C087 | Integration of Next Generation Sequencing in Measurable Residual Disease Detection and Prognostic Stratification in Acute Myeloid Leukemia and Myelodysplastic Neoplasm
Year: 2025
Type: article
Abstract: Recent data demonstrated the role of somatic mutations in diagnosis and risk stratification of myelodysplastic neoplasms(MDS) and acute myeloid leukemia(AML). This prospective study assessed gene mutation dynamics by next-generation sequencing(NGS) in 84 high-risk MDS/AML patients treated with standard chemotherapy (N76) or hypomethylating agents plus venetoclax (N8). NGS analysis of 30 genes (MYS,SOPHiA Genetics) was performed at diagnosis, at complete remission (CR), at relapse and before and after allogeneic transplantation(alloHSCT). Median age at diagnosis was 63 years.After a median follow-up of 26 months 46% of patients relapsed, 37% underwent alloHSCT and 34% died.Ninety-five percent of patients had somatic mutations by NGS at diagnosis, whereas only 29% had a molecular marker for measurable residual disease (MRD) detection by qPCR. NGS analysis at CR was performed in 56/71 patients who achieved CR and in 59% mutations persisted at variable variant allele frequencies (1-83%),predominantly in DNMT3A,TET2 and ASXL1 (DTA mutations).Persistent mutations in CR predicted higher relapse (78% vs 22%),worse RFS (median 8 months vs NR,p<0.001) and shorter OS (2-year OS: 55% for DTA-mutations, 48% for non-DTA, 87% for no mutations, p=0.003). NGS and multiparameter flow cytometry (MFC) were concordant in detecting MRD in 50% of cases.By combining the MRD detection with both techniques we divided patients into 3 groups with significantly different RFS and OS,favoring double-negative patients:NGS-/MFC-(N9), NGS-/MFC+ or NGS+/MFC- (N26) and NGS+/MFC+(N21),p<0.001(Figure 1). By multivariate analysis NGS,qPCR and MFC MRD were independent predictors of RFS. NGS before transplantation was performed in 19/31 transplanted patients.The persistence of DTA or non-DTA mutations before alloHSCT was associated with shorter OS(median 18 months vs median NR, p<0.038).The reappearance after alloHSCT of a pre-existing mutation preceded clinical relapse in 2 out of 3 patients that were MRD negative before transplant. NGS is not yet recommended as a stand-alone technique in clinical practice given lack of standardization and incomplete validation of its target mutations.However,in our real-world setting, NGS analysis performed with a commercially available kit successfully integrated into diagnostics of MDS/AML patients improving MRD detection and relapse prediction. While requiring validation in larger cohorts, this approach may improve treatment strategies and patient prognosis.
Authors: E. Crisà, I. Dogliotti, G. Lia, M. Cerrano, E. Audisio, G. Lanzarone, L. Brunello, D. Caravelli, F. Carnevale Schianca, E. Berrino, S. E. Bellomo, A. Bartolini, P. Francia Di Celle, L. Riera, G. Gaidano, M. Lunghi, L. Giaccone, B. Bruno
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7093121868
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