Managing Toxicity, Sequencing for Long-Term BTKIs: Kerry Rogers, MD

When initiating a covalent Bruton tyrosine kinase (BTK) inhibitor for chronic lymphocytic leukemia (CLL), clinicians must prepare patients for years of therapy.

In an interview with The American Journal of Managed Care^®, Kerry Rogers, MD, hematologist, associate professor, and CLL specialist at The James/The Ohio State University Comprehensive Cancer Center, emphasized that the median progression-free survival (PFS) with ibrutinib in the frontline setting is 8.9 years, and newer agents may go even longer before a median is reached.

“I always counsel people on it being a long-term strategy,” she said. “They have to be mentally prepared to take the drug for many years. I usually say at least 5.”

Rogers identified 2 primary risks of continuous BTK inhibitor therapy. First is the eventual development of resistance, at which point the entire BTK inhibitor class may no longer be effective. Second is the accumulation of cardiovascular toxicity over time. Hypertension and atrial fibrillation are among the adverse effects whose incidence increases the longer a patient remains on therapy.

Bleeding risk also persists and does not diminish if a patient requires surgery or concurrent anticoagulation. Some adverse events, including loose stools, joint pain, and headaches associated with acalabrutinib, tend to improve with continued use, but Rogers said she is clear with patients that cardiac-related risks do not follow the same trajectory.

Once CLL becomes resistant to a covalent BTK inhibitor, the sequencing question becomes urgent and largely unresolved. Venetoclax as continuous monotherapy after BTK inhibitor failure yields a median PFS of roughly 2 years, but Rogers noted there are no prospective data to support the widely used venetoclax-plus-obinutuzumab combination in that setting.

Emerging questions include whether fixed-duration venetoclax-based regimens are viable post-BTK failure and whether noncovalent BTK inhibitors like pirtobrutinib can be combined with venetoclax in this context. Early data suggest pirtobrutinib-venetoclax combinations are feasible, and Rogers noted that investigator-initiated phase 2 trials are beginning to generate answers. However, she stressed that prospective evidence in this sequencing setting remains a critical unmet need that patients frequently raise in the clinic.