Myelodysplastic syndrome (MDS)

  • Method:
  • Anticoagulant:
  • Recommendation:
  • Method:
    Cytomorphology
  • Anticoagulant:
    EDTA
  • Recommendation:
    obligatory
  • Method:
    Immunophenotyping
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Chromosome analysis
  • Anticoagulant:
    Heparin
  • Recommendation:
    obligatory
  • Method:
    FISH
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    facultative
  • Method:
    Molecular genetics
  • Anticoagulant:
    EDTA or Heparin
  • Recommendation:
    obligatory

A myelodysplastic syndrome (MDS) is an acquired clonal bone marrow disease that occurs primarily in older age (mean age of onset 70 years) and with an age-related incidence of 4-50/100,000 per year. Starting from a pluripotent haematopoietic stem cell, it often causes anaemia, but also neutropenia and/or thrombocytopenia. Dysplasia signs can be recognized in at least one of the three hematopoietic cell lines and leukemic transformations/transitions to acute myeloid leukemia are frequent.

Classification of MDS

While the classification of myelodysplastic syndromes (MDS) used to be based exclusively on FAB via cytomorphology, the WHO has also included cytogenetics and clinical characteristics. In addition, molecular markers are being investigated with regard to their significance in MDS and are increasingly being implemented in routine. Below you will find the current classification of myelodysplastic syndromes (MDS) according to WHO 2017.


MDS WHO Classification 2017 (Swerdlow et al. 2017)

Myelodysplastic syndromes (MDS)

  • MDS with single lineage dysplasia (MDS-SLD)

  • MDS with ring sideroblasts (MDS-RS)

    • MDS-RS and single lineage dysplasia

    • MDS-RS and multilineage dysplasia

  • MDS with multilineage dysplasia (MDS-MLD)

  • MDS with excess blasts (MDS-EB)

  • MDS with isolated del(5q)

  • MDS, unclassifiable (MDS-U)

  • Childhood myelodysplastic syndrome

Diagnostic criteria for myelodysplastic syndrome

The morphological classification of myelodysplastic syndrome (MDS) is basically based on the percentage of blasts in bone marrow and peripheral blood, the form and degree of dysplasia and the percentage of ring sideroblasts in bone marrow (see Table 1).

Table 1: Diagnostic criteria for myelodysplastic syndrome

(Swerdlow et al. 2017)

Entity

Number of dysplastic lineages
Number of cytopeniasa

Ring sideroblasts as percentage of marrow erythroid elements

Bone marrow (BM) and peripheral blood (PB) blasts)

Cytoegenetics by conventional karyotype analysis

MDS with single lineage dysplasia (MDS-SLD)

1

1 or 2

< 15% / < 5%b

BM < 5%, PB < 1%, no Auer rods

Any, unless fulfils all criteria for MDS with isolated del(5q)

MDS with multilineage dysplasia (MDS-MLD)

2 or 3

1-3

< 15% / < 5%b

BM < 5%, PB < 1%, no Auer rods

Any, unless fulfils all criteria for MDS with isolated del(5q)

MDS with ring sideroblasts (MDS-RS)

MDS-RS with single lineage dysplasia (MDS-RS-SLD)

1

1 or 2

≥ 15% / ≥ 5%b

BM < 5%, PB < 1%, no Auer rods

Any, unless fulfils all criteria for MDS with isolated del(5q)

MDS-RS with multilineage dysplasia (MDS-RS-MLD)

2 or 3

1-3

≥ 15% / ≥5%b

BM < 5%, PB < 1%, no Auer rods

Any, unless fulfils all criteria for MDS with isolated del(5q)

MDS with isolated del(5q)

1-3

1 or 2

None or any

BM < 5%, PB < 1%, no Auer rods

del(5q) alone or with 1 additional abnormality, except loss of

chromosome 7 oder del(7q)

MDS with excess blasts (MDS-EB)

MDS-EB-1

1-3

1-3

None or any

BM 5-9% or PB 2-4%, no Auer rods Auerstäbchen

any

MDS-EB-2

1-3

1-3

None or any

BM 10-19% or PB 5-19% or Auer rods

any

MDS, unclassifiable (MDS-U)

with 1% blood blastsc

1-3

1-3

None or any

BM < 5%, PB = 1%c, no Auer rods

any

with single lineage dysplasia and pancytopenia

1

3

None or any

BM < 5%, PB < 1%, no Auer rods

any

due to certain cytogenetic abnormalities

0

1-3

< 15%d

BM < 5%, PB < 1%, no Auer rods

MDS defining abnormalitye


a Cytopenia defined as haemoglobin concentration < 10 g/dl, platelet count < 100 x 109/l and absolute neutrophil count < 1.8 x 109/l
b if SF3B1 mutation is present
c 1% PB blasts must be recorded on > 2 separate occasions
d Cases with ≥ 15% ring sideroblasts by definition have significant erythroid dysplasia and are classified as MDS-RS-SLD
e see Table 2

