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Figure 1. Survival and gene expression of NUP98-KDM5A+ and NUP98-KDM5- acute myeloid leukemia. (A) Kaplan-Meier survival curve of event-free survival (EFS) of NUP98-KDM5A+ versus NUP98-KDM5– patients. (B) Kaplan-Meier survival curve of overall survival (OS) of NUP98-KDM5A+ versus NUP98-KDM5A– patients. (C) Relapse risk (RR) of NUP98-KDM5A+ versus NUP98-KDM5A– patients. (D) Unsupervised hierarchical clustering analysis by pairwise sample corre- lations (Pearson R). (E) HOX expression-based clustering using principal component analysis. The five distinct groups were determined using K-means clustering and depicted in convex hulls. (F) Venn diagram of differentially expressed genes in NUP98-KDM5A+ and NUP98-NSD1– cases as compared to other subtypes of acute myeloid leukemia (excluding those with NUP98 rearrangements).
KDM5A+ patients was significantly lower than that of NUP98-KDM5A− patients (11.7x109/L vs. 23.9x109/L, P=0.006). Previously described as a recurrent rearrange- ment in acute megakaryoblastic leukemia, this study identified NUP98-KDM5A in all French-American-British (FAB) types of AML, with the rearrangement being pres- ent most frequently in M7 (34%), M5 (21%) and M6 (17%) (Online Supplementary Figure S1B).8 Interestingly, these characteristics were different from those previously described for NUP98-NSD1-rearranged pediatric AML (n=37), in which patients had a median age of 10.4 years (range, 1.2-19.4), a median white blood cell count of 181.2x109/L, and the rearrangement was most frequent in FAB types M4/M5 (51%).7,9
In concordance with other studies, we found that NUP98-KDM5A+ patients lacked other common AML fusions.8,10 Mutations in genes that are recurrently mutat- ed in other AML subtypes, such as RAS, WT1 and FLT3, occurred with very low frequency in NUP98-KDM5A+ cases, suggesting that the fusion itself may have a suffi- cient transforming effect (Online Supplementary Table S1).
There was not a significant difference in complete remission rates between NUP98-KDM5A+ and NUP98- KDM5A− patients (Table 1). Minimal residual disease (MRD) data were available for 31 NUP98-KDM5A+ patients; 17/31 (55%) NUP98-KDM5A+ patients were
MRD+ (>10-3 blasts detected) at the end of induction, compared to 471/1740 NUP98-KDM5A− patients (27%, P<0.001). MRD status did not clearly influence outcome, as survival rates of NUP98-KDM5A+ patients were simi- lar between MRD+ patients (4-year event-free survival of 27% ± 25.4% and overall survival of 29.9% ± 31.7%), and MRD– patients (4-year event-free survival of 36% ± 25.6% [P=0.30] and overall survival of 42.9% ± 26.5% [P=0.65]) (Online Supplementary Figure S2A and B). These survival rates were comparable to those of NUP98- KDM5A− but MRD+ patients (5-year event-free survival of 30.8% ± 3.4% and overall survival of 48.5% ± 3.7%), and significantly lower than survival rates of NUP98- KDM5A− patients who were MRD– (5-year event-free survival of 58.3% ± 2.2% [P<0.001] and overall survival of 73.3% ± 2.0% [P<0.001]). However, as the numbers of NUP98-KDM5A+ patients with available MRD data were low, definitive conclusions cannot be drawn.
Event-free and overall survival rates of NUP98- KDM5A+ patients were nearly superimposable with 5-year survival rates of 29.6% ± 14.6%, and 34.1% ± 16.1%, respectively. This illustrates that NUP98- KDM5A+ AML is more difficult to rescue than other AML subtypes. The relapse risk of NUP98-KDM5A+ patients was 62.6% ± 16.7%. These outcomes were significantly worse when compared to those of NUP98-KDM5A-
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