Authored by Ann Liu, PhD
Medically Reviewed by Ed Ratner, MD
The Bottom Line:
In an early analysis, fixed-duration pirtobrutinib plus obinutuzumab shows promise for treating previously untreated CLL.
Who Performed the Research and Where Was it Presented:
Dr. Inhye Ahn from Dana-Farber Cancer Institute and colleagues presented the results at the European Hematology Association (EHA) Annual Meeting in 2026.
Background:
Bruton tyrosine kinase inhibitors (BTKi) are a highly effective treatment for chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) that inhibit BTK, a protein that is critical for CLL cell survival. Covalent BTKi (ibrutinib, acalabrutinib, zanubrutinib) bind to BTKi irreversibly, while noncovalent BTKi (pirtobrutinib) bind reversibly. This study is associated with effectiveness even if resistance to a covalent BTKi develops. Pirtobrutinib is currently approved for patients with relapsed / refractory CLL who have previously been treated with covalent BTKi. However, researchers are interested in understanding how well pirtobrutinib works in earlier lines of therapy and in fixed-duration combinations. This study looked at the efficacy of the combination of pirtobrutinib and obinutuzumab (an anti-CD20 monoclonal antibody) as a fixed-duration therapy for patients with previously untreated CLL.
Methods and Participants:
This interim analysis of a phase 2 clinical trial testing the combination pirtobrutinib plus obinutuzumab in patients with previously untreated CLL. The fixed-duration treatment was given for approximately one year (12 cycles of pirtobrutinib with obinutuzumab added for cycles 6-12). Patient response was assessed three months after the end of therapy.
Results:
- A total of 60 patients enrolled in the initial study cohort, and the median duration in the study at the time of data cutoff was 11 months.
- Median age was about 65 years, and over half had unmutated IGHV and/or another adverse genetic marker
- 20% of patients had completed their end-of-treatment response assessment, 52% had completed therapy but had not yet completed their response assessment, and 22% were still on active therapy.
- At cycle 6, the overall response rate was 75%.
- Three months after the end of treatment, the overall response rate was 100%, and the complete response rate was 25%. However, these are based on small numbers since only 12 patients have reached this time point so far.
- The rates of undetectable measurable residual disease (uMRD) in the blood were 3% at cycle 6 and 52% at the end of treatment.
- No patients have had their disease progress or died thus far.
- Two patients developed Richter transformation during the study.
- Common side effects included bruising (30%), headache (22%), low neutrophils (20%), and low platelets (13%).
- Rates of serious infections were low (5%).
- One patient developed an abnormal heart rhythm (atrial fibrillation).
- Rates of hypertension were low (7%).
Conclusions:
While it is still very early, fixed-duration pirtobrutinib plus obinutuzumab shows similar effectiveness in clearing CLL from the blood (uMRD) compared those in the CLL17 trial receiving ibrutinib and venetoclax, but not as high as the combination of obinutuzumab and venetoclax. No significant safety issues of concern have been identified thus far. As of Sept. 2026, this study (in New England) appears open to additional enrollees with information at Fixed Duration Pirtobrutinib and Obinutuzumab in Chronic Lymphocytic Leukemia. Further study of fixed duration combination therapy with pirtobrutinib in treatment naïve patients with CLL seems warranted. How frontline use of pirtobrutinib will affect the development of mutations that may make future BTKi therapy ineffective is a concern when considering sequencing.
Links and Resources:
You can read the actual EHA abstract here: A Phase 2 Study Of Fixed-Duration Pirtobrutinib And Obinutuzumab In Previously Untreated CLL
Take care of yourself first.
Ann Liu, PhD
