Re-Examination Of 2017 Eln Risk Classification By A Cohort Of 739 De Novo Aml Patients In Taiwan: Co-Occurring Poor-Risk Mutations May Further Predict Outcome In Flt3-Itd Patients
BLOOD(2018)
摘要
Introduction Recent advances in the discovery of the genomic landscape in AML prompts necessity to re-examine the 2017 European LeukemiaNet (ELN) recommendation. In this study we aimed to validate the usefulness of 2017 ELN risk stratification in a large Taiwan cohort with special focus on the prognostic relevance of FLT3 -ITD allelic ratio and its interaction with other mutations. Methods We retrospectively included 1040 de novo non-M3 AML patients. AML was risk-stratified according to the 2017 ELN recommendation. 739 (71.1%) patients who received standard chemotherapy were included for survival analysis. Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in 293 (39.6%) patients. Mutational analyses of fifteen genes, including CEBPA , NPM1, FLT3, RUNX1 , ASXL1, TP53 , splicing factors (SF), such as SRSF2 , U2AF1 , and SF3B1 , as well as KIT , NRAS , KRAS , DNMT3A , TET2 , and WT1 were performed. FLT3- ITD/wild allelic ratios were calculated as the ratio of the area under the curve by fragment analysis. High FLT3- ITD allelic ratio ( FLT3- ITD high ) was defined as ³ 0.5 and low allelic ratio ( FLT3- ITD low ) defined as Results According to the 2017 ELN risk classification, favorable, intermediate and adverse categories comprised 34.6%, 29.2% and 36.2% patients, respectively. NPM1 mutations and FLT3 -ITD, the most common mutations in this cohort, were detected in 217 (20.9%) and 216 (20.8%) patients, respectively, with a significant association between each other. The median value of the FLT3- ITD/wild ratio was 0.68 without difference between NPM1 -mutated and NPM1 -wild group. Of note, patients with FLT3- ITD high had higher WBC count and LDH level than those with FLT3- ITD low . Overall, the CR rate and relapse rate were 74.2% and 54.7%, respectively and 5-year overall survival (OS) was 43.2±1.9%. The CR rate (92.3%) was higher in the 2017 ELN favorable risk group than in the intermediate (73.0%) and adverse groups (52.0%, P As to the prognostic impact of FLT3 -ITD, we showed that FLT3 -ITD patients had significantly lower CR rate, higher relapse rate, reduced DFS and OS than those without. There was a strikingly difference in treatment response between the low and high FLT3 -ITD allelic ratio groups: CR rate (80.7% vs. 63.6%, P=0.0319), relapse rate (56.5% vs. 66.2%, P=0.329), DFS (14.2 vs. 4.6 months P=0.011) and OS (24.0 vs. 11.9 months, P=0.048). Interestingly, patients with FLT3- ITD high had a better OS if they received allogeneic HSCT than those who did not. Among the 2017 ELN favorable-risk category, we found that patients with mutated NPM1 and FLT3- ITD low had significantly shorter OS (median, not reached vs. 31.6 months, P=0.003, Figure. 1A) and a trend of shorter DFS (median 14.9 months vs. 93.9 months, P=0.089, Figure. 1B) compared to other ELN favorable subgroups. To find the cause of the difference, we investigated the concurrent mutations in the patients with mutated NPM1 and FLT3- ITD low . 46.2% of them had concurrent poor-risk mutations, such as ASXL1 , RUNX1 , TP53 , WT1, TET2 , DNMT3A , and SF mutations. Similarly, among the 2017 ELN intermediate-risk category, patients with mutated NPM1 and FLT3- ITD high had more unfavorable outcomes compared to those with wild-type NPM1 and without FLT3 -ITD (DFS, median 3.7 vs. 11.6 months, P=0.028 and OS, median, 11.4 vs. 26.5 months, P=0.067). Presence of concurrent poor-risk mutations were also identified in 72.9% of these patients. Based on these findings, we postulated that concomitant poor-risk genetic alterations at least partially affected the prognosis of FLT3 /ITD patients. In the cohort of FLT3 -ITD patients, patients harboring poor-risk mutations had shorter DFS and OS than those without (P=0.028 and P=0.031, respectively). Further, co-occurrence of FLT3- ITD high and poor-risk mutations that predicted a worst outcome, seemed to define a highly adverse prognostic group. Conclusions We showed that ELN 2017 risk classification could well stratify AML patients in Taiwan. The prognostic relevance of FLT3 -ITD may further depend on the presence or absence of co-occurring poor-risk genetic alterations, which seemed to add an adverse effect in patients with FLT3 -ITD. These observations warrant confirmation in other prospective and large-scale studies. Disclosures Ko: Roche: Research Funding; GNT Biotech u0026 Medicals Crop.: Research Funding; Abbevie: Research Funding; Mumdipharma Taiwan: Consultancy.
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