Overview
Adult acute myeloid leukemia (AML) with NUP98 rearrangement is a rare but biologically important subgroup of AML. NUP98 is a gene located on chromosome 11 that normally helps regulate transport between the cell nucleus and cytoplasm. When NUP98 becomes rearranged with another gene, the resulting fusion protein can disrupt normal blood cell development and promote leukemia. Although NUP98 rearrangements are often discussed in pediatric leukemia, this study provides one of the largest adult cohorts to date and shows that the disease carries distinct molecular features and a poor overall prognosis.
Why this study matters
AML is not one disease, but a group of related cancers with different genetic drivers, treatment responses, and outcomes. Identifying the exact mutation pattern is essential because modern AML care increasingly depends on molecular profiling to guide risk classification and therapy. NUP98-rearranged AML appears to behave aggressively in adults, but previous data were limited by small sample sizes. This study analyzed 95 adult patients, helping clarify how these leukemias present, which mutations commonly coexist, and how they respond to treatment.
Key patient characteristics
The cohort included 95 adults with AML harboring NUP98 rearrangements. The median age was 50 years, with an interquartile range of 38 to 64 years, showing that many patients were relatively young for AML. About 20% had therapy-related AML, meaning the leukemia developed after prior exposure to chemotherapy or radiation for another cancer. Patients often presented with a high white blood cell count, with a median of 52 × 10^9/L, suggesting a significant disease burden at diagnosis.
Cytogenetic and molecular features also stood out. A normal karyotype was seen in 32% of patients, which is clinically important because AML can appear deceptively “normal” under standard chromosome testing despite having major molecular abnormalities. FLT3-ITD mutations were present in 48% of patients, and WT1 mutations in 34%. These co-mutations are highly relevant because they influence disease biology, risk assessment, and treatment planning.
NUP98::NSD1 was the most common fusion
Among the various NUP98 rearrangements, NUP98::NSD1 was the most frequent, accounting for 54% of cases. Patients with this fusion were notably different from those with other NUP98 rearrangements. They were younger, with a median age of 41 years versus 61 years in the non-NSD1 group. They were also much more likely to have de novo AML, meaning AML arising without a prior known hematologic disorder or cytotoxic treatment exposure.
In addition, NUP98::NSD1 cases had a higher rate of normal karyotype, much higher FLT3-ITD frequency, and more WT1 mutations. Specifically, compared with other NUP98-rearranged AML, they had normal karyotypes in 56% versus 4.5%, FLT3-ITD in 76% versus 18%, and WT1 mutations in 50% versus 16%. This pattern suggests that NUP98::NSD1 defines a particularly molecularly distinct subtype of AML.
Clinical outcomes were poor overall
The overall prognosis for the entire cohort was unfavorable. Median overall survival was 15.2 months, and median event-free survival was only 5.8 months. In practical terms, this means many patients experienced relapse, treatment failure, or death within a relatively short period after diagnosis.
Among the 73 patients who received intensive treatment, several factors influenced overall survival in univariate analysis. Age was associated with worse outcomes, as expected in AML. Two interventions appeared beneficial: FLT3 inhibitor therapy and hematopoietic stem cell transplantation. The hazard ratio for FLT3 inhibitor therapy was 0.45, and for stem cell transplant it was 0.5, suggesting both were associated with improved survival in this cohort. While univariate analysis cannot prove causation, the findings support the idea that targeted therapy and transplant may help offset the high-risk biology in selected patients.
How NUP98-rearranged AML compares with other AML risk groups
The investigators compared these patients with NUP98 wild-type AML, including patients classified by the European LeukemiaNet (ELN) as intermediate or adverse risk. Their analysis suggested that NUP98-rearranged AML behaves more like ELN adverse-risk disease, even when patients were initially categorized differently based on conventional risk systems.
For patients initially classified as intermediate risk, median overall survival was 20.3 months. For those classified as adverse risk, median overall survival was 15.7 months. These figures indicate that NUP98 rearrangement may identify a biologically high-risk leukemia that is not fully captured by routine cytogenetics alone.
