Improving risk stratification for 2022 European LeukemiaNet favorable-risk patients with acute myeloid leukemia

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Assignment of patients diagnosed with acute myeloid leukemia (AML) to the 2022 European LeukemiaNet (ELN) Favorable genetic-risk group has important clinical implications, as allogeneic stem-cell transplantation in first complete remission (CR) is not advised due to a relatively good outcome of patients receiving chemotherapy alone and transplant-associated mortality. However, not all Favorable genetic-risk patients experience long-term relapse-free survival (RFS), making recognition of patients who would most likely be cured of high importance. We analyzed 297 patients aged <60 years with de novo AML classified as 2022 ELN Favorable genetic-risk who achieved a CR and had RNA-seq and gene mutation data from diagnostic samples available (Alliance trial A152010). To identify prognostically relevant transcripts that can distinguish patients cured from patients susceptible to lower- or higher-risk of relapse or death, we fit a regularized mixture cure model (MCM), where RNA-seq expression values were our candidate covariates. To validate the identified transcripts, we analyzed 75 patients with de novo AML aged <60 years included in the 2022 ELN Favorable genetic-risk group who achieved a CR in an independent test set from Gene Expression Omnibus (GSE37642). Our MCM identified 145 transcripts associated with cure, or long-term RFS, and 149 transcripts associated with latency, or shorter-term time-to-relapse. The area under the curve and C-statistic were, respectively, 0.946 and 0.856 for our training and 0.877 and 0.857 for our test sets. Our results suggest that the Favorable-risk group includes distinct transcriptionally defined subgroups with different biological properties, which may be useful for refining this genetic-risk category.