Clinical Features and Prognostic Implications of BCMA, BAFF, and APRIL Expression in Acute Myeloid Leukemia

Introduction:

B-cell maturation antigen (BCMA, also known as TNFRSF17) can be cleaved from the cell membrane, allowing it to capture B cell-activating factor (BAFF, also known as TNFSF13B) and a proliferation-inducing ligand (APRIL, also known as TNFSF13). BCMA binds with BAFF and APRIL with high affinity, and all are significant in the pathogenesis of hematologic malignancies. The BAFF-APRIL system is implicated in many hematological malignancies, leading to the development of various drugs such as targeted therapies, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies. While these interaction are well-studied in multiple myeloma, their role in acute myeloid leukemia (AML) remains unclear.

Methods:

RNA sequencing data from 475 de novo non-M3 AML patients treated with standard chemotherapy at National Taiwan University Hospital were analyzed. Maximally selected rank statistics were used to determine the cut-off values. Expression levels of BCMA (TNFRSF17), BAFF (TNFSF13B), and APRIL (TNFSF13) were evaluated for associations with clinical characteristics, treatment response, and survival outcomes.

Results:

According to the 2022 European Leukemia Network (ELN), the risk stratification of this patient cohort was as follows: favorable (40.6%, n=193), intermediate (28.2%, n=134), and adverse (31.2%, n=148). Lower BAFF (p<0.001) and APRIL (p=0.005) expression levels were noted in AML patients compared to healthy donors, with no significant difference in BCMA expression (p=0.388).

Of the 475 AML patients undergoing conventional intensive induction chemotherapy, 362 (76%) patients achieved a CR. Among these patients, APRIL expression correlated with higher complete remission (CR) rates (75.5% vs 65.2%, p=0.02), while no significant differences in CR rates were observed among patients with higher BCMA or BAFF expression. Additionally, patients with lower BAFF or APRIL expression were more likely to have ELN 2022-defined favorable-risk subtype (p<0.001). Higher BCMA was associated with improved overall survival (OS) (median 27.3 vs. 17.7 months, p=0.01) and relapse-free survival (RFS) (median 18.6 vs. 10.6 months, p=0.005). In contrast, higher expression of BAFF and APRIL correlated with inferior OS and RFS. In multivariate analysis, higher BCMA expression remained an independent favorable prognostic factor for both OS (HR 0.713, 95% CI 0.553-0.921, p=0.009) and RFS (HR 0.674, 95% CI 0.500-0.908, p=0.009) irrespective of age, ELN-2022 and white blood cell count. Network analysis revealed EZH2 and MYC as hub genes among the differentially expressed genes.

Conclusion:

BCMA, BAFF, and APRIL expression levels have prognostic significance in AML. Higher BCMA expression is associated with improved survival outcomes, while lower BAFF and APRIL expression correlate with favorable-risk disease and better prognosis. These findings warrant further investigation of BCMA-targeted therapies in AML.

No relevant conflicts of interest to declare.