The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based “Mediators of apoptosis combinatorial score” (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN. Significance: Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making. This article is highlighted in the In This Issue feature, p. 1275

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

Chronic kidney disease (CKD) before treatment and renal function decline during treatment are common in elderly patients receiving hypomethylating agents (HMAs) and venetoclax (VEN). This retrospective multicenter study of 130 newly diagnosed older acute myeloid leukemia (AML) patients evaluated the prognostic impact of renal function before and during the first treatment cycle. A total of 56 patients (43%) had CKD, and 49 (38%) developed acute kidney injury (AKI) during treatment. AKI occurrence was associated with laboratory tumor lysis syndrome (LTLS). CKD before treatment showed a trend towards a lower overall response rate (ORR, OR 0.5, p = 0.07) in multivariable analysis (MVA) and inferior relapse-free survival (RFS, HR 2.16, p = 0.06) in univariate analysis (UVA), but not MVA (RFS, HR 1.93, p = 0.15). CKD did not affect overall survival (OS) or event-free survival (EFS). AKI during HMA/VEN therapy was associated with significantly higher 30-day and 60-day mortality rates and emerged as an independent prognostic factor for inferior OS (HR 1.86, p = 0.01) and EFS (HR 1.81, p = 0.007). RFS did not differ significantly by AKI status. Sepsis was a more frequent cause of death in patients with vs. without AKI (33% vs. 5%). In conclusion, kidney function is a key prognostic factor in HMA/VEN-treated patients, warranting further study on treatment adjustments and supportive care.

MAC-Score predict response within mutational subgroups

Bcl-2 family gene expression in LSCs predicts in vitro response to HMA/VEN