DNMT3Awt NPM1-Mutation Defines a Subgroup of MDS with Special Favorable Outcomes Towards Decitabine Therapy
Authors: Wu Lingyun , Li Xiao , Xu Feng , Qi He , Zhang Zheng , Wu Dong , Song Luxi , Zhou Liyu , Xiao Chao , Su Jiying , Guo Juan , Chang Chunkang 
Published: November 2019

Hypomethylating agents (HMA) (including decitabine and azacitidine) are considered standard of care for higher risk myelodysplastic syndrome (MDS). Clinical data showed only about 30% cases achieved complete response (CR) by decitabine. Mutations in the nucleophosmin-1 (NPM1) gene is one of the most common somatic mutations identified in de novo acute myeloid leukemia (AML) and have also been found in 1% to 5% of MDS patients although with different mutation locus (L287fs) when compared to that in AML (W288fs). Till now, the response and survival of NPM1-mutated MDS patients treated with HMA remains unknown.
Here, we retrospectively analyzed higher risk MDSs who accepted decitabine therapy in our center. From December 2009 to July 2018, a total of 194 patients received decitabine induction treatment by 20mg/m2 intravenously for 5 consecutive days every 4-6 weeks. The median therapy course was four. Among them, twelve patients (6.2%) harbored NPM1/L287fs mutation. The median decitabine therapy cycle for the 12 NPM1 mutated patients was also four. To our interest, patients harboring NPM1 mutations achieved a relatively higher CR rate (6 of 12 cases, 50%) when compared to that of patients without NPM1 mutations (59 of 182 cases, 32.4%) , although without statistical significance (p = 0.304). Moreover, when the most common co-mutated genes DNMT3A (6 of 12 cases, 50%) (Figure 1a) was ruled out, patients harboring NPM1 mutation (DNMT3A wild type) achieved a CR rate of 83.3% (five of six), which is significantly higher than that of patients without NPM1 mutation (p = 0.018) (Figure 1b). Of note, when paired sequencing were analyzed, six patients who achieved CR by decitabine showed loss of mutated NPM1; One patients who achieved hematological improvement (HI) showed decreased variant allele frequency (VAF) of NPM1 mutation; Whereas two patients with no response (NR) showed unchanged NPM1 mutation (Figure 1d).
Notably, a prolonged relapse-free survival (PFS) was observed in CR patients with NPM1 mutation and DNMT3A wild type (NPM1mut DNMT3Awt) even without any subsequent therapies after receiving 4-5 cycles of decitabine (Figure 1c). The median RFS of CR patients with NPM1mut DNMT3Awt was 66 months, which is significantly longer than that in patients without NPM1mutation (13.5M, p = 0.006) (Figure 1e). A remarkably prolonged median survival was also shown in patients harboring NPM1mut DNMT3Awt (median survival of 80M), which is significantly longer than that of patients without NPM1 mutation (18M) (p = 0.012) (Figure 1f). Interestingly, except with DNMT3A and PTPRD co-mutations, the response and survival of patients harboring NPM1 mutations treated with decitabine were favorable even when co-mutated with IDH2, NRAS, FLT3.
In conclusion, NPM1 mutation with DNMT3A wild type defines a specific subgroup of MDS with a good response and prolonged survival by decitabine therapy, even when they were with some prognosis-poor co-mutations and without subsequent treatment. Enlarged sample of randomized controlled studies are needed to confirm our preliminary findings.
Figure 1

Disclosures
No relevant conflicts of interest to declare.