FLT3 inhibitors may improve outcomes
One of the most clinically relevant findings was the apparent benefit of FLT3 inhibitor therapy. Patients receiving FLT3-targeted treatment had a median overall survival that was not reached during follow-up, and 5-year overall survival was 53.3%. That outcome approaches what is often seen in intermediate-risk AML rather than the poor survival expected for high-risk disease.
This is especially important because FLT3-ITD was common in the cohort, particularly among patients with NUP98::NSD1. It supports routine molecular testing for FLT3 mutations in NUP98-rearranged AML and suggests that prompt incorporation of a FLT3 inhibitor may meaningfully improve prognosis. In real-world practice, FLT3 inhibitors may be used in combination with induction therapy, consolidation, or in relapsed disease, depending on the specific agent, patient fitness, and treatment setting.
Implications for diagnosis
This study reinforces the importance of comprehensive molecular profiling in AML. A patient may have a normal karyotype or nonspecific features on initial testing, yet still carry a high-risk fusion such as NUP98::NSD1. Because standard cytogenetics alone may miss the full picture, next-generation sequencing and fusion testing are increasingly necessary.
For clinicians, the presence of NUP98 rearrangement should prompt careful evaluation for co-mutations, especially FLT3-ITD and WT1. For pathologists and laboratory teams, this supports expanding fusion detection strategies, including RNA-based assays or other methods capable of identifying cryptic rearrangements.
Treatment considerations
Although this study was not a randomized treatment trial, it offers practical signals for management. Adult AML with NUP98 rearrangement appears aggressive and should generally be treated as high risk. Many patients may be candidates for intensive induction chemotherapy if medically fit, followed by consolidation and consideration of allogeneic hematopoietic stem cell transplantation in first remission, especially if additional high-risk features are present.
The data also suggest that targeted therapy matters. In patients with FLT3 mutations, especially FLT3-ITD, a FLT3 inhibitor should be considered as part of frontline or salvage treatment, according to local guidelines and drug availability. Because this subgroup still has poor outcomes overall, clinical trial enrollment is strongly worth considering whenever possible. Trials exploring novel combinations, post-transplant maintenance, or targeted agents may be especially relevant.
What the findings mean for patients and families
For patients and families, the key message is that NUP98-rearranged AML is a serious diagnosis, but molecular testing can reveal treatment opportunities. The presence of a fusion gene does not only help explain why the leukemia developed; it can also point to therapies that may improve survival. In particular, identifying FLT3 mutations can open the door to precision medicine approaches.
It is also important to understand that prognosis in AML depends on many factors, including age, overall health, genetic findings, response to initial therapy, and access to transplantation or targeted drugs. While the study shows that outcomes remain challenging, it also suggests that better risk-adapted treatment can make a meaningful difference.
Study limitations
As with any retrospective cohort study, there are limitations. Treatment decisions were not uniform across patients, and follow-up and supportive care may have varied by center and time period. Univariate analysis can identify associations, but it cannot fully separate the effect of treatment from other patient characteristics. In addition, the rarity of NUP98 rearrangements means that even a large study like this still contains a relatively modest number of cases for subgroup analyses.
Despite these limitations, the study is valuable because it brings together a large adult cohort and provides a clearer picture of a rare AML subtype.
Conclusion
This comprehensive analysis shows that adult AML with NUP98 rearrangement is a high-risk leukemia characterized by younger age, frequent FLT3-ITD and WT1 mutations, and poor survival. NUP98::NSD1 is the most common fusion and is associated with an especially distinct molecular profile. The findings support broad molecular testing at diagnosis, aggressive risk-adapted treatment, consideration of allogeneic stem cell transplantation, and use of FLT3 inhibitors when appropriate.
Overall, the study suggests that NUP98-rearranged AML should be recognized as a biologically distinct entity with clinical behavior closer to adverse-risk AML, while also highlighting a pathway toward improved outcomes through precision therapy.