Transcriptomically Defined Acute Myeloid Leukemia, Myelodysplasia-Related (AML-MR) Phenotype Governs Mutation-Based Disease Group Assignment

Introduction The revised 5^th edition of the World Health Organization Classification of Haematolymphoid Tumours and the 2022 European LeukemiaNet (ELN) genetic-risk classification have led to profound changes in the classification, risk assignment, and associated treatment options for AML pts. One of the major changes affects AML-MR. Pts with MR-mutations are now considered to have adverse-risk, except when MR-mutations co-occur with favorable-risk AML subtypes. However, AML-MR is a clinically and molecularly heterogeneous group with diverse clinical outcomes when treated with intensive chemotherapy. Although gene mutations and recurrent cytogenetic abnormalities are equally included as AML-MR-defining genetic events, the associations of specific genetic lesions with pretreatment features and clinical outcome may differ. Thus, data-driven support for the definition of AML-MR is needed to improve risk assignment and subsequent treatment guidance for pts. We hypothesized that better portrayal of tumor biology characterized by gene expression-based genetic phenotype may help refine AML-MR classification.

Methods We performed transcriptome-based gene-expression profiling and t-distributed stochastic neighbor embedding (t-SNE) data visualization on a clinically and molecularly well-characterized cohort of 971 newly diagnosed AML pts who were similarly treated with intensive chemotherapy on CALGB/Alliance frontline chemotherapy-based protocols. Using transcriptome-based gene-expression profiles of pts diagnosed with myelodysplastic neoplasms, we defined an MDS similarity score, which was almost exclusively found in a relatively large, central t-SNE cluster enriched for pts with AML-MR-defining genetic lesions. We recognized 3 pt groups (n=377 pts): pts with both AML-MR-defining genetic lesions and MR-expression profile (n=149), pts who had the MR-expression profile but not AML-MR-defining genetic lesions (n=99) and pts who harbored AML-MR-defining genetic lesions but did not have the MR-expression profile (n=129). Clinical and molecular characteristics and treatment outcomes of pts in these 3 groups were then compared.

Results Treatment outcomes of pts with MR-expression profile with and of those without AML-MR-defining genetic lesions were equally poor, whereas pts with AML-MR-defining genetic lesions but without the MR-expression profile had superior complete remission (CR) rates (43% vs 45% vs 69%, P<.001), and overall survival (OS; 3-y rates: 18% vs 14% vs 39%, P<.001). Because the outcome of pts with MR-expression profile who harbored AML-defining genetic lesions was very similar to outcome of pts with MR-expression profile who did not, we next combined these 2 pt groups into one MR-expression group (termed “MR-e”, n=248) and compared this group with the “mutation only” (“MR-mut”, n=129) group. Pts in the MR-e group were older than pts in the MR-mut group (median, 57 vs 48 y, P<.001). We next performed cell type quantifications using Dampened Weighted Least Squares (DWLS) based on our recently established single cell labels (Lasry et al, 2022) for deconvolution. Here, MR-e patients had a more HSC-like phenotype and a larger fraction of CD4+ T cells. In comparative survival analyses, MR-e patients had lower CR rates (44% vs 69%, P<.001), and worse OS (3-y rates: 15% vs 39% P<.001) than MR-mut pts. Within the 2022 ELN Favorable genetic-risk group, although pts with MR-expression profile had similar CR rates (60% vs 81%, P=.21), their OS was worse (3-y rates: 11% vs 60%, P<.001) than OS of MR-mut pts. In multivariable analyses, the presence of MR-e independently associated with lower CR rates (P=.004), adjusting for SF3B1 mutations and shorter OS (P<.001), adjusting for IDH1/2 mutations). Co-existing IDH1/2 mutations were the only identified genetic feature outweighing the negative prognostic effect of MR-e.

Conclusions We have identified an expression-based MDS-similarity score (MR-e) as a possible phenotypic correlate for AML-MR pts that also includes patients without AML-MR defining genetic lesions. Its presence portends very poor treatment outcome, especially in pts classified in the 2022 ELN Favorable genetic-risk group. In contrast, the absence of MR-e associates with better CR and OS in pts carrying AML-MR-defining lesions. Validation of these findings in an independent data set of intensive chemotherapy treated AML-MR patients is ongoing.