Dr Ahn: Exploring Treatment-Free Remissions With Pirtobrutinib in CLL

Although Bruton tyrosine kinase (BTK) inhibitors have transformed the treatment of chronic lymphocytic leukemia (CLL), most patients remain on therapy indefinitely, creating challenges related to long-term toxicity, adherence, and cost. As interest grows in time-limited treatment strategies, investigators are exploring whether fixed-duration regimens can provide durable disease control while allowing patients meaningful time off therapy.

At the 2026 European Hematology Association (EHA) Congress, early results from a phase 2 study suggested that a fixed-duration regimen of pirtobrutinib (Jaypirca) and obinutuzumab (Gazyva) may offer a feasible path toward treatment-free remission in previously untreated CLL while maintaining a favorable cardiac safety profile.¹

In an on-site interview with Targeted Oncology at the Congress, Inhye Ahn, MD, associate director of the CLL Center at Dana-Farber Cancer Institute, discussed the rationale for the study, early efficacy and safety data, and the potential implications of a time-limited pirtobrutinib-based strategy for newly diagnosed patients with CLL.

Targeted Oncology: What was the rationale for the study?

Inhye Ahn, MD: We asked 2 key questions in this abstract. The first was to see if we can induce a response and long duration of treatment-free interval by combining BTK inhibitor and CD20 monoclonal antibodies for a fixed duration. There have been studies like this before, but all in the context of continuous BTK inhibitors, so we wanted to look at the fixed-duration approach. The second question... was the cardiac safety of pirtobrutinib, a noncovalent BTK inhibitor, in depth by using sensitive tests prospectively.

What were the key design features of the trial?

This is an all-comer frontline CLL trial that used a regimen of pirtobrutinib monotherapy for the first 6 cycles followed by a combination of pirtobrutinib and obinutuzumab for the next 6 cycles, a total of 12 cycles, and everyone stopped after completing cycle 12, no matter what their clinical responses or minimal residual disease status were at the end of. The target population was previously untreated patients [with CLL].

Can you describe the efficacy and safety data that were presented at EHA?

We [had] 2 key findings regarding efficacy. The overall response rate at the end of therapy was over 79%. The efficacy data are still preliminary and early and continue to mature... In terms of the safety data, we saw that low-grade infection was the most common [adverse event]. Fortunately, the [rate of] grade 3 infections was low, found in 5% only. In terms of the cardiac safety, which was one of the key secondary end points, we found very little changes in the blood pressure, only 1 case of atrial fibrillation in a patient who had prior atrial fibrillation, and no structural or functional change to the heart, which is based on the cardiac MRI and echocardiogram.

How feasible was this regimen in this setting, particularly given the infusion requirements of obinutuzumab during the first cycle?

The study [regimen] was very well tolerated, partially because there were 6 months of pirtobrutinib lead-in before obinutuzumab was added at cycle 7, and that dramatically decreased the risk of infusion-related reactions. That occurred in only 1 patient as a grade 2 event. So overall, very well tolerated, and over 88% of the patients completed the planned 12 cycles at the time of the cutoff.

Does this regimen avoid the inpatient or intensive tumor lysis syndrome (TLS) infrastructure that centers associate with venetoclax initiation?

Yes, the regimen was developed as an outpatient regimen with no mandatory admissions associated with the study therapy. TLS was not observed; although we monitored [for] it during the seventh cycle during the initiation of obinutuzumab, we did not see any laboratory or function changes related to TLS.

What are the next steps for the study and key areas for future investigation?

This is still an investigational regimen that is not approved by the FDA, nor in the national guidelines. I envision that the most exciting part of the data on this study would be the treatment-free interval when patients finish their 12 cycles of therapy. The study actually has built-in retreatment criteria for patients who develop symptomatic CLL progression. They can receive pirtobrutinib monotherapy at the time of relapse during the treatment-free period, and how long that treatment-free period would be is a big question that we're trying to ask. So, if there is a durable treatment-free remission, I think this could give hope for the patients to get time-limited BTK inhibitor-based therapy.

[The study is designed] an all-comer study, so we included patients without and with high-risk disease…[and] we did not distinguish patients by either disease characteristics or other risk characteristics. We hope to identify patients who will benefit most from the study regimen in the future.

REFERENCE

1. Ahn IE, Tyekucheva S, Lipsky A, et al. A phase 2 study of fixed-duration pirtobrutinib and obinutuzumab in previously untreated CLL. Presented at the 2026 European Hematology Association Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S148.