Background

Prior studies showed treatment with combined covalent BTK-inhibitor (cBTKi) with venetoclax +/- obinutuzumab achieved high rates of undetectable MRD (U-MRD) remission in patients with CLL. We report the results of time-limited, combined non-covalent BTKi, pirtobrutinib, with venetoclax and obinutuzumab in untreated CLL (NCT05536349).

Methods

Patients with previously untreated CLL were enrolled. Patients initiated pirtobrutinib 200 mg daily (through C13) and Obinutuzumab (standard 6 cycles) on C1D1. Venetoclax daily was started on C2D1 and continued through C13 on 28 day cycles. Imaging and bone marrow MRD assessments (on peripheral blood and marrow) were performed at the end of C7 and C13. Patients with persistent MRD (≥10-5) at the end of C13 could continue therapy with pirtobrutnib and venetoclax for 12 additional cycles. At treatment completion, peripheral blood MRD is monitored every 3 months for the first year and every 6 months thereafter. The primary endpoint is bone marrow U-MRD at the end of C7.

Results

40 patients have been enrolled between February and September 2023 with a median age of 64 (range: 38-76). 75% with IGHV-unmutated CLL and 10% with del(17p)/TP53. 39 evaluable patients were included with median follow up of 11.7 months. At the end of C7, 90% (35/39) patients achieved U-MRD (10-4) in bone marrow and 64% achieving U-MRD of 10-6. At end of C13 (n=20), U-MRD rates improved to 95% and 85% respectively (Figure 1). Grade 3-4 neutropenia and thrombocytopenia occurred in 60% and 18%, respectively. 55% required G-CSF. Dose reductions in pirtobrutinib and venetoclax occurred in 30% of patients. 3 patients developed neutropenic fever and 1 patient developed atrial fibrillation. No progression/death observed.

Figure 1
Figure 1.

Conclusion

The combination of pirtobrutinib, venetoclax and Obinutuzumab is demonstrating high rates of bone marrow U-MRD at 6 and 12 months of combined treatment. No new toxicity signals have been observed. Enrollment ongoing.