An IHC-based apoptotic priming profile from whole-slide imaging stratifies survival in venetoclax-based AML therapy

Venetoclax-based regimens are used for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy, but prognostic biomarkers for this regimen remain limited. This study investigated the association between immunohistochemistry (IHC)-based profiling of BCL-2 family proteins and clinical outcomes in elderly AML patients treated with venetoclax-based therapy. We retrospectively analyzed 52 newly diagnosed elderly AML patients treated with venetoclax-based therapy at Taipei Veterans General Hospital (2019-2023). Diagnostic bone marrow biopsies were assessed for 11 BCL-2 family proteins via immunohistochemistry with whole-slide imaging and digital quantification (QuPath), providing an IHC-based apoptotic priming profile reflecting the balance of pro- and anti-apoptotic protein expression; expression levels were dichotomized using Youden's index-derived H-score cutoffs. The median age was 74 years, with 26.9% aged ≥ 80 years; 76.9% had adverse-risk cytogenetics per ELN 2022. In multivariable analysis, age ≥ 80 years (HR 2.46, p = 0.046) and adverse ELN risk (HR 6.02, p = 0.004) independently predicted mortality. In multivariable models, higher expression of the BH3-only proteins BAD, HRK, and NOXA was associated with longer overall survival, whereas elevated anti-apoptotic BCL-XL and MCL-1 were associated with poorer outcomes. These findings suggest that WSI-enabled, IHC-based apoptotic pathway profiling may provide additional prognostic information beyond established clinical and cytogenetic factors in elderly AML patients receiving venetoclax-based therapy.