MINIMAL RESIDUAL DISEASE-DRIVEN TREATMENT INTENSIFICATION WITH SEQUENTIAL ADDITION OF IBRUTINIB TO VENETOCLAX IN R/R CLL

Undetectable MRD (uMRD) is achievable in patients with CLL with the BCL2-inhibitor venetoclax alone or combined with the BTK-inhibitor ibrutinib. This phase 2 multicenter MRD-driven study was designed to discontinue treatment upon reaching uMRD4(<10-4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary endpoint of the study was proportion of uMRD4 with venetoclax+/-ibrutinib. Secondary endpoints were ORR, PR, CR, PFS, DOR, OS, and safety of venetoclax+/-ibrutinib. Patients with uMRD4 at Cycle12Day1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle24Day28/uMRD4/progression/toxicity. After Cycle24Day28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53-aberrations; 79% unmutated IGHV) started venetoclax. ORR with venetoclax was 36/38(95%) (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle12Day1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range 3-10) of combined treatment, 16/19 (84%) achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median PFS was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, 1 dropped-out). 7/32 patients (22%) remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent G3-4 adverse event, no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33/38 patients (87%) with venetoclax monotherapy or combined with ibrutinib., delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. Clinical trial number: NCT04754035.