EBMT 2025 | The role of NGS profiling in patients with AML undergoing alloSCT

AML is a very heterogeneous hematological malignancy, which includes numerous genetically defined subsets. The genomic classification of AML with the identification of mutations in the transcription factors, epigenetic modifiers, spliceosome, cohesion complex, and signaling pathways led to a more accurate risk stratification model. However, in the context of allogeneic hematopoietic stem cell transplant, the frequency and prognostic value of different gene-gene interactions has not been studied and may differ from that of patients treated with chemotherapy alone. 

So therefore, we realized a retrospective registry-based analysis using the EBMT registry to assess the frequency and impact of different recurrent somatic mutation alone or in association on the prediction of relapse and survival in patients receiving allotransplant. 

So we included adult patients with AML, first allotransplant between 2013 and 2023, with available genetic profile at diagnosis by next-generation sequencing. So we could identify 952 allografted AML patients, 77% had de novo AML, 76% were allografted in first complete remission. So the median number of genes in the NGS panel was 40. And when we looked at the somatic mutations, the median number of somatic mutations per patient was two with an IQR from one to four. Eight percent of patients had no detected mutation. 28 percent had four or more mutations. And the frequency was a bit different from that of AML at diagnosis, with the most frequent mutation being DNMT3A, followed by FLT3-ITD, NPM1, RUNX1, and NRAS. 

And then we assessed the association of somatic mutations by investigating the most frequently mutated genes, more than 5% positivity, and the gene tested in at least 800 patients. And 12 genes satisfied these criteria. These were NPM1, FLT3-ITD, DNMT3A, RUNX1, ASXL1, SRSF2, TET2, IDH1, IDH2, KRAS, NRAS, and TP53. Then we assessed association of these genes. and basically we find by multiple correspondence analysis, three groups of mutations close to each other. The DNMT3A, NPM1, and FLT3-ITD, this is one group. ASXL1, SRSF2, and RUNX1, this is one group. IDH1, IDH2, and TET2, this is a third group. 

So when we look to the outcome for patients allografted in first complete remission, basically if you take the outcome by single mutation, then NPM1, FLT3, and IDH2 had a positive effect on survival. Conversely, TP53 had a negative effect on survival. 

Importantly, when assessing groups of mutations, we found that the two-year outcome were excellent for patients with NPM1 mutation in the absence of TP53 and regardless of other co-mutations with a two-year overall survival of 82%, as well as in the presence of RUNX1 and/or ASXL1 and/or SRSF2 mutation with a two-year overall survival of 81%. Conversely, outcomes were much less favorable for patients with TP53 mutation, two-year survival 47%, or patient with all 10 genes unmutated, two-year survival 67%. So despite their older age and higher frequency of secondary AML and adverse cytogenetics, the excellent outcome for patients harboring what we call the SAR mutation for SRSF2, ASXL1, and RUNX1 indicate that allotransplant can overcome their adverse risk at diagnosis.

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