Paper Details

ABSTRACT

Introduction: The phase (ph) 3 AMPLIFY study, which investigated the BTKi acalabrutinib (A) + BCL-2i venetoclax (V) + anti-CD20 mAb obinutuzumab (O) triplet in treatment-naïve (TN) CLL utilized fixed duration AVO and excluded pts with TP53 aberrancy (Brown et al., NEJM, 2025). We conducted a ph 2 trial of minimal residual disease (MRD)-guided AVO in a TN CLL population enriched for TP53-aberrant disease (Davids et al, J Clin Oncol., 2025). Here, we report 6-year (yr) follow-up results, including outcomes for AV retreatment (re-tx).

Methods: This investigator-sponsored, ph2 study initially enrolled 37 all-comer pts with TN CLL, followed by a multi-center expansion restricted to 35 TN pts with TP53-aberrant CLL (NCT03580928). Pts received one 28-day cycle (C) of A, followed by 2 Cs of AO (O at standard dosing), with V then added with an abbreviated 4-week ramp-up: C4D1 20 mg, C4D2 50mg, weekly ramp-up thereafter to 400 mg QD. AVO was given C4-7, then AV C8-15. If the primary endpoint of bone marrow (BM)-uMRD4 (by flow at 10^-4) with CR was reached at C16D1, pts discontinued (dc’d) tx; if not, pts continued AV through C24 and dc’d if BM-uMRD4 at C25D1. Pts with detectable BM-MRD4 after C24 continued AV indefinitely. Pts with either detectable peripheral blood (PB) MRD or clinical progression could restart AV tx. Efficacy was assessed by 2018 iwCLL criteria, toxicities by CTCAE v5, and MRD by central 8-color flow and clonoSEQ. MRD kinetics were analyzed using a 400-fold reduction threshold (as used with BOVen [Soumerai et al, Blood Adv, 2026]); achievement of BM delta400 from C8 to C16 was tested for association with outcomes by Fisher’s exact test.

Results: Pt characteristics included: median age 63 yrs (range 36-80); 68% male; 63% TP53-aberrant (del[17p] or TP53 mutated); 28% complex karyotype (≥3 abnormalities); 75% unmutated IGHV (uIGHV). At the data cutoff of July 13, 2026, median follow-up was 6.3 yrs (range 0.3-7.8). Median number of tx cycles was 25 (range 3-102).

As previously reported, the primary endpoint of BM-uMRD4 with CR at C16D1 was reached in 42% (30/72) pts, with an additional 39% achieving BM-uMRD4 at C25D1, for a total of 81% (58/72) of pts dc’ing tx due to achieving BM-uMRD4. Within the 14 remaining pts: 7 pts are on active tx, 4 pts d/c’d prior to C16 (2 withdrew consent, 1 non-compliance, 1 Gr5 COVID-19), and 3 pts d/c’ed after C25 per pt decision. Median tx-free duration for the 58 pts who d/c’d tx in BM-uMRD4 is 46.5 months (mos) (range 0.6-78.4).

17/72 pts have progressed (13 CLL, 4 transformation [2 DLBCL, 2 Hodgkin]) and 3 pts have died (Gr5 COVID while on tx, DLBCL Richter’s, complications from polysubstance use). 6-yr PFS and OS point-estimates (95% CI) for the whole study, uIGHV subgroup, and TP53 aberrant subgroup were 69% (58-82) and 96% (91-100), 65% (51-82) and 94% (88-100), 59% (43-80) and 93% (86-100), respectively.

12 pts restarted AV following a median tx-free interval of 26.5 mos (range 0.6-56). 10/12 were uIGHV and 9/12 TP53 aberrant. 7 pts restarted due to iwCLL progressive disease (PD), and 5 pts restarted due to recurrent detectable MRD alone. Median duration of re-tx was 25.3 mos (range 3.8-55.9). The ORR was 92% (11/12), with all responders achieving radiographic CR
(BM assessments for iwCLL CR are ongoing). 83% (10/12) achieved PB-uMRD4. At the data cutoff, only 1 of 12 pts had progressed (3.6 mos after re-tx start).

ClonoSEQ BM-MRD5 rates at C8, C16, and C25 were: 21/72 (29%), 40/72 (56%), and 42/72 (58%). Achievement of BM-MRD5 delta400 from C8 to C16 was associated with BM-uMRD at C25 (p<0.001), but not with C25 iwCLL response (p=0.3), TP53 aberrancy (p=0.3), or IGHV mutational status (p=0.1). Pts with BM-uMRD5 vs detectable BM-MRD at C25 had a subsequent 3-yr PFS of 86% vs 57% (p=0.03).

Conclusion: In a population of pts with TN CLL enriched for high-risk genetics, the MRD-guided AVO triplet achieved durable remissions and clinically meaningful tx-free intervals, with a 6-yr PFS of 69% (59% for TP53 aberrant pts). To date only 1 pt has d/c’d tx due to tx-related toxicity. Re-tx was effective, with a 92% ORR and 83% with PB uMRD4. Early delta400 BM-MRD5 was associated with later BM-uMRD5. These long-term results support the AVO triplet as a frontline, time-limited option for a broad population of pts with CLL, including those with high-risk genetics, and suggest that AV re-tx may be an effective second-line option to further extend the benefit of BTKi/BCL-2i therapy.