Diagnostics of MDS

Prognosis of MDS

IPSS-R: Risk startification for MDS

For many years the "International Prognostic Scoring System" (IPSS), which was first published by Peter Greenberg in 1997 (Greenberg et al. 1997), was the main pillar of prognosis classification for patients with myelodysplastic syndrome (MDS). Prognostically relevant parameters are the proportion of bone marrow blast, the cytogenetic risk group and the number of relevant cytopenia. For an improved or more detailed risk stratification of patients with myelodysplastic syndrome (MDS) the IPSS was revised in 2012 (Revised-IPSS, "IPSS-R") (Greenberg et al. 2012, see Table 6). This should now be used.

The components used to determine the IPSS-R are the percentage of blasts in the bone marrow, the degree of cytopenia (Hb value as well as the number of platelets and neutrophils) and the cytogenetic risk group according to Schanz et al. 2012 (see Table 6 and Figure 1 in the section 'Classification of MDS into 5 cytogenetic risk groups'). The scoring points determined from this result in the classification of patients into five clinically relevant risk groups:

  • "very low": ≤ 1.5

  • "low": > 1.5-3

  • "intermediate": > 3-4.5

  • "high": > 4.5-6

  • "very high": > 6

Table 6: Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndrome

(Greenberg et al. 2012)

Parognostic variable

Scoring points

 

0
0.5
1.0
1.5
2.0
3.0
4.0

Cytogenetics

very good

 

good

 

intermediate

poor

very poor

BM-Blasts (%)

≤ 2

 

> 2 - < 5

 

5-10

> 10

 

Hemoglobin (g/dl)

≥ 10

 

8 - < 10

< 8

 

 

 

Platelets (x 109/l)

≥ 100

50 - < 100

< 50

 

 

 

 

ANC (x 109/l)

≥ 0.8

< 0.8

 

 

 

 

 

The risk model is predictive both for the estimation of overall survival and for the transformation to secondary AML according to MDS (s-AML) (see Table 7). At the same time, it offers the possibility of age-adapted modification of the score. It thus enables the best possible risk stratification for patients with myelodysplastic syndrome (MDS) without taking into account previous findings in molecular genetics. Please note the different blast limits of the IPSS-R and the WHO 2017.

Table 7: IPSS-R prognostic risk category clinical outcomes

(according to Greenberg et al. 2012)

IPSS-R risk group

very low

low

intermediate

high

very high

OS, all

8.8

5.3

3.0

1.6

0.8

HR AML

0.5

1.0

3.0

6.2

12.7


OS: median overall survival in years, HR: AML Hazard-Ratio transformation to AML

Recommendation for MDS

Peripheral blood diagnostics and cytomorphological bone marrow diagnostics in combination with cytogenetics represent the current gold standard in MDS diagnostics (Onkopedia Guideline MDS 2020). The European Leukemia Competence Network ("European LeukemiaNet" ELN, Malcovati et al. 2013) specifies in detail the methods summarised in Table 8.

Table 8: Diagnostic methods for myelodysplastic syndrome (MDS)

according to ELN (2013)
MethodDiagnostic value
Priority

Peripheral blood smear

  • Evaluation of dysplasia in one or more cell lines
  • Enumeration of blasts

mandatory

Bone marrow aspirate

  • Evaluation of dysplasia in one or more hematopoietic cell lines
  • Enumeration of blasts
  • Enumeration of ring sideroblasts

mandatory

Bone marrow biopsy

  • Assessment of cellularity, CD34+ cells, and fibrosis

mandatory

Cytogenetic analysis

  • Detection of acquired clonal chromosomal abnormalities that can allow a conclusive diagnosis and also prognostic assessment

mandatory

FISH

  • Detection of targeted chromosomal abnormalities in interphase nuclei following repeated failure of standard G-banding

recommended

Flow cytometry immunophenotyping

  • Detection of abnormalities in erythroid, immature myeloid, maturing granulocytes, monocytes, immature and mature lymphoid compartments

recommended

SNP array

  • Detection of chromosomal defects at a high resolution in combination with metaphase cytogenetics

suggested

Mutation analysis of candidate genes

  • Detection of somatic mutations that can allow a conclusive diagnosis and also reliable prognostic evaluation

suggested

MDS-Therapy

The therapy of a myelodysplastic syndrome (MDS) according to German guidelines depends amongs others on the risk group as well as the age and clinical condition of the patients (Onkopedia guideline MDS 2020). In addition to cytogenetics, which is included in risk stratification and therapy selection, the German guideline also classifies the molecular genetic analysis of the genes listed in Table 9 as clinically relevant.

