Primary Endpoint Evaluation of a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease

Background
The phase (ph) 3 AMPLIFY study for patients (pts) with treatment-naïve (TN) CLL will provide data on a fixed-duration acalabrutinib (A), venetoclax (V), obinutuzumab (O) triplet; however, AMPLIFY excluded pts with TP53 aberrant CLL. In the initial paper on our ph2 trial of an MRD-guided AVO triplet regimen in all-comers with TN CLL (Davids et al., Lancet Onc, 2021), we reported high rates of CR and uMRD irrespective of TP53 status. We therefore added an expansion cohort restricted to pts with TP53 aberrancy. Here, we report the primary endpoint evaluation for the entire study.

Methods
All-comer pts with TN CLL were initially enrolled in this investigator-sponsored, ph2 study (cohort 1), followed by a multi-center expansion restricted to TN pts with TP53-aberrant CLL (cohort 2) (NCT03580928). Pts received one 28-day cycle (C) of A 100 mg bid, 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 BM-uMRD (by flow at 10^-4) with CR was reached at C16D1, pts discontinued (dc’d) therapy (tx); if not, pts continued AV through C24 and dc’d if BM-uMRD at C25D1. Pts who dc’d and later developed recurrent MRD could restart AV. Pts with detectable BM-MRD after C24 continued AV indefinitely. Efficacy was assessed by 2018 iwCLL criteria, toxicities by CTCAE v5, MRD by central 8-color flow and NGS clonoSEQ. BH3 profiling was performed as previously described (Ryan J et al., Biol Chem, 2016) on PB samples at screening and after C3.

Results
The study is fully enrolled with 72 pts (cohort 1 all-comers: n=37 (including 10 TP53-aberrant), cohort 2 TP53-aberrant: n=35). Median age 63 yrs (range 36-80); 68% male; 63% TP53-aberrant (del[17p] or TP53 mut); 17% NOTCH1 mutation, 28% complex karyotype (≥3 abnormalities); 75% unmutated IGHV (uIGHV). As of April 10, 2024, median follow-up was 54.8 mo. (cohort 1, 60.9 mo, cohort 2, 38.5 mo), and median number of cycles given was 25 (range 3-70).

The primary endpoint of BM-uMRD CR at C16D1 was achieved in 42% (30/72), with no difference for pts with TP53 aberration at 42% (19/45). The best ORR was 98.6% (including 61% CR). C16 CR rates for mIGHV and uIGHV pts were 60% and 44%. At C16D1, MRD by flow at 10^-4 in pts without and with TP53 aberration was: PB-uMRD 85%, 71% and BM-uMRD 89%, 71%, and in pts with mIGHV and uIGHV: PB-uMRD: 67%, 80% and BM-uMRD: 73%, 78%. Rates of best PB- and BM-uMRD overall were 94% and 85%. At C16, PB-uMRD by NGS at 10^-5 was 56% (37/66, with 6 pts not tested), with no difference based on TP53 status.

79% (57/72) of pts with BM-uMRD electively d/c’d tx (39% and 40% after C15 and C24), 11 pts remain on active tx, and 4 pts d/c’d prior to C16 (2 withdrew consent, 1 non-compliance, 1 Gr5 COVID-19). Median time off tx for pts who d/c’d is 27.5 mo (range 1-50). 7 pts have progressed (3 CLL, 4 transformation (2 DLBCL, 2 Hodgkin), and 2 pts have died (Gr5 COVID-19 while on tx and DLBCL Richter’s). 5 pts have started re-treatment with AV, with 3 achieving response (including 2 CR), 1 not yet evaluated, and one with Richter soon after re-starting. 4-yr PFS/OS for the whole study population, uIGHV, and TP53 aberrant was 89%/99%, 87%/95%, 77%/92%.

In all 72 pts, all-grade heme tox included: neutropenia (73%; 37% Gr3/4) and thrombocytopenia (72%; 29% Gr3/4). Selected non-heme tox: headache (76%, 63% Gr1, 11% Gr2, 1% Gr3), bruising (66%, 65% Gr1, 1% Gr2), diarrhea (46%; 34% Gr1, 7% Gr2, 6% Gr3), infection (46%, 9.7% Gr3, 1 Gr5 COVID-19), hypertension (34%; 10% Gr3), infusion-related reaction (28%, 4% Gr3), arthralgia (30%, 27% Gr1, 1.5% Gr2, 1.5% Gr3), and any grade afib 4 pts (5.6%). Non-skin second malignancies occurred in 6 pts (8.3%), including 1 MDS. 18 pts (25%) had dose-reduction of only A (4.2%), only V (8.3%), or both drugs (12.5%).

BH3 profiling in 53 pts with available serial samples found no difference in apoptotic priming based on TP53 or IGHV status, consistent with the similar efficacy of AVO in higher risk pts. Increased dependence on BCL-2 was observed in pts who achieved uMRD at C16.

Conclusion
In pts with TP53-aberrant CLL, the AVO triplet is a well-tolerated and highly active MRD-guided frontline therapy, with 71% of pts achieving PB and BM-uMRD (flow at 10^-4) at C16. Responses are durable, with 89%, 87%, and 77% 4-yr PFS in all-comer, uIGHV, and TP53 aberrant pts. Our data support further study of AVO for pts with TN high risk CLL in GCLLSG CLL16 and future trials.