Introduction: Combined therapy with covalent BTK inhibitors (BTKi) and BCL2 inhibitor +/- CD20 mAb leads to high rates of undetectable MRD (U-MRD) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023/2025; Wierda, JCO 2021; Kater, NEJM Evid 2022). Pirtobrutinib is a non-covalent BTKi approved for pts with R/R CLL. Given the safety and efficacy of pirtobrutinib in R/R CLL, we hypothesized that combined pirtobrutinib, venetoclax, and obinutuzumab will be safe and effective in first-line CLL.

Methods: We conducted an investigator-initiated Phase II trial of time-limited, combined therapy with pirtobrutinib, venetoclax, and obinutuzumab as first-line treatment for pts with CLL (NCT05536349). 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 continued until end of C13. Each cycle was 28 days. Response evaluations (iwCLL 2018 criteria) were done, including imaging and bone marrow (BM) assessment at the end of C7 (6-month of the triplet combination) and C13. MRD was assessed by next-generation sequencing (NGS; ClonoSEQ assay) 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 could continue pirtobrutinib and venetoclax for another 12 cycles. Once off therapy, pts 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 September 2024, 80 pts were enrolled. Median age was 63 years (range, 38-78); 26% (21/80) pts were ≥70 years. 75% (60/80) pts were men. 79% (63/80) had IGHV-unmutated CLL. CLL FISH panel showed del(17p) in 9%, del(11q) in 29%, trisomy 12 in 20%, del(13q) in 26% and no FISH abnormalities in 16% of pts. 13% (10/80) had either del(17p) and/or TP53 mutation. 17% (13/77) had complex karyotype (≥3 abnormalities). At the time of treatment initiation, 49% (39/80) were Rai III-IV stage, and maximum lymph node dimension was ≥5 cm in 43% (34/80) pts.

3 pts came off trial [2 in C1, due to travel logistics (n=1) and insurance denial (n=1); 1 in C3 because of newly diagnosed head/neck cancer]; the remaining 77 pts continue on trial. The median follow-up for all pts is 18.8 months (range, 2.0-28.6). All 77 pts completed Cycle 7 (primary endpoint assessment), and 73 pts completed Cycle 13 (remaining 4 pts are receiving ongoing treatment; 1 pt in C11 and 3 pts in C12).

At the end of C7, U-MRD6 (10-6 sensitivity) remission rates were 58/77 (75%) in blood and 47/77 (61%) in BM; U-MRD4 (10-4 sensitivity) rates were 71/77 (92%) in the blood and 68/77 (88%) in the BM. We also assessed MRD in BM by flow-cytometry at the end of C7; 65/77 (84%) achieved U-MRD4.

At the end of C13, U-MRD6 rates were 64/73 (88%) in blood and 55/73 (75%) in BM; U-MRD4 rates were 73/73 (100%) in the blood and 71/73 (97%) in the BM. We also assessed MRD in BM by flow-cytometry at the end of C13; 71/73 (97%) achieved U-MRD4.

Early (end of C4) achievement of blood U-MRD4 was highly correlated with U-MRD6 by end of C13; among the 60 pts who achieved U-MRD4 in blood at end of C4, 59/60 (98%) were U-MRD6 in blood and 50/60 (83%) were U-MRD6 in BM at end of C13. Conversely, among the 13 pts who were MRD4+ in blood at end of C4, only 5/13 (38%) and 4/13 (31%) achieved U-MRD6 in blood and BM at end of C13, respectively.

Of the 73 pts who completed C13, 63 (86%) discontinued all therapy and are in post treatment follow-up; the remaining 10 pts were eligible (9 continued; 1 pt declined) to continue for an additional 12 cycles of pirtobrutinib and venetoclax per protocol due to disease detectable at ≥MRD5 at the end of C13.

Of the 63 pts who discontinued treatment at end of C13, no pt had MRD recurrence (defined as MRD ≥0.01% in blood in 2 consecutive assessments) at a median follow-up of 8.6 months (range, 0.1-16.6 months) after stopping treatment.

Grade 3-4 neutropenia and thrombocytopenia occurred in 69% and 19% pts, respectively. 4 pts had neutropenic fever.

No pt progressed/died.

Conclusions: We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in pts with previously untreated CLL. We observed a very high rate of BM and blood U-MRD6 remission after 6-months and 12-months of combined treatment.

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2025
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