Trial Support Center. Additionally, oncology social workers and nurse navigators can provide valuable assistance to not only increase patient access to potentially life-changing treatments but also to ensure that patients receive the comprehensive support needed to make trial participation a viable option.
Just ASK!™, adapted from a course developed at Duke University, is an online training program jointly offered by the Association of Cancer Care Centers and the American Society of Clinical Oncology. It offers training on implicit bias in clinical trial enrollment. This training is valuable for any provider who refers or seeks to refer patients to clinical trials. For more information, visit the Just ASK™ Training Program.
At the 2026 ASCO Annual Meeting, the Louisiana Oncology Society received the ASCO Jeffrey C Ward Affiliate Advocacy Award for advancing critical advocacy priorities that have translated into meaningful legislative victories. The Iowa Oncology Society and Washington State Medical Oncology Society were also recognized for their advocacy efforts in 2025 at the meeting, receiving second place awards.
