S148: time-limited venetoclax and ibrutinib for patients with relapsed/refractory cll who have undetectable mrd – 4-year follow up from the randomized phase ii vision/ho141 trial

Background: In patients with relapsed/refractory (RR) CLL efficacy and safety of MRD guided treatment cessation of venetoclax+ibrutinib (V+I) with the option to reinitiate V+I based on MRD reappearance was evaluated in the randomized Phase 2 Ho141/VISION study. Primary analysis, when the last patient reached 27 months, showed a favorable benefit-risk profile of MRD based cessation and reinduction (Lancet Oncol 2022). Aims: To analyze long-term clinical outcome and MRD-kinetics with a median follow up of 50.8 months for patients enrolled in the VISION trial. Methods: Patients received I for 2 (28-day) cycles followed by V+I combination. Patients reaching at least partial remission (PR) and flow-based undetectable (u)MRD (<10-4) in blood (PB) and bone marrow (BM), at cycle 15 (C15) were randomized 1:2 between I maintenance (arm A) or treatment cessation (arm B). Patients in arm B becoming MRD positive (>10-2) reinitiated V+I. MRD positive patients at C15 remained on I. Results: 225 patients were enrolled: median age 68 years (IQR 61-72), median CIRS score 2 (IQR 1-4), Binet stage B/C 84%, IGHV unmutated: 64%, TP53 aberrations: 24%. Seventy-two (32%) of the 225 patients achieved uMRD and were randomized to I maintenance (arm A; n=24), or treatment cessation arm B (n=48). Patients who did not achieve uMRD (n=116) continued I maintenance without randomization while 37 patients went off protocol prior to randomization. For all patients enrolled (n=225), long term follow-up at a median of 51 months showed an overall survival (OS), progression free survival (PFS) and time to next treatment (TtNT) of 88%, 79% and 83%, respectively. Patients that received I maintenance (non-randomized), OS, PFS and TtNT was 86%, 76% and 81%. For patients randomized in arm A, OS, PFS and TtNT were 95%, 90% and 86% and in arm B 91%, 85% and 88% respectively. During 3 years post-C15 follow up, 36 (31%) of the non-randomized patients went off protocol due to toxicity (n=19, 16%), progression (n=2, 2%), death (n=3, 3%) or other reason (n=12, 10%). For the 24 uMRD patients on ibrutinib in arm A, 13 (54%) went off protocol due to toxicity (n=6, 25%), progression (n=1, 4%), death (n=1, 4%) or other reason (n=5, 21%). Twenty-nine of the 48 patients in treatment cessation arm B (60%), did not receive retreatment. At data cutoff date, 8 of these went off protocol (toxicity (n=1), progression (n=1), death (n=2) and other reason (n=4)). In arm B treatment was reinitiated per-protocol due to MRD conversion in 19 patients (40%) of whom 4 went off protocol due to toxicity (n=1), progression (n=2 including 1 death) and other reason (n=1). Following 12 cycles of re-treatment with V+I, a second uMRD response was achieved in 8 (42%) whereas 3 (16%) and 2 (11%) had low and high MRD positive responses, respectively. Retreatment resulted in a clinical remission in 10 (53%) while 2 (11%) progressed and 1 patient went off protocol (toxicity). Six patients are still under evaluation for responses and MRD. uMRD rate in PB of non-randomized patients on maintenance shows at 22% at the end of follow-up. uMRD rate for the 24 uMRD patients in arm A was maintained at 67% at end of 2nd year (C39). The uMRD rate for the 48 patients in arm B in treatment cessation was maintained at 38% and 21% at month at month 39 and 51, while 11 (23%) and 19 (40%) patients reinitiated treatment respectively (Figure). In arm B, genomic complexity (GC; ≥3 aberrations) and TP53 aberrations tend to be enriched in patients who had a MRD conversion compared to patients who did not: GC 47% versus 24, TP53ab 26% versus 14%. No such pattern was detected for IGHV status. Summary/Conclusion: MRD-guided V+I therapy for patients with RR CLL is a favorable option. For patients achieving uMRD after 15 cycles of treatment, treatment cessation with MRD guided reinitiation is a feasible approach.Keywords: Minimal residual disease (MRD), B-CLL, Targeted therapy