Have Fixed-Duration (FD) Regimens Delivered on Their Promise in Chronic Lymphocytic Leukemia and What Is the Future...

Treatment for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has shifted from chemoimmunotherapy (CIT) to targeted therapies, administered as continuous treatment until progression or in fixed-duration regimens. Fixed-duration regimens with targeted therapies (usually in combination regimens with venetoclax and a Bruton tyrosine kinase inhibitor [BTKi] and/or an anti-CD20 monoclonal antibody) are of increasing interest, and recent phase 3 trial results support this approach. Fixed-duration treatment offers a pre-defined treatment stopping point and may provide patients with a treatment-free interval, potentially reducing the burden of long-term therapy while minimizing cumulative toxicity and costs.

Here, we review the currently approved fixed-duration regimens and some investigational combinations in ongoing registrational clinical trials.

The registrational fixed-duration studies CLL14 (venetoclax plus obinutuzumab), GLOW (ibrutinib plus venetoclax), CAPTIVATE (ibrutinib plus venetoclax), AMPLIFY (acalabrutinib plus venetoclax with or without obinutuzumab), and MURANO (venetoclax plus rituximab) along with the investigator-initiated CLL17 study, which may impact treatment guidelines, demonstrated extended treatment-free intervals. Generally, targeted fixed-duration regimens in patients with unmutated immunoglobulin heavy chain variable region or TP53 and/or del(17p) demonstrated greater efficacy than CIT, but outcomes were typically poorer than in patients without these high-risk features. Cardiovascular toxicity and death remain a significant concern with ibrutinib plus venetoclax, which was also associated with high rates of diarrhea and atrial fibrillation.

Successful fixed-duration regimens in CLL should achieve deep remission (i.e., undetectable minimal residual disease), sustain long-term progression-free survival, decrease the burden of treatment-related adverse events, and allow for re-treatment with minimal risk of drug resistance. Although fixed-duration treatment represents a positive step forward for most patients with CLL/SLL, the currently approved regimens often fall short in patients at high risk of progression. Continued research and development of next-generation drugs is essential to enhance efficacy and safety, ultimately improving outcomes in all patients with CLL/SLL.