Breaking Down ASH 2025 Data on Frontline Pirtobrutinib in CLL

Bita Fakhri, MD, MPH Stanford Medicine | Mahesh Swaminathan, MB, MS MD Anderson Cancer Center

December 18, 2025

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Key Points

  • The BRUIN CLL-313 trial provided favorable response and safety data for frontline pirtobrutinib in patients with chronic lymphocytic leukemia (CLL).

  • Frontline time-limited pirtobrutinib, venetoclax, and obinutuzumab yielded high rates of undetectable minimal residual disease (MRD).

  • More data are needed on whether exposure to noncovalent Bruton’s tyrosine kinase (BTK) inhibitors hampers the efficacy of subsequent covalent BTK inhibitor therapy.

Pirtobrutinib Versus Ibrutinib and Pirtobrutinib Triplet in Frontline CLL

Mahesh Swaminathan, MB, MS, of MD Anderson Cancer Center, and Bita Fakhri, MD, MPH, of Stanford Medicine, discussed two presentations from the 2025 ASH Annual Meeting (ASH 2025) on frontline pirtobrutinib therapy in patients with CLL. 

The phase 3 BRUIN CLL-313 trial evaluated pirtobrutinib versus ibrutinib in first-line therapy for CLL. Pirtobrutinib had a noninferior overall response rate (ORR) compared with ibrutinib across subgroups. Between the pirtobrutinib and ibrutinib arms, the rates of atrial fibrillation or flutter were 2.4% versus 13.5% and the rates of hypertension were 10.6% versus 15.1%, respectively. 

Overall, 7.9% of pirtobrutinib patients versus 18.2% of ibrutinib patients required dose reductions due to adverse events (AEs), and 4.5% of the pirtobrutinib group compared with 10.9% of the ibrutinib group had treatment discontinuation due to disease progression.

While the frontline data are promising, it’s unclear if patients with CLL who progress on a noncovalent BTK inhibitor will still respond to covalent BTK inhibitors. Even without further efficacy data in sequence, frontline pirtobrutinib may already be a reasonable choice for older patients, given its favorable safety profile, said Dr. Fakhri.

The doctors also discussed the latest data update from MD Anderson Cancer Center’s trial evaluating time-limited pirtobrutinib, venetoclax, and obinutuzumab in frontline CLL. The study has reported “impressive” rates of durable undetectable MRD responses, said Dr. Fakhri. “This is a regimen I would consider for my high-risk patients, particularly TP53 aberrant disease patients.” 

While this trial also raises the question of sequencing covalent and noncovalent BTK inhibitors, the time-limited nature of the triplet regimen may help avoid resistance mutations and opens the possibility to rechallenge with pirtobrutinib, said Dr. Fakhri.