Impact of prognostic mutations on outcomes with fixed-duration acalabrutinib-venetoclax combinations versus chemoimmunotherapy: An exploratory analysis from AMPLIFY

Abstract Introduction: The AMPLIFY trial evaluated fixed-duration acalabrutinib + venetoclax ± obinutuzumab (AV/AVO) vs chemoimmunotherapy (CIT) in fit patients (pts) with treatment-naive (TN) chronic lymphocytic leukemia (CLL) (Brown et al. NEJM 2025;392:748-62). In the ITT population, AV/AVO demonstrated prolonged progression-free survival (PFS) vs CIT. However, shorter PFS occurs with certain genetic factors, such as unmutated IGHV (uIGHV) and NOTCH1, even with targeted treatment (tx) (Tausch et al. Blood 2022;140(Suppl 1):839-41). This exploratory analysis evaluated the relationship between prognostic genetic aberrations and clinical outcomes in AMPLIFY. Methods AMPLIFY (ACE-CL-311; NCT03836261) is an ongoing, randomized, open-label, phase 3 trial in pts with TN CLL aged ≥18 y with ECOG performance status ≤2 and without del(17p) or TP53 mutation. Pts were randomized to receive AV (acalabrutinib, cycles [C] 1–14; venetoclax, C3–14), AVO (AV as described; obinutuzumab, C2−7), or investigator's choice of fludarabine + cyclophosphamide + rituximab or bendamustine + rituximab (FCR/BR, C1−6). Subgroup analyses were performed for blinded independent central review–assessed PFS and time to next tx (TTNT) according to baseline and disease characteristics for AV and AVO vs FCR/BR. Blood samples collected at baseline were analyzed centrally for genetic factors, including uIGHV and 6 mutations (ATM, CARD11, NOTCH1, BIRC3, MYD88, SF3B1) by next-generation sequencing. PFS and TTNT (AV and AVO vs FCR/BR) were calculated using an unstratified Cox proportional-hazards model. Results In total,867 pts were randomized (AV=291; AVO=286; FCR/BR=290); 57% (AV), 59% (AVO), and 59% (FCR/BR) had uIGHV; median follow-up was 40.8 mo. Mutation analysis demonstrated comparable prevalence of mutations across arms, most commonly ATM (24% AV, 24% AVO, 20% FCR/BR), NOTCH1 (14% AV, 16% AVO, 17% FCR/BR), and SF3B1 (15% AV, 16% AVO, 16% FCR/BR). Across arms, most ATM, SF3B1, and NOTCH1 mutations occurred in pts with uIGHV (AV: 71%, 78%, and 76%, respectively; AVO: 74%, 70%, 91%; FCR/BR: 73%, 80%, 86%), with significantly higher frequencies in pts with uIGHV vs mutated IGHV (mIGHV; P<0.01). Among pts with ≥1 mutation (AV=145; AVO=150; FCR/BR=137), co-mutation rates in the AV, AVO, and FCR/BR arms were ATM/NOTCH1 (6.2%, 10.0%, 10.2%), ATM/SF3B1 (12.4%, 10.0%, 10.9%), and NOTCH1/SF3B1 (5.5%, 4.7%, 8.8%), respectively. The 36-mo PFS (ITT) was 76.5% (AV), 83.1% (AVO), and 66.5% (FCR/BR). PFS improvement was observed with AV vs FCR/BR in pts with uIGHV (hazard ratio [HR] 0.69; 95% CI 0.48–0.97) and mutated ATM (0.50; 0.25–1.0), NOTCH1 (0.72; 0.36–1.42), and SF3B1 (0.22; 0.09–0.55), and with AVO vs FCR/BR (uIGHV: 0.35, 0.23–0.53; ATM: 0.41, 0.19–0.86; NOTCH1: 0.26, 0.10–0.65; SF3B1: 0.34, 0.15–0.77). Among pts with/without ATM, 36-mo PFS was 76%/74% (AV), 82%/84% (AVO), and 58%/68% (FCR/BR). Among pts with/without NOTCH1, 36-mo PFS was 57%/79% (AV), 86%/83% (AVO), and 50%/69% (FCR/BR). A 36-mo PFS rate difference in AV with/without NOTCH1 was seen in the uIGHV subgroup (49%/73%; HR 0.46; 95% CI 0.24–0.87) but not in the mIGHV subgroup (80%/85%; 0.77; 0.18–3.37); however, sample size was limited in this subgroup. For those with/without SF3B1, 36-mo PFS was 85%/74% (AV), 79%/85% (AVO), and 51%/69% (FCR/BR). The 36-mo TTNT (ITT) was 88.5% (AV), 85.4% (AVO), and 75.2% (FCR/BR). TTNT improvement for AV and AVO vs FCR/BR was observed for pts with uIGHV (HR 0.50 [95% CI 0.33–0.74] and 0.35 [0.22–0.54], respectively) and mutated ATM (0.32 [0.14–0.75] and 0.53 [0.25–1.14]), NOTCH1 (0.56 [0.24–1.29] and 0.42 [0.17–1.05]), and SF3B1 (0.24 [0.08–0.74] and 0.43 [0.17–1.09]). For those with/without ATM, 36-mo TTNT was 89%/88% (AV), 82%/88% (AVO), and 69%/77% (FCR/BR). For those with/without NOTCH1, 36-mo TTNT was 77%/90% (AV), 84%/86% (AVO), and 64%/78% (FCR/BR); for those with/without SF3B1, 36-mo TTNT was 91%/87% (AV), 85%/86% (AVO), and 68%/77% (FCR/BR). Conclusion This analysis from AMPLIFY demonstrates an association between presence of mutations and uIGHV status. Similar benefits in PFS and TTNT with AV and AVO vs FCR/BR were observed across these mutations. In the AVO arm, ATM, SF3B1, and NOTCH1 mutations were not associated with poorer outcomes. In the AV arm, pts with uIGHV without a NOTCH1 mutation had better outcomes vs patients with uIGHV with a co-occurring NOTCH1 mutation. The predictive values of these mutations will be explored via multivariate analysis.