Fixed-Duration Therapy Gains Ground in Chronic Lymphocytic Leukemia (CLL) Treatment
For decades, the standard of care for Chronic Lymphocytic Leukemia (CLL), a slow-progressing blood cancer, has largely involved continuous treatment with targeted therapies like Bruton’s tyrosine kinase (BTK) inhibitors. However, emerging data is challenging this paradigm, suggesting that fixed-duration treatment regimens may offer comparable efficacy with significant benefits for patients and healthcare systems alike. Recent findings presented at the 67th American Society of Hematology (ASH) Annual Meeting & Exposition in December 2025 are fueling this shift, prompting clinicians to re-evaluate treatment strategies.
The Burden of Continuous Therapy: Toxicity, Cost, and Adherence
While continuous BTK inhibitor therapy has demonstrably improved outcomes for many CLL patients, it’s not without its drawbacks. A key concern is the potential for long-term toxicities. As Dr. Ira Zackon of Ontada highlighted in a separate ASH presentation, real-world data reveals higher discontinuation rates for covalent BTK inhibitors compared to those observed in clinical trials. These discontinuations are “largely driven by toxicities,” and are further influenced by patient comorbidities, specific genetic abnormalities within the leukemia cells (cytogenic abnormalities), and overall health status (performance status).
This prolonged exposure to medication also raises financial concerns. The indefinite nature of continuous therapy is a significant cost driver for payers in the US and a strain on healthcare systems globally.Cost-effectiveness studies are increasingly evaluating fixed-duration regimens as viable alternatives. A recent Canadian study (published November 7, 2025 in PharmacoEconomics - Open) found that the combination of venetoclax and obinutuzumab offered a cost-effective treatment option compared to both first- and second-generation BTK inhibitors from the perspective of Canada’s public healthcare system.
Beyond cost, adherence to continuous regimens is a persistent challenge. Patients understandably prefer the idea of a defined treatment period. “When you discuss the options with patients, most will prefer a fixed duration,” explains Dr. Omar Al-Sawaf,a leading researcher in the field.
The Rise of Fixed-Duration Regimens: A New Approach
The CLL17 trial, presented at ASH 2025, provides compelling evidence supporting the efficacy of fixed-duration therapy.This randomized trial compared continuous BTK inhibitor therapy (ibrutinib) with a fixed-duration regimen of venetoclax combined with obinutuzumab. The results demonstrate that the fixed-duration approach achieves comparable progression-free survival, offering a possibly more manageable treatment experience.
Though, fixed-duration regimens aren’t without their complexities. The ramp-up phase of venetoclax requires careful monitoring for tumor lysis syndrome (TLS), a potentially serious complication. Dr. Al-Sawaf acknowledges that this intensive monitoring can be challenging for frail patients,who may prefer the simplicity of continuous dosing.
Despite this caveat, the long-term benefits of a finite treatment course are substantial. ”In the long run, I think for most patients, it makes much more sense to say that after a year, I do not need to come to clinic anymore,” Dr. al-Sawaf states. He notes significantly poorer adherence rates with continuous ibrutinib, notably among elderly or less fit patients.
Tailoring Treatment: The role of TP53 Mutation Status
While fixed-duration therapy appears promising for many, certain patient populations may still benefit from continuous treatment. Patients with a TP53 mutation, a genetic alteration associated with a higher risk of disease progression, are generally advised to continue BTK inhibitor therapy indefinitely, aligning with current clinical guidelines.
However, Dr. Al-Sawaf emphasizes that TP53 mutations were present in only a small percentage (8%) of patients in the CLL17 study, limiting the strength of conclusions regarding this specific subgroup. He notes that updated guidelines in German-speaking parts of Europe now recommend considering fixed-duration treatment for all patients except those with TP53 alterations, even those with unmutated IGHV status (another prognostic marker).
Looking Ahead: Personalized Treatment Strategies
The evolving landscape of CLL treatment is moving towards a more personalized approach.The CLL17 trial and supporting data underscore the importance of carefully considering individual patient characteristics, including genetic risk factors, overall health, and treatment preferences.
While continuous BTK inhibitor therapy remains a valuable option, particularly for high-risk patients, fixed-duration regimens are emerging as a compelling
