Combined Pirtobrutinib, Venetoclax, and Obinutuzumab As First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL)

Introduction: Combined treatment with covalent BTK-inhibitor (cBTKi), such as ibrutinib, acalabrutinib, or zanubrutinib with BCL2-inhibitor, venetoclax, +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectable MRD (U-MRD4, 10^-4 sensitivity) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report results of time-limited, combination therapy with non-covalent BTKi, pirtobrutinib with venetoclax and obinutuzumab as first-line treatment for pts with CLL (NCT05536349).

Methods: Pts with previously untreated CLL meeting iwCLL treatment criteria were enrolled. Pts received pirtobrutinib 200mg daily starting Cycle 1 Day 1 (C1D1) continuously until end of C13. Obinutuzumab was given as standard 6 cycles starting C1D1. Venetoclax standard ramp-up was initiated C2D1 to the target dose of 400mg daily and then continued until end of C13. Each cycle is 28 days. Response evaluations (iwCLL 2018 criteria) were done by imaging and bone marrow (BM) assessment at the end of C7 (6-month of the triplet combination) and C13. MRD was assessed by ClonoSEQ next-generation sequencing in both blood and BM at the end of C7 and C13. Pts with detectable MRD5 (≥10^-5 in either blood or BM) at the end of C13 can continue pirtobrutinib and venetoclax for another 12 cycles per protocol. All pts, once off therapy, are monitored by blood MRD by NGS every 3 months for the first 12 months off therapy, and then every 6 months.

Results: Between February 2023 and June 2024, a total of 74 pts were enrolled. Median age is 64 years (range, 38-79 years). 77% had IGHV-unmutated CLL. 12% had del(17p)/TP53 mutation.

2 pts came off trial (1 pt in C3 for treatment of newly diagnosed head/neck cancer; 1 pt in C1 due to noncompliance with study requirements); the remaining 72 pts continue on the trial. The median follow-up is 10.3 months (range, 1.1-17.5 months).

At the end of C7, among the 43 pts who reached this time-point, BM and blood NGS showed U-MRD6 (10^-6 sensitivity) in 28/43 (65%) and 34/43 (79%), respectively. The corresponding U-MRD4 rates at end of C7 were 39/43 (91%) in BM and 40/43 (93%) in blood.

At the end of C13, among the 27 pts who reached this time-point, BM and blood NGS showed U-MRD6 in 22/27 (81%) and 24/27 (89%), respectively. The corresponding U-MRD4 rates at end of C13 were 26/27 (96%) in BM and 27/27 (100%) in blood.

Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 18% pts, respectively.

No pt has progressed/died. Of the 27 pts who completed C13, 24 discontinued all therapy and are in post treatment follow-up; the remaining 3 pts are continuing additional 12 cycles of pirtobrutinib and venetoclax per protocol due to detectable MRD5 at the end of C13.

Conclusions: We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in pts with previously untreated CLL. We observed a very high rate of BM U-MRD6 at 6-months and 12-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents. Updated data will be presented.