Fixed vs Continuous CLL Treatment: Clinical and Economic Perspectives

Seema A. Bhat, MD, a physician at The Ohio State University and a member of both the chronic lymphocytic leukemia (CLL) and hairy cell leukemia treatment groups, shared her expertise with First Report Managed Care on the evolving landscape of CLL therapy, particularly around the sequencing of treatments and the choice between fixed-duration and continuous regimens. She treats patients across the full spectrum of CLL, from those who are asymptomatic and do not yet need treatment to those who are relapsed, refractory, or experiencing complications such as Richter transformation or autoimmune issues.

Dr Bhat noted that CLL treatment options have significantly expanded in recent years. The emergence of venetoclax-based, fixed-duration regimens has enabled more personalized approaches to care. These include venetoclax combined with obinutuzumab in the frontline setting and with rituximab or obinutuzumab in the relapsed setting. Promising investigational combinations—such as venetoclax with Bruton's tyrosine kinase (BTK) inhibitors like acalabrutinib, with or without obinutuzumab—have shown favorable results in studies like AMPLIFY. While the combination of venetoclax and acalabrutinib is not yet approved by the US Food and Drug Administration (FDA), its inclusion in National Comprehensive Cancer Network (NCCN) guidelines signals increasing clinical interest.

Dr Bhat emphasized the clinical appeal of fixed-duration regimens, particularly their ability to offer patients a defined period of treatment followed by time off therapy.

“This type of regimen is very well-suited for young, fit, and motivated patients who prioritize time off treatment and who do not mind coming in for that intense ramp-up and monitoring for tumor lysis syndrome,” she stated.

While this initial phase requires significant resources and coordination, the benefit is a durable remission and often achieving undetectable minimal residual disease (MRD).

Treatment decisions in CLL, according to Dr Bhat, are highly individualized and depend on multiple factors, including disease risk characteristics, patient comorbidities, preferences, and logistical issues.

“For example, if a patient has underlying renal disease, they may not be best for venetoclax ramp-up due to the risk of tumor lysis which can affect the kidneys,” she explained. “Or, if the patient preference is not to come in for regular monitoring—distance is an issue, travel is an issue, weather is an issue—they don't want to come for venetoclax or they don't want to come for the 6 months of obinutuzumab, then we can lean toward BTK inhibitors.”

In real-world settings, where patients often present with comorbidities, limited mobility, or restricted access to care, fixed-duration therapies may not be practical due to their intensive monitoring requirements.

“We are in a very good place in that we have all these different choices,” said Dr Bhat. “Having these different choices does increase the discussions that we have in our clinic, but this is a good problem to have.”

From an economic perspective, Dr Bhat observed that although fixed-duration therapy involves higher initial costs, it may be more cost-effective long term. BTK inhibitors require indefinite administration, contributing to higher cumulative costs and prolonged financial burden for patients due to ongoing copayments and medication adherence. In contrast, venetoclax-based therapies are typically limited to 1 to 2 years.

“Even though up-front treatment is more, overall it's limited to 1 or 2 years; it's still less costly compared to ongoing, continuous treatment with BTK inhibitors,” she noted.

Barriers to broader adoption of fixed-duration regimens remain. Chief among these are logistical challenges of monitoring during venetoclax ramp-up, particularly in community settings that may lack adequate infrastructure. Additionally, provider unfamiliarity with venetoclax protocols contributes to hesitancy. Dr Bhat’s team often collaborates with community oncologists to manage the ramp-up at specialized centers, then transitions patients back to their local providers.

Patients and clinicians may also struggle with the decision to discontinue therapy, especially if MRD negativity or complete response has not been achieved. This uncertainty around stopping treatment remains a concern.

While Dr Bhat has not personally encountered insurance denials for FDA-approved fixed-duration therapies listed in the NCCN guidelines, she acknowledged that payer influence sometimes affects the choice of BTK inhibitor. Nonetheless, she asserted that clinical judgment should guide therapy selection.

“We have to stand up and say, ‘No this is the right way to do it.’ The payers don't get to decide,” she said. “There's a reason why I choose a particular treatment for a particular patient and, being an expert, we know what we are doing.”

Dr Bhat concluded by stating that time-limited therapy offers broad benefits: fewer long-term adverse effects and improved quality of life for patients, decreased burden of chronic toxicity for clinicians, and reduced long-term costs for the health care system.

"Overall, time-limited therapy aligns with the goals of value-based care,” she said. “It delivers effective outcomes with lower long-term cost and treatment burden.”