NUP98::NSD1 and FLT3/ITD co-expression is an independent predictor of poor prognosis in pediatric AML patients.

ABSTRACT

OBJECTIVE: Patients who carry NUP98NSD1 or FLT3/ITD mutations are reported to have poor prognosis. Previous studies have confidently reported that the poor outcome in younger AML patients is owning to dual NUP98NSD1 and FLT3/ITD positivity, with a high overlap for those two genetic lesions. In this study, we assessed the prognostic value of the presence of both NUP98NSD1 and FLT3/ITD in pediatric AML patients. METHODS: We screened a large cohort of 885 pediatric cases from the COG-National Cancer Institute (NCI) TARGET AML cohort and found 57 AML patients with NUP98 rearrangements. RESULTS: The frequency of NUP98 gene fusion was 10.8% in 529 patients. NUP98NSD1 fusion was the most common NUP98 rearrangement, with a frequency of 59.6%(34 of 57). NUP98NSD1 -positive patients who carried FLT3/ITD mutations had a decreased CR1 or CR2 rate than those patients carried FLT3/ITD mutation alone (P = 0.0001). Moreover, patients harboring both NUP98NSD1 fusion and FLT3/ITD mutation exhibited inferior event-free survival (EFS, P < 0.001) and overall survival (OS, P = 0.004) than patients who were dual negative for these two genetic lesions. The presence of only NUP98NSD1 fusion had no significant impact on EFS or OS. We also found that cases with high FLT3/ITD AR levels ( > = 0.5) with or without NUP98NSD1 had inferior prognosis. Multivariate analysis demonstrated that the presence of both NUP98NSD1 and FLT3/ITD was an independent prognostic factors for EFS (hazard ratio 3.2, P = 0.001) in patients with pediatric AML. However, there was no obvious correlation with OS (hazard ratio 1.3, P = 0.618). Stem cell transplantation did not improve the survival rate of cases with NUP98 fusion or NUP98NSD1 AML in terms of EFS or OS. CONCLUSION: Presence of both NUP98NSD1 and FLT3/ITD was found to be an independent factor for dismal prognosis in pediatric AML patients. Notably, lack of FLT3/ITD mutations in NUP98NSD1 -positive patients did not retain its prognostic value.