The standard approach to treating chronic lymphocytic leukemia (CLL) with Bruton tyrosine kinase (BTK) inhibitors is being re-evaluated as new data emerges. Traditionally, these inhibitors were administered continuously due to concerns about disease flare upon treatment cessation. However, recent studies suggest that treatment breaks may not always compromise outcomes, especially when BTK inhibitors are combined with other targeted agents.
Challenging the Continuous BTK Inhibition Paradigm
Post hoc analyses and retrospective studies have questioned the necessity of uninterrupted BTK inhibitor therapy. For instance, a phase 2 study analysis involving 84 CLL patients treated with ibrutinib (Imbruvica) found no significant differences in progression-free survival (PFS) or overall survival (OS) among subgroups with varying dose intensities or interruption durations. Similarly, a Mayo Clinic retrospective analysis of 209 CLL patients showed no OS differences between those with and without ibrutinib interruptions.
Long-term data from prospective trials like ECOG-E1912 (NCT02048813) and Alliance A041202 (NCT01886872) have also reported durable disease control after stopping BTK inhibitors for reasons other than disease progression. In ECOG-E1912, 101 patients who stopped ibrutinib had a median of 25 months from treatment cessation to disease progression or death. The A041202 study showed a median time from ibrutinib cessation to disease progression of 24 months among 75 patients.
The Rise of Time-Limited Targeted Therapy
Combining a BTK inhibitor with a B-cell lymphoma 2 (BCL-2) inhibitor has shown potential in achieving high rates of undetectable minimal residual disease (uMRD) and durable, treatment-free remission. A University of Texas MD Anderson Cancer Center phase 2 study (NCT02756897) of ibrutinib plus venetoclax (Venclexta) reported a 5-year PFS rate of 90% in treatment-naive CLL patients with high-risk markers or older age. Triplet regimens involving a BTK inhibitor, a BCL2 inhibitor, and an anti-CD20 monoclonal antibody (mAb) are also proving highly effective.
The ongoing CLL17 study (NCT04608318) is comparing fixed-duration regimens (ibrutinib + venetoclax; venetoclax plus obinutuzumab [Gazyva]) against continuous ibrutinib treatment, offering insights into the comparative efficacy and safety of time-limited versus continuous approaches in treatment-naive CLL.
Exploring BCL2 Inhibitor-Free Regimens
Researchers are actively investigating BCL2 inhibitor–free, fixed-duration regimens in CLL. Studies have shown that adding a CD20 mAb to a BTK inhibitor improves uMRD rates (e.g., 38% with ibrutinib plus obinutuzumab) and complete response (CR) rates (e.g., 13% with acalabrutinib plus obinutuzumab). Ongoing trials are testing time-limited BTK inhibitor plus mAb regimens, including acalabrutinib + obinutuzumab (NCT04505254 and NCT04722172), ibrutinib + obinutuzumab (NCT04908228), and pirtobrutinib plus obinutuzumab (NCT06333262). Intermittent BTK inhibitor dosing without mAb is also being explored in the IbruOnOff study (NCT04771507).
Strategic Decision-Making in BTK Inhibitor Cessation
Deciding when to stop BTK inhibitor therapy involves considering host-, disease-, and treatment-related factors. Remission durability after stopping BTK inhibitors likely depends on disease genetic markers (e.g., TP53 aberration, IGHV mutation, BTK mutations), prior treatment status, and response depth at treatment cessation. Patient preference, BTK inhibitor tolerance, treatment adherence, and cost are also crucial. Further research is needed to understand the long-term impact of BTK inhibitor cessation on disease biology and to define monitoring and subsequent treatments after time-limited BTK inhibitor therapy.
