Inflammatory Biomarkers Predict Response and Survival in Chemotherapy-Ineligible and Untreated Acute Myeloid Leukemia Patients Receiving Venetoclax-Azacytidine As Front-Line Therapy

Inflammation may play a major role in acute myeloid leukemia (AML), influencing disease progression, chemoresistance or myelosuppression, especially after intensive chemotherapy. In patients (pts) with untreated AML ineligible to chemotherapy (Di Nardo, NEJM 2020), the venetoclax-azacytidine (VENAZA) combination is now a first-line standard of care. Yet, little is known about the impact of inflammatory markers in such pts. Here, a multicentric retrospective French study from Grand Ouest Against Leukemia (GOAL) investigated pts 60 years or older who received at least one cycle of VENAZA as front-line therapy. The primary objective was to study the influence of inflammatory markers at diagnosis on response (complete remission [CR]/CR without blood count recovery [Cri]), progression-free (PFS) and overall (OS) survival. Levels of serum ferritin, albumin, haptoglobin, C-reactive protein (CRP) and fibrinogen were considered, as well as two inflammatory scores known for their prognostic significance in hematological malignancies including AML (CRP/albumin [CAR], and CRPxfibrinogen/albumin [CFA]). Statistical analyses were performed using R version 4.2.2. A cohortof 123 pts was collected (50.7% men, median age 73 years [interquartile range, IQR] 69-76; range 60-84) with a first cycle of VENAZA between October 2018 and June 2024. According to the European LeukemiaNet (ELN) 2022 risk classification (Döhner, Blood, 2022), 60%, 30% and 11% of the pts were classified as of adverse, intermediate or favorable risk. Complex karyotype was present in 37% of the pts as well as mutations of NPM1 in 14%, IDH1/2 in 16%, FLT3-ITD/TKD in 13% and TP53 abnormalities in 27%. Median levels of baseline inflammatory markers were all above normal: ferritin 760 µg/L (IQR: 315-1021, normal range [NR] 30-400), haptoglobin 1.6 g/L (IQR 0.8-2.40, NR 0.55-1.47), CRP 25 mg/L (IQR 4-58, NR<5) and fibrinogen 4.15 g/L (IQR 3.33-4.88, NR 2-4), except for albumin (37 g/L, IQR 32-42, NR 35-52). Median CAR and CFA ratios were respectively 1 (IQR 0.1-2.21) and 5 (IQR 0-10). A median of 4 (range: 1-35) VENAZA cycles were received, resulting in CR/CRi for 66% of evaluable pts. Median levels of ferritin (659 vs 905, p=0.01) and haptoglobin (1.5 vs 2.15, p=0.03) were significantly lower in responders. With 24.6 months median follow-up (IQR 7.1-31.0), 2-year OS and PFS are respectively 32% (IQR: 23-45) and 24% (IQR 16-34). Of the inflammatory markers evaluated, only CRP was associated with OS in univariate and multivariate analyses (Hazard Ratio [HR] 1.01; 95% confidence interval [CI] 1.00-1.01, p=0.005). None was associated with PFS nor CR/CRi. Using receiving operator curve (ROC) analysis for OS, cut-off values identified for CAR and CFA are 0.58 and 2.17 respectively. Considering CAR as the sole inflammatory marker for multivariate analysis, a higher CAR was associated with lower OS (HR: 3.74, 95%CI: 1.61-8.69, p=0.002), PFS (HR: 2.01, 95%CI: 1.02-3.95, p=0.04), and higher treatment failure (no CR/CRi, HR: 8.25, 95%CI: 1.89-48.69, p=0.009). Similarly, a higher CFA ratio was associated with lower OS (HR: 5.26, 95%CI: 2.07-13.34, p<0.001); PFS (HR:2.25, 95%CI:1.12-4.53, p=0.023), and higher treatment failure (HR: 27.28, 95%CI: 3.89-588.02, p=0.005). Although complex karyotype was associated with higher treatment failure (HR: 27.12, 95%CI:3.61-605.29, p=0.006), ELN 2022 risk factor classification was not predictive of outcome in this cohort. In conclusion, this study shows that the inflammatory status of chemotherapy-ineligible patients with AML at diagnosis influences unfavorably both response and survival to VENAZA as front-line therapy. These results prompt to develop prospective clinical trials evaluating the benefits of anti-inflammatory drugs in VENAZA-treated elderly pts with AML.