Impact of baseline genetic profile and treatment on outcome and hematological toxicity in CEBPA-mutated AML

CEBPA-mutated acute myeloid leukemia (AML) is recognized as a distinct entity in WHO and ICC classification. Several additional gene mutations are enriched in this subset compared to CEBPA-wild type AML, including recurrent myeloid mutations (involving TET2, FLT3, NRAS) as well as others (GATA2, CSF3R, WT1), but no conclusive findings on their prognostic value were drawn. Our study aimed to correlate baseline characteristics and treatment variables with outcomes and hematological toxicity in an intensively treated CEBPA-mutated cohort. From 2004 to 2023, 50 patients met the inclusion criteria at study sites (Firenze, Bergamo). Based on NGS, 25 (50.0%) patients showed at least one additional mutation (NGS+), the majority involving GATA2 (n=15, 30.0%). While a significant difference in DFS was observed (HR=3.20; P=0.041) in favor of NGSwt patients, there was a trend only toward shorter survival in NGS+ group (HR=3.76; P=0.081). The latter was also characterized by a delayed hematopoietic recovery, with slower neutrophil (22 days to ≥ 0.5 x109/L) and platelet recovery (29 days to ≥ 50 x109/L) after consolidation compared to NGSwt group (20 days, P=0.011, and 25 days, P=0.035, respectively). In CEBPAmut patients, the delay in hematopoietic recovery was enhanced by treatment with anthracyclines. As many as 46.1% (6/13) of NGS+ patients receiving two anthracyclines-containing cycles were unable to complete the planned chemotherapy program, compared to 18.7% (6/32, P=0.075) in other categories. Our findings suggest the cumulative dosage of anthracyclines should be limited in CEBPAmut/NGS+ patients to avoid excessive hematological toxicity that could potentially impair the therapeutic plan.