Abstract
Introduction:
Nucleoporin 98 (NUP98) rearrangement has been proposed as a type of acute myeloid leukemia (AML) with defining genetic abnormalities, occurring in approximately 2-3% of adult AML patients. While used to be reported with poor survival in children, adult AML with NUP98 rearrangement may present different genetic profiles and outcomes, particularly owing to targeted agents such as Bcl-2, FLT3 and Menin inhibitors in recent years.
Method:
We retrospectively collected the data of adult AML patients with NUP98 rearrangement who were diagnosed at 12 hospitals of East China Leukemia Alliance (ECLA) from June 2019 to February 2025, including baseline clinical features, laboratory examinations, morphological, chromosomal and genetic abnormalities (tested by next generation sequencing and RNA sequencing), treatment strategies and outcome. Rates of complete remission (CR) between groups were compared by Chi square test or Binary logistic regression, while median survival time was estimated by the Kaplan-Meier method and compared by log rank test. COX regression model was used to figure out independent favorable or risk factors for overall survival (OS).
Results:
A total of 71 (35 male and 36 female) AML patients with NUP98 rearrangement were enrolled in the ECLA database. The median age was 46 years old (range, 16~86). The median white blood cell count and bone marrow blast% were 31.1 (1.5-313.63) ×109/L and 64.5% (8.5%-93%), respectively. The FAB types were mainly concentrated in M2 (26 cases, 36.6%), M4 (20 cases, 28.2%) and M5 (17 cases, 23.9%), while 8 (11.3%) were unknown types. The most common abnormal karyotype was t(7;11)(p15;p15), carried by 19 patients. Among them, 17 were found with NUP98::HOXA9 fusion gene, and the other two with NUP98::HOXA6 and NUP98::HOXA13. Another 4 patients with NUP98::HOXA9 owned normal karyotype (2 cases), t(7;15) (1 case) and unknown type (1 case). A total of 15 fusion partners with NUP98 were detected, of which the most frequently occurring were NSD1 (occurred in 31 cases, 43.7%) and HOXA9 (21 cases, 29.6%), and the other 13 different partners were found in the rest 19 (26.8%) patients. NUP98 rearrangement often co-existed with several mutations, among which FLT3-ITD (40 cases, 56.3%) and WT1 (24, 33.8%) were most frequently detected. According to ELN 2022 risk classification, 55 (77.5%) were at intermediate risk and 16 (22.5%) at adverse risk.
The induction therapy was divided into two types: targeted agents-based therapy (including Venetoclax or Gilteritinib, combining with low-intensity or intensive chemotherapy, however Menin inhibitors have not been available in China till now) or traditional chemotherapy (including 7+3, hypomethylation agents (HMA), Homoharringtonine-based therapy, et al.). A total of 55 (77.5%) patients achieved composite CR (CRc, CR+CRi+CRp) after 1-2 cycles of induction therapy. Age, gender, blast% in bone marrow, FAB types, karyotypes involving t(7;11) or not, fusion partners carrying NSD1, HOXA9 or others, ELN 2022 risk stratification, and chemo vs targeted therapies were calculated by univariate analysis to investigate the risk factors of non-remission individuals. Significant difference in CRc rates was only observed between different treatment groups (67.5% in chemotherapy vs 90.3% in targeted therapy, Chi-square 5.211, P=0.022).
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) was implemented in 36 (50.7%) patients, of whom 27 were transplanted in CR1. With a median follow-up time of 14.8 months, the median overall survival (OS) and event-free survival (EFS) of all patients were 50.9m and 13.3m, respectively. The estimated 4-year OS and EFS rates were 56.2% and 45.3%. Patients without HSCT would only reach a 2-year OS and EFS rate of 20.9% and 12.4%, respectively, comparable to that of the ELN 2022 adverse risk group. Univariate analysis (P<0.1) identified younger age, targeted therapy, reaching CRc and allo-HSCT as favorable factors for longer OS. But COX regression reserved younger age (OR 0.968 (95% CI: 0.939-0.998) P=0.037), CRc (OR 0.206 (95% CI: 0.08-0.53), P=0.001) and allo-HSCT (OR 0.024 (95% CI: 0.004-0.128), P<0.001) as independent favorable factors for OS.
Conclusion:
Adult AML with NUP98 rearrangement should be recognized as one of adverse risk subgroups, irrespective of different fusion partners. Targeted therapy had higher chance of achieving CRc, and bone marrow transplantation in CR1 was the key to long-term survival.