Table 9: Clinically relevant molecular markers

(according to Onkopedia guideline MDS 2020)

Function

Mutation

Splicing

SF3B1, SRSF2, U2AF1, ZRSR2

Methylation

DNMT3A, TET2

Methylation/Histone modification

IDH1/2

Histone modification

ASXL1, EZH2

Transcription factor

RUNX1, TP53, BCOR, ETV6

Signaling

NRAS/KRAS

The therapeutic breadth in low-risk MDS (IPSS-R score "very low", "low" and "intermediate") ranges from a watch-and-wait strategy (in the presence of asymptomatic cytopenia and absence of high-risk cytogenetics), through supportive therapies to the indication for allogeneic stem cell transplantation. The latter may be indicated in good clinical condition and in the presence of high-risk cytogenetics and/or pancytopenia. The group of patients with isolated del(5q) shows good response to the immunomodulator lenalidomide (Oncopedia Guideline MDS 2020).

In the group of high-risk MDS (IPSS-R score "high" and "very high") azacitidine, chemotherapy and allogeneic stem cell transplantation (allo-SZT) are the main pillars of therapy (Onkopedia Guideline MDS 2020).


Influence of genetic abnormalities on azacitidine therapy

In line with the effect of azacitidin as a DNA hypomethylating agent (HMA), there is evidence for a possible association between genetic abnormality and treatment response, especially in the case of mutations of epigenetic factors. In one study, azacitidin resistance was associated with DNMT3A R882 mutations and mutations of the SKI domain of SETBP1 (Falconi et al. 2019). In contrast, patients with TET2 mutation (without concurrent ASXL1 mutation) showed a particularly high sensitivity to HMAs (Itzykson et al. Leukemia 2011, Bejar et al. Blood 2014). However, in comparison of patients with mutated and wild type TET2 there were no significant differences in overall survival and duration of response (Itzykson et al. Leukemia 2011, Bejar et al. Blood 2014).

Cytogenetic abnormalities may also influence the response to azacitidine. In one study, abnormal karyotypes were associated with a reduced response rate to azacitidine therapy and complex karyotypes with a shortened response time (Itzykson et al. Blood 2011, Kubasch & Platzbecker 2019). Patients with abnormalities of chromosome 7 had a survival advantage compared to conventional therapy by treatment with azacitidine (Raj et al. 2007, Rüter et al. 2007, Fenaux et al. 2009).


Gene mutations with potential influence on therapy decisions

NPM1 mutations

NPM1 mutations are extremely rare with an estimated mutation frequency of 2% in patients with myelodysplastic syndrome (MDS). Their presence should give rise to a thorough differential diagnosis, since they can also occur in the context of CMML. Due to the rarity it is unclear which therapy regimen is suitable for this patient group. The largest study to date includes a cohort of 31 patients with MDS and MDS/MPN neoplasias. In a comparison of the four therapeutic arms (HMA, HMA + allo-SZT, intensive chemotherapy, intensive chemotherapy + allo-SZT), intensive chemotherapy was superior to HMA treatment in terms of response rates and progression-free and overall survival. Patients on the HMA therapy arm also benefited significantly from allogeneic stem cell transplantation (Montalban-Bravo et al. 2019).

TP53 mutations

The mutation status of TP53 plays a role in therapy planning in several ways.

While patients with isolated 5q deletion benefit from treatment with lenalidomide, TP53 mutations against this genetic background are associated with a reduced response and an increased risk of progression (Jädersten et al. 2011). Therefore, a TP53 mutation analysis should be performed before the administration of lenalidomide and the use of lenalidomide despite TP53 mutation detection should only take place after thorough consideration and under close monitoring of clonal evolution (Onkopedia guideline MDS 2020).

According to the German guideline, an indication for an allogeneic stem cell transplantation should be considered also for younger low-risk patients, among others in the presence of prognostically unfavourable genetic markers such as ASXL1 and TP53 mutations (Onkopedia Guideline MDS 2020). The TP53 mutation status should also be known for the choice of conditioning regimen, as patients with TP53 mutation do not benefit from myeloablative conditioning (Lindsley et al. 2017). However, a TP53 mutation retains its negative prognostic value with regard to overall survival even after allogeneic stem cell transplantation (Bejar et al. JCO 2014, Della Porta et al. 2016, Lindsley et al. 2017, Sperling et al. 2017). Further studies are needed to improve survival after transplantation in this patient group (Steensma et al. 2018).

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