Understanding the Continuum between High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia

Abstract

Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm characterized by bone marrow dysplasia, failure of hematopoiesis and variable risk of progression to acute myeloid leukemia (AML). Recent large-scale studies have demonstrated that distinct molecular abnormalities detected at earlier stages of MDS alter disease biology and predict progression to AML. Consistently, various studies analyzing these diseases at the single-cell level have identified specific patterns of progression strongly associated with genomic alterations. These pre-clinical results have solidified the conclusion that high-risk MDS and AML arising from MDS or AML with MDS-related changes (AML-MRC) represent a continuum of the same disease. AML-MRC is distinguished from de novo AML by the presence of certain chromosomal abnormalities, such as deletion of 5q, 7/7q, 20q and complex karyotype and somatic mutations, which are also present in MDS and carry crucial prognostic implications. Recent changes in the classification and prognostication of MDS and AML by the International Consensus Classification (ICC) and the World Health Organization (WHO) reflect these advances. Finally, a better understanding of the biology of high-risk MDS and the mechanisms of disease progression have led to the introduction of novel therapeutic approaches, such as the addition of venetoclax to hypomethylating agents and, more recently, triplet therapies and agents targeting specific mutations, including FLT3 and IDH1/2. In this review, we analyze the pre-clinical data supporting that high-risk MDS and AML-MRC share the same genetic abnormalities and represent a continuum, describe the recent changes in the classification of these neoplasms and summarize the advances in the management of patients with these neoplasms.

Keywords: AML with MDS-related changes; MDS; classification; molecular alterations; therapeutic approaches.

Figure 1

The classification algorithm of MDS based on the new changes. ¹ Diagnosis of MDS/AML or AML with mutated TP53 can be made with any somatic TP53 mutation with VAF > 10%, whereas MDS with mutated TP53 requires the presence of a multi-hit TP53 mutation or a TP53 mutation (VAF > 10%) and a complex karyotype, often with loss of 17p if LOH information is not available. A multi-hit TP53 mutation is defined as either two distinct TP53 mutations, each with VAF > 10%, or a single TP53 mutation with either 17p deletion on cytogenetics, VAF ≥ 50%, or copy-neutral LOH at the 17p locus. Abbreviations: MDS, myelodysplastic syndromes; AML, acute myeloid leukemia; EBs, excess blasts; NOS, not otherwise specified; CCUS, clonal cytopenia of undetermined significance.

Figure 2

The classification algorithm of AML based on the new changes. (A) AML with recurrent genetic abnormalities takes precedence in the diagnostic algorithm, and the blast cut-off for diagnosis is lowered to 10%, with the exception of BCR::ABL-mutated AML. Within this group, PML::RARA mutations supersede RUNX1::RUNX1T1 mutations, followed by CBFB:MYH11, then MLLT3:KMT2A, then DEK::NUP214, then GATA2;MECOM(EV11), followed by other rare recurring translocations as depicted below, then BCR.:ABL1, then NPM1, and last in-frame bZIP CEBPA mutations. Among the remaining categories, (B) TP53-mutated AML supersedes (C) AML with myelodysplasia-related gene mutations and the latter supersedes (D) AML with myelodysplasia-related cytogenetic abnormalities. If none of the aforementioned genetic abnormalities are present, then AML is defined as (E) not-otherwise specified. ¹ Acute myeloid leukemia (AML) with other rare recurring translocations includes the following: t(1;3)(p36.3;q21.3)/PRDM16::RPN1, t(3;5)(q25.3;q35.1)/NPM1::MLF1, t(8;16)(p11.2;p13.3)/KAT6A::CREBBP, t(1;22)(p13.3;q13.1)/RBM15::MRTF1, t(5;11)(q35.2;p15.4/NUP98::NSD1, t(11;12)(p15.4;p13.3)/NUP98::KMD5A, NUP98 and other partners, t(7;12)(q36.3;p13.2)/ETV6::MNX1, t(10;11)(p12.3;q14.2)/PICALM::MLLT10, t(16;21)(p11.2;q22.2)/FUS::ERG, t(16;21)(q24.3;q22.1)/RUNX1::CBFA2T3, inv(16)(p13.3q24.3)/CBFA2T3::GLIS2. ² The MDS/AML category is not applicable due to its overlap with progression of BCR::ABL1-positive CML. Abbreviations: MDS, myelodysplastic syndromes; AML, acute myeloid leukemia; NOS, not otherwise specified.