Two Onc Docs, hosted by Samantha A. Armstrong, MD, and Karine Tawagi, MD, is a podcast dedicated to providing current and future oncologists and hematologists with the knowledge they need to ace their boards and deliver quality patient care. Dr Armstrong is a hematologist/oncologist and assistant professor of clinical medicine at Indiana University Health in Indianapolis. Dr Tawagi is a hematologist/oncologist and assistant professor of clinical medicine at the University of Illinois in Chicago.

In this episode, OncLive On Air® partnered with Two Onc Docs to highlight chronic lymphocytic leukemia (CLL) updates from the 2025 ASH Annual Meeting. Drs Armstrong and Tawagi noted that CLL is typically diagnosed in asymptomatic, elderly individuals presenting with lymphocytosis. A definitive diagnosis is established by confirming the clonality of circulating B lymphocytes via immunoglobulin light chain restriction on flow cytometry, they explained. Treatment initiation is reserved for active disease, which is indicated by B symptoms, progressive cytopenias, threatened organ function, or bulky disease such as splenomegaly, they said.

They continued by reporting several prognostic features that denote poor outcomes. Current standard frontline regimens use covalent BTK inhibitors or time-limited targeted regimens that include venetoclax (Venclexta), often combined with an anti-CD20 monoclonal antibody, according to the experts. They added that TKI-based therapy is preferred for patients with high-risk features.

The phase 3 BRUIN CLL-313 trial (NCT05023980) investigated pirtobrutinib (Jaypirca), a highly selective noncovalent BTK inhibitor, compared with bendamustine and rituximab (BR) in patients with treatment-naive CLL. The trial showed a significant improvement in progression-free survival with pirtobrutinib vs BR. Pirtobrutinib was also associated with a favorable safety profile, with modest rates of class-associated toxicities, including all-grade bleeding, arthralgia, and atrial fibrillation.

Although pirtobrutinib showed superior efficacy in BRUIN CLL-313, the clinical interpretation of these data is complicated because BR is an outdated control arm compared with contemporary frontline standards, Armstrong and Tawagi emphasized. Furthermore, the requirement for indefinite therapy with BTK inhibitors is a sequencing challenge, particularly as pirtobrutinib is currently approved in the post-covalent BTK inhibitor setting, they continued. However, its favorable toxicity profile suggests potential utility in elderly patients with pre-existing cardiovascular comorbidities, they noted. Future studies are focused on comparing pirtobrutinib vs time-limited venetoclax and evaluating various triplet regimens, they concluded.