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

Development of MDS/AML:
Role of Clonal Hematopoiesis, CHIP and CCUS

Development of MDS/AML: Role of Clonal Hematopoiesis, CHIP and CCUS

MDS/AML arises through the sequential acquisition of somatic mutations with oncogenic potential in hematopoietic stem cells (HSC). Acquisition of these mutations begins prior to MDS/AML and confers a growth advantage upon these cells, leading to their clonal expansion, a phenomenon known as clonal hematopoiesis (CH).10,11 Subsequent acquisition of mutations and clonal expansion can lead to a spectrum of clinical conditions of CH that include MDS and AML.

MDS/AML arises through the sequential acquisition of somatic mutations with oncogenic potential in hematopoietic stem cells (HSC). Acquisition of these mutations begins prior to MDS/AML and confers a growth advantage upon these cells, leading to their clonal expansion, a phenomenon known as clonal hematopoiesis (CH).10,11 Subsequent acquisition of mutations and clonal expansion can lead to a spectrum of clinical conditions of CH that include MDS and AML.

Relationship of MDS/AML with CHIP and CCUS.11,12

Relationship of MDS/AML with CHIP and CCUS.11,12

When these mutations are detected in peripheral blood or bone marrow with a variant allele frequency (VAF) ≥ 2% and without morphologic evidence of a hematologic disorder, the condition is defined as clonal hematopoiesis of indeterminant potential (CHIP).10,12 If CHIP is present with one or more persistent cytopenias that are unexplained by hematologic or non-hematologic conditions and that do not meet diagnostic criteria for defined myeloid neoplasms, it is defined as clonal cytopenia of undetermined significance (CCUS).12

CHIP and CCUS are associated with an increased risk of developing a myeloid neoplasm, with a higher risk imparted by CCUS13,14 — in one study, individuals with CCUS had a 14-fold risk of developing a myeloid neoplasm compared to patients without clonality, with a 10-year cumulative incidence of 95%.13

When these mutations are detected in peripheral blood or bone marrow with a variant allele frequency (VAF) ≥ 2% and without morphologic evidence of a hematologic disorder, the condition is defined as clonal hematopoiesis of indeterminant potential (CHIP).10,12 If CHIP is present with one or more persistent cytopenias that are unexplained by hematologic or non-hematologic conditions and that do not meet diagnostic criteria for defined myeloid neoplasms, it is defined as clonal cytopenia of undetermined significance (CCUS).12

CHIP and CCUS are associated with an increased risk of developing a myeloid neoplasm, with a higher risk imparted by CCUS13,14 — in one study, individuals with CCUS had a 14-fold risk of developing a myeloid neoplasm compared to patients without clonality, with a 10-year cumulative incidence of 95%.13

Cumulative probability of myeloid neoplasm in patients who have CCUS vs patients with no clonality.13

A CH risk score (CHRS) based on a model incorporating several risk factors has been proposed to stratify CHIP/CCUS according to low, intermediate, or high risk for progression to a myeloid neoplasm.14 The CRHS is available online at http://www.chrsapp.com/

In addition to an increased risk of myeloid neoplasms, CHIP/CCUS is associated with an increased risk of cardiovascular disease15 and all-cause death.16

A CH risk score (CHRS) based on a model incorporating several risk factors has been proposed to stratify CHIP/CCUS according to low, intermediate, or high risk for progression to a myeloid neoplasm.14 The CRHS is available online at http://www.chrsapp.com/

In addition to an increased risk of myeloid neoplasms, CHIP/CCUS is associated with an increased risk of cardiovascular disease15 and all-cause death.16

The MDS-AML Spectrum

The MDS-AML Spectrum

As described above, MDS and AML are part of a spectrum of disease resulting from successive acquisition of mutations during clonal hematopoiesis. A spectrum also exists between MDS and AML, with MDS skewing toward dysplasia and ineffective hematopoiesis, and AML skewing toward increased blasts.17,18

Guidelines are relaxing the traditional blast count cut-offs to suggest MDS-AML is more a spectrum of disease.11,12,19,21-23

Acquisition of mutations in stem cells disrupt the normal formation and differentiation of peripheral blood cells19,20 resulting in an increase in blast counts as MDS progresses to AML.11 The 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.12

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.12,23,24 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%.12,23 WHO 2022 eliminated blast cutoffs for most AML types with defining genetic alterations but retained a 20% blast cutoff to delineate MDS from AML.12 The lowered ICC 2022 blast cutoff suggests both the relevance of genetic alterations and that MDS-AML is a spectrum of disease.23

WHO 2016 and prior WHO classifications were mostly based on morphology and cytogenetics.25 WHO 2022 and ICC 2022 reorganized MDS categories by emphasizing histological and genetic co-variates with slightly different blast categories.12,23,26

Genetic Drivers of
MDS and AML

Genetic Drivers of MDS and AML

Mutated IDH1/2, recurrent genetic drivers, may be expressed in both MDS and AML patients as indicated by genetic profiling.20,27

Hematology studies have shed light on the impact of IDH1/2 mutations in MDS and AML. In MDS, mIDH1 and mIDH2 are considered early “driver” mutations, occurring in approximately 3.6% and 5% of MDS patients, respectively.27-30 As the disease progresses from low-risk MDS to high-risk MDS to AML, the frequency of mIDH1 and mIDH2 in patient populations increases, indicating its role in disease evolution.30-32 mIDH1 and mIDH2 also have been shown to be associated with direct transformation to AML from LR-MDS.33

In addition to transformation from MDS to AML, mIDH1 and mIDH2 have been shown to increase transformation to AML in patients who have CHIP. Although mIDH1 and mIDH2 are rare in CHIP, an analysis of the Women’s Health Initiative demonstrated that all 15 healthy subjects who had mIDH1 or mIDH2 at baseline developed AML after a median follow up of 9.6 years.34

Multivariable analysis of the risk to develop AML associated with the presence of mutated genes. Individuals who had an IDH1 or IDH2 mutation at baseline had a 28.5-fold odds of developing AML vs not developing AML.34

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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