Sequencing BTKi Therapies in Patients With CLL

Claudia Villa Celi, MD Cleveland Clinic Florida | Daniel Ermann, MD University of Utah Health

December 18, 2025

Copy Link Share
Key Points

  • Covalent Bruton’s tyrosine kinase inhibitors (BTKi) are the mainstay treatments in chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

  • The BRUIN CLL-313 trial found that the noncovalent BTKi, pirtobrutinib, was noninferior to ibrutinib for response rate across subpopulations.

  • If pirtobrutinib is approved for earlier lines of therapy, the optimal sequencing of covalent and noncovalent inhibitor therapies will need to be evaluated.

BRUIN CLL-313 Data at ASH 2025

Claudia Villa Celi, MD, of Cleveland Clinic Florida, spoke with Daniel Ermann, MD, of University of Utah Health, at the 2025 ASH Annual Meeting (ASH 2025). The doctors discussed treatment sequencing for patients with CLL in light of data from the BRUIN CLL-313 trial showing that pirtobrutinib was noninferior to ibrutinib for overall response rate (ORR) in the first-line setting. 

The BRUIN CLL-313 ASH 2025 presentation reported primary ORR findings and not-yet mature survival outcomes. The study enrolled 662 patients with treatment-naïve (n = 225) or covalent BTKi-naïve relapsed or refractory (n = 437) CLL or SLL. In the overall population, pirtobrutinib had an ORR of 87.0% (95% CI, 82.9-90.4) versus ibrutinib at 78.6% (95% CI, 73.7-82.9), for an ORR ratio of 1.11 (95% CI, 1.03-1.19; 2-sided P < .0001). Likewise, patients in the relapsed or refractory population had an ORR of 84.0% (95% CI, 78.5-88.6) with pirtobrutinib versus 74.8% (95% CI, 68.5-80.4) with ibrutinib for an ORR ratio of 1.12 (95% CI, 1.02-1.24; 2-sided P < .0001).

Progression-free survival outcomes favored pirtobrutinib for the overall (hazard ratio [HR], 0.57; 95% CI, 0.39-0.83), relapsed or refractory (HR, 0.73; 95% CI, 0.47-1.13), and treatment-naïve  (HR, 0.24; 95% CI, 0.10-0.59) populations. Overall survival was comparable between the two arms (HR, 0.961; 95% CI, 0.55-1.69).

Based on the study, the FDA may approve pirtobrutinib for earlier lines of therapy, said Dr. Ermann, though that raises the question of skipping covalent BTKi therapy. “By moving [pirtobrutinib] earlier, you may omit an entire line of therapy, which I’m not sure if that’s the right move at this point.” In his practice. Dr. Ermann still sequences a covalent BTKi like zanubrutinib or acalabrutinib first and reserves pirtobrutinib for the relapsed or refractory setting.