Dr Anderson on How to Approach Continuous vs Fixed-Duration Frontline Therapy in CLL

“Just because [a treatment] looks effective doesn’t mean that, when looking at a sequencing horizon, it’s necessarily the best choice.… Some of the old paradigms [for measuring efficacy with CLL regimens] are starting to fall by the wayside.”

Mary Ann Anderson, MBBS, FRACP, FRCPA, PhD, an associate professor at Royal Melbourne Hospital and Peter MacCallum Cancer Centre and a clinician scientist at the Walter and Eliza Hall Institute, discussed individualizing frontline therapy in patients with chronic lymphocytic leukemia (CLL), weighing continuous vs time-limited approaches.

In frontline CLL, the key first decision is whether to pursue a continuous or time-limited approach, each with pros and cons, Anderson explained.A continuous BTK inhibitor–based approach is easy to start, Anderson noted, whereas a time-limited approach requires a BCL-2 inhibitor and carries a risk of tumor lysis syndrome, necessitating slow ramp-ups and close blood test monitoring that make it more demanding.

BTK inhibitors are associated with hypertension, atrial fibrillation, and bleeding risk, which may make them less attractive for patients who are receiving blood thinners or those with cardiovascular comorbidities, according to Anderson. BCL-2 inhibitors must be partnered with other agents, bringing a risk of viral infections with monoclonal antibodies or the same adverse effects when paired with a BTK inhibitor, she added.

Progression on indefinite BTK inhibitor therapy is often associated with on-target resistance mutations, Anderson said. Data suggest that pirtobrutinib (Jaypirca) is effective in frontline CLL and can rescue from progression on covalent BTK inhibitors, such as acalabrutinib (Calquence) and zanubrutinib (Brukinsa), but no data show that pirtobrutinib progression can be rescued with those agents, she noted.

With time-limited therapy, patients who relapse do so off treatment and are less likely to harbor on-target mutations, and emerging data suggest that they can be salvaged with BCL-2 or BTK inhibitor retreatment, Anderson said. Therefore, comparing progression-free survival (PFS) on a continuous BTK inhibitor with PFS on a BCL-2 inhibitor is not a fair comparison, she explained; a better measure may be total PFS from a line of therapy, such as PFS with a first-line venetoclax (Venclexta)–based regimen combined with time to second progression with a second-line therapy.

Anderson concluded by describing the choice between a continuous BTK inhibitor and a BCL-2 inhibitor–based approach as a key, complex medical decision.