Pirtobrutinib at the Crossroads: Shaping Its Future Role in Chronic Lymphocytic Leukemia ( CLL ) Care

ABSTRACT Covalent Bruton tyrosine kinase inhibitor (cBTKi)‐based regimens have redefined therapy for chronic lymphocytic leukemia (CLL). However, continuous treatment with BTKis can select for therapy resistance, typically associated with BTK C481 mutations and fosfolipasi C gamma 2 (PLCγ2) activation. In addition, continuous BTKi therapy poses challenges for treatment interruptions and dose modifications, with implications for clinical outcomes. Pirtobrutinib, a highly selective, reversible (noncovalent) BTKi, inhibits BTK independently of C481 and maintains sustained target engagement. In patients with cBTKi‐pretreated relapsed/refractory (R/R) CLL, the BRUIN‐CLL‐321 trial demonstrated improved progression‐free survival (PFS) and time to next treatment (TTNT) compared with idelalisib/rituximab or bendamustine/rituximab, accompanied by a favorable tolerability profile. Data from randomized phase III BRUIN‐CLL‐313 and BRUIN‐CLL‐314 trials demonstrate the superiority of pirtobrutinib over chemoimmunotherapy in untreated patients and non‐inferiority to ibrutinib in untreated patients or in patients with R/R disease who had no prior exposure to cBTKis. These data are not sufficient to justify a change in clinical practice; however, they lay the groundwork for a potential future repositioning of pirtobrutinib from the treatment of R/R CLL to earlier lines of therapy. In this review, we address a range of current and prospective aspects of pirtobrutinib‐based therapies: (1) the strengths and limitations of the trial datasets; (2) the biological rationale for frontline noncovalent BTK inhibition; (3) sequencing trade‐offs; and (4) prospective scenarios, including combination strategies and time‐limited regimens.