MDS-AML Spectrum

Background on MDS and AML

Background on MDS and AML

Myelodysplastic syndromes (MDS) are a clonal disorder of hematopoiesis characterized by ineffective maturation of blood cells.1,2 This results in varying degrees of peripheral blood cytopenias and is associated with a risk of progression to acute myeloid leukemia (AML).1,2 Individuals with MDS have a 1-in-3 chance of their disease transforming into secondary AML (sAML), which may have negative implications on disease management as well as overall survival (OS).3-5

While transformation to AML is the primary factor impacting mortality, untransformed MDS patients are also at increased risk of death due to causes including infection, uncontrolled bleeding/hemorrhage, stroke, and heart failure.6-8 Fatalities rise with increasing risk-group categorization in MDS, but low-risk patients also suffer increased mortality from MDS complications.7

Hemorrhage and cardiovascular disease (CVD) contribute to increased mortality rates in the untransformed MDS population, due to low platelet counts or iron overload from repeated blood transfusions.8,9

Myelodysplastic syndromes (MDS) are a clonal disorder of hematopoiesis characterized by ineffective maturation of blood cells.1,2 This results in varying degrees of peripheral blood cytopenias and is associated with a risk of progression to acute myeloid leukemia (AML).1,2 Individuals with MDS have a 1-in-3 chance of their disease transforming into secondary AML (sAML), which may have negative implications on disease management as well as overall survival (OS).3-5

While transformation to AML is the primary factor impacting mortality, untransformed MDS patients are also at increased risk of death due to causes including infection, uncontrolled bleeding/hemorrhage, stroke, and heart failure.6-8 Fatalities rise with increasing risk-group categorization in MDS, but low-risk patients also suffer increased mortality from MDS complications.7

Hemorrhage and cardiovascular disease (CVD) contribute to increased mortality rates in the untransformed MDS population, due to low platelet counts or iron overload from repeated blood transfusions.8,9

The MDS-AML Spectrum

The MDS-AML Spectrum

While MDS and AML are both characterized by an excess of myeloblasts and cytopenias, MDS skews toward dysplasia and ineffective hematopoiesis, whereas AML skews toward increased “blasts”.10,11 As the spectrum of disease progresses, stem cells acquire mutations that disrupt the normal formation and differentiation of peripheral blood cells.12,13

Guidelines are relaxing the traditional blast count cut-offs to suggest MDS-AML is more a spectrum of disease.12,14-18

MDS and AML are now thought to be part of a spectrum of disease, with blast counts increasing as MDS progresses to AML.14 This blast count cutoff is traditionally defined at 20%; however, guidelines are rapidly changing to reflect the overlap of the two related disease states and to take into account mutational status, which may influence risk stratification.15

Updated Guidelines Reflect
MDS-AML Spectrum

Updated Guidelines Reflect MDS-AML Spectrum

Recent changes to the World Health Organization (WHO) and International Consensus Classification (ICC) classifications reflect a move away from morphological definition of disease and toward a genetic basis for defining MDS and AML.15,18,19 The ICC has refined the bone marrow blast categories for MDS from <5% to 9% and created a new MDS/AML category for 10%-19% blasts, whereas the WHO categories of MDS-IB2 and MDS-f retain blast counts up to 19%.15,18 WHO 2022 eliminated blast cutoffs for most AML types with defining genetic alterations but retained a 20% blast cutoff to delineate MDS from AML.15 The lowered ICC 2022 blast cutoff suggests both the relevance of genetic alterations and that MDS-AML is a spectrum of disease.18

WHO 2016 and prior was mostly based on morphology and cytogenetics.20 WHO 2022 and ICC 2022 reorganized MDS categories by emphasizing histological and genetic co-variates with slightly different blast categories.15,18,21

Genetic Drivers of
MDS and AML

Genetic Drivers of MDS and AML

Mutated IDH, a recurrent genetic driver, may be expressed in both MDS and AML patients as indicated by genetic profiling.13,22

Hematology studies have shed light on the impact of IDH1 mutations in MDS and AML, revealing a poorer prognosis for patients with these mutations compared to those with IDH2 mutations or IDH wild-type.23,24 In MDS, IDH1 mutations are considered early “driver” mutations, occurring in approximately 3.6% of MDS patients.22-25 As the disease progresses from low-risk MDS to high-risk MDS to AML, the frequency of mIDH1 in patient populations increases, indicating its role in disease evolution.25-27

Clinical Crossfire: Expert
Discussion on MDS and AML

Clinical Crossfire: Expert Discussion on MDS and AML

Expert Joshua Zeidner, MD discusses recent updates to the ICC and WHO classification of AML and MDS.

Expert Uma Borate, MD discusses the impact of high-risk mutations on MDS to AML progression.

What additional topics in IDH science
would you like to hear about?

What additional topics in IDH science would you like to hear about?

LearnMore about the prognostic impact of mIDH in MDS and AML LearnMore about the prognostic impact of IDH mutations in Glioma

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References:

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