Genetic Factors in Acute Myeloid Leukemia With Myelodysplasia-Related Changes

A Study of 186 Cases

Hong Fang, MD; Rong He, MD; April Chiu, MD; David S. Viswanatha, MD; Rhett P Ketterling, MD; Mrinal S. Patnaik, MBBS; Kaaren K. Reichard, MD


Am J Clin Pathol. 2020;153(5):656-663. 

In This Article

Abstract and Introduction


Objectives: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous category with a broad range of underlying genetic abnormalities. We investigated the significance of genetic factors in a large series of AML-MRC cases.

Methods: The morphologic findings, genetic data, and patient outcomes were assessed in 186 AML-MRC cases.

Results: The median overall survival (OS) was dismal in AML-MRC patients (median, 7.6 months; 95% confidence interval, 5–10.6 months). Karyotypically normal cases and cytogenetically abnormal cases without myelodysplastic syndrome (MDS)-related cytogenetic abnormalities showed similar OS, significantly better than cases carrying MDS-related cytogenetic abnormalities. MDS-related cytogenetic abnormalities, monosomal or complex karyotype, and history of MDS or myelodysplastic/myeloproliferative neoplasm were all associated with dismal outcome.

Conclusions: AML-MRC predicts a poor prognosis. Our study supports the finding that the genetic profile plays a key role in determining prognosis in AML-MRC as defined according to the World Health Organization revised fourth edition (2017) diagnostic criteria.


The concept of acute myeloid leukemia (AML) with multilineage dysplasia (MLD) was initially introduced in the 1980s.[1,2] This category was first formally integrated in the World Health Organization (WHO) classification of AML in 2001, and was defined as an AML with 20% or more peripheral blood or bone marrow blasts and with dysplasia in at least 50% of the cells in at least two cell lineages.[3] After being challenged with respect to its clinical relevance, a new entity named AML with myelodysplasia-related changes (AML-MRC) was introduced in the fourth edition of the WHO classification.[4] By definition, it included three subcategories of cases with 20% or more blasts in peripheral blood or bone marrow plus at least one of the following criteria: (1) a history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN); (2) presence of MDS-related cytogenetic abnormalities; and/or (3) dysplasia in at least 50% of the cells in at least two cell lineages. In the updated revised fourth edition of the WHO classification of myeloid neoplasms,[5] in order to better align the prognosis with molecular data, de novo AML cases showing MLD alone and harboring an NPM1 or biallelic CEBPA mutation are no longer classified as AML-MRC. This is due to the demonstration of improved outcome, similar to those AML cases with these mutations but without MLD.[6,7] In addition, the cytogenetic abnormality del(9q) has been removed from the cytogenetic criteria sufficient to diagnose AML-MRC due to its association with NPM1 or biallelic CEBPA mutations and its lack of prognostic significance in the presence of these mutations.[5]

The recognition of AML-MRC as a distinct entity has been driven by the presence of distinctive clinical, pathologic, and survival features. It has an overall poor prognosis with a lower rate of complete remission than AML not otherwise specified (AML-NOS), although allogeneic hematopoietic stem cell transplant may overcome the poor prognosis of AML-MRC.[5,8–12] Many prognostic factors have been proposed and continue to be under evaluation, including age, various subtypes of cytogenetic abnormalities, and history of MDS or MDS/MPN.[12–15] Vardiman et al[14] reported that most cases of AML-MRC were associated with adverse genetic abnormalities, particularly –5/del(5q), −7/del(7q), and/or complex karyotype (CK). A few studies have shown that AML with monosomal karyotype (MK) presented with a significantly worse overall survival, disease-free survival, and complete response rate and predominantly was subclassified as AML-MRC, suggesting MK as a possible stronger adverse prognostic factor than the traditionally defined CK.[16–18] Since the introduction of AML-MRC, the specificity of sole MLD to define its prognostic significance has been actively debated, particularly in cases harboring NPM1 or biallelic CEBPA mutations.[6,7,19,20] In addition, recent studies have reported a number of other somatic mutations and cytogenetic aberrations that may affect the outcome of patients with AML-MRC, and further investigations may allow for additional genomic refinement of this entity in the future.[21–25] In this study, we aimed to study the clinicopathologic features of a large series of AML-MRC patients seen at our institution and explore the clinical significance of the three subcategories in AML-MRC.