Updated Results of the Phase 1b BRUIN Study of Fixed-Duration Pirtobrutinib Combined with Venetoclax ± Rituximab in Relapsed/Refractory CLL

The multicenter phase 1/2 BRUIN study (NCT03740529) is evaluating the safety and efficacy of the highly selective non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi) pirtobrutinib (fixed duration) combined with venetoclax ± rituximab in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). Results of the phase 1b portion of the BRUIN were presented at the 2023 American Society of Hematology annual meeting and summarized here

The BRUIN study enrolled patients with R/R CLL, who had not received prior venetoclax; prior covalent BTKi therapy was allowed. Eligible patients were enrolled into sequential cohorts, first in the pirtobrutinib + venetoclax (PV) cohort and then the PV + rituximab (PVR) cohort. The primary end point was safety; key secondary end points included overall response rate (ORR), progression-free survival (PFS), and minimal residual disease (MRD). Undetectable MRD (uMRD) was defined as <1 CLL cell/10,000 nucleated cells (<1x10-4) in peripheral blood (PB). Date of data cut-off was May 5, 2023.

A total of 25 patients were enrolled (PV, n=15; PVR, n=10). In the PV cohort, median age was 66 years, median number of prior lines of therapy was 1; the majority had received prior chemotherapy (53%), CD20 monoclonal antibody (73%), and cBTKi (73%), and had IGHV unmutated CLL (73%). In the PVR cohort, median age was 69 years, median number of prior lines of therapy was 2; the majority had received prior chemotherapy (60%), CD20 monoclonal antibody (70%), and cBTKi (60%), and had IGHV unmutated CLL (89%)

The PV cohort achieved an ORR of 93.3%, including 7 complete responses (CR); ORR was 100% in the PVR cohort, including 3 CRs. The median time to best response was 2.4 months in all patients and the median time on treatment was 23 months. At median duration of follow-up of 22.1 months, 18-month PFS was 92.9% for PV and 80.0% for PVR cohort. At cycle 13, the overall uMRD rate was 70.8%, 87.5% of patients achieved uMRD at some point during the trial. Median time to first uMRD was 4.3 months for PV and 3.7 months for PVR.

The most common any grade treatment-emergent adverse events (TEAE) in both cohorts included neutropenia, nausea, fatigue, and diarrhea. In both cohorts, the most common grade ≥3 TEAE were neutropenia/neutrophil count decreased (PV=46.7%; PVR=60.0%). Grade ≥3 clinical tumor lysis syndrome (TLS) was reported in 2 patients during venetoclax dose escalation in the PV cohort. Dose reductions due to treatment-related AE were reported in 3 patients (PV=1; PVR=2).

These results of the phase 1/2 BRUIN study indicate that fixed-duration pirtobrutinib combined with venetoclax ± rituximab was well tolerated and showed promising efficacy in patients with R/R CLL.


Roeker L, Woyach J, Cheah C, et al. Fixed-duration pirtobrutinib combined with venetoclax ± rituximab in relapsed/refractory chronic lymphocytic leukemia: updated results, including MRD data, from the BRUIN phase 1b study. Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Poster 3269.

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