MRD-Guided Therapy Reshapes CLL Treatment, Despite Hurdles

Targeted therapy has been the standard of care for chronic lymphocytic leukemia (CLL) for years, and the field continues to evolve as clinicians refine how and for how long these therapies are used. According to Madhav R. Seshadri, MD, an assistant professor in the malignant hematology group at UCSF Health, the most significant recent advances haven’t been new drug classes so much as smarter ways of combining and sequencing existing therapies. Seshadri also serves on the National Comprehensive Cancer Network guidelines panel for CLL.

Bruton tyrosine kinase (BTK) inhibitors, beginning with ibrutinib, and BCL2 inhibitors such as venetoclax have anchored CLL treatment for years. What has changed more recently, Seshadri explained, is the shift toward fixed-duration courses and measurable residual disease (MRD)-guided therapy, rather than indefinite drug administration. Instead of keeping patients on a BTK inhibitor indefinitely, clinicians are increasingly combining it with venetoclax for a finite course, either for a predefined period or guided by serial MRD testing; that shift matters to patients directly.

“That can help patients to get time off therapy, which is something that everyone values, as well as doing it in a more kind of rational way with MRD guidance rather than just picking 12 months or 14 months as an arbitrary time point,” Seshadri said.

Still, MRD-guided approaches come with logistical hurdles. Trials evaluating this strategy, such as SEQUOIA Arm D (NCT03336333), have required multiple bone marrow biopsies, an invasive step many patients are reluctant to undergo. Sending MRD assays like clonoSEQ also is not standard outside academic centers. Despite those barriers, Seshadri said newer fixed-duration regimens, including acalabrutinib plus venetoclax, are being adopted broadly.

On sequencing, Seshadri pointed to pirtoburtinib, a noncovalent BTK inhibitor increasingly studied earlier in CLL treatment rather than reserved for patients refractory to BTK inhibitors. That earlier use has raised concerns that it could select for BTK inhibitor–resistant clones, complicating later use of a covalent BTK inhibitor. Seshadri said those concerns are legitimate, but long-term follow-up data are not yet available, which is why covalent BTK inhibitors are still typically used first. Regarding venetoclax-based vs BTK inhibitor–based sequencing, he noted there isn’t strong evidence favoring either. Increasingly, the 2 are being combined into fixed-duration regimens.