Comprehensive mutational profiling and clinical outcome of adults AML with NUP98 rearrangement

Abstract Acute myeloid leukemia (AML) harboring NUP98 rearrangements (NUP98r) is recognized as a distinct entity in the 2022 WHO classification; however, it is not as a prognostic factor within the ELN 2022 classification. We report a large cohort of 95 adult patients with NUP98r AML. Patient characteristics included a young age (median 50 years [IQR 38-64]), 20% of therapy-related AML, a high WBC count (median 52×109/L), normal karyotype in 32%, FLT3-ITD in 48% and WT1 mutations in 34%. NUP98::NSD1 fusion was the most common (54%), and these patients were significantly younger (41y vs 61y), had more de novo AML (94% vs 64%), higher rates of normal karyotypes (56% vs 4.5%), FLT3-ITD (76% vs 18%) and WT1 mutations (50% vs 16%) than other NUP98r AML. The median overall survival (OS) for the entire cohort was 14.8 months (95% CI, 11.9–20.8) and event-free survival was 3.3 months (2-7.5). Among patients treated intensively (n=73), age (HR = 1.04) and FLT3 inhibitor therapy (HR = 0.45) influenced OS in univariate analysis, while leukocytosis, partner type, ELN classification, presence of a FLT3-ITD or WT1 mutation or hematopoietic stem cell transplant did not. Compared with NUP98 wild-type (WT) AML, NUP98r patients had a prognosis more similar to that of NUP98 WT ELN adverse patients whether initially classified as intermediate (20.3 months [11.7-30.2]) or adverse (15.7 months [13.5-42.9]). However, treatment with FLT3 inhibitors improved prognosis, with OS approaching that of intermediate-risk AML patients (33.3 months [11.9–not reached]).