**3.1 Classifications and prognostic scores systems in myelodysplastic syndrome**

Until 1980, the MDS included a variety of hematologic abnormalities classified as syndromes or pre-leukemic states. However, these denominations were unsatisfactory, not grouping all the patients who showed an ineffective hematopoiesis and not progressed to acute leukemia, occurring complications because of the cytopenias leading to death. The term "pre-leukemia" disappeared and the term myelodysplstic syndrome became widely accepted in 1982 with the FAB classification.

### **3.1.1 FAB classification**

In 1982, the FAB group (French, American and British group) proposed a classification for primary MDS into five subgroups: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t) and chronic myelomonocytic leukemia (CMML).

Epigenetics in Cancer: The Myelodysplastic Syndrome as a

Refractory cytopenias with unilineage dysplasia (**RCUD**)

Refractory anemia with ring sideroblasts

Refractory cytopenia with multilineage dysplasia (**RCMD**)

Refractory anemia with excess blasts-1

Refractory anemia with excess blasts-2

(**RAEB-1**)

(**RAEB-2**)

Syndrome 5q-

Myelodysplastic syndrome,

unclassified (MDS-U)

(**RARS**)

**Subgroup Peripheral Blood Bone marrow**

Unicytopenia or bicytopenia;

Anemia; No blasts

Cytopenia(s); or rare blasts (<1%); No Auer rods; monocytes <1 x 109/ L

Cytopenias; <5% blasts; No Auer rods; monocytes <1 x 109/ L

Cytopenias; 5-19% blasts; ± Auer rods;

Anemia;

Cytopenias; Blasts ≤1%

**3.1.3 Classification of myelodysplastic syndrome in childhood** 

Some studies have shown differences in morphological, cytogenetic, molecular and clinical manifestations of primary MDS in childhood that affect their inclusion in traditional classification systems (FAB and WHO), based mainly on adult patients. The rarity of childhood MDS and the heterogeneous nature of the disease have further contributed to the difficulties in classifying this disease (Hasle &Niemeyer, 2011). In 2003, Hasle and colleagues proposed a pediatric approach to the WHO classification of myelodysplastic syndrome: 1- MDS occurring both "de novo" and secondary, including the subtypes refractory cytopenia (RC), RAEB, and RAEB-t.; 2- a group of myelodysplastic/ myeloproliferative disorders with Juvenile Myelomonocytic Leukemia (JMML) as the most common disorder of this category; 3- myeloid leukemia of Down syndrome (DS), a disease with distinct clinical and biological features, encompassing both MDS and AML. In this classification, the minimal diagnostic criteria are: unexplained cytopenia (neutropenia,

Table 2. The WHO 2008 Classification of MDS.

monocytes <1 x 109/ L

No or rare blasts (<1%); Platelet count usually normal or increased

No or rare blasts (<1%)

Model to Study Epigenetic Alterations as Diagnostic and Prognostic Biomarkers 27

Unilineage dysplasia;

are dysplastic; <5% blasts; <15% ring sideroblasts

Erythroid dysplasia only;

≥15% ringed sideroblasts

more myeloid lineages;

<5% blasts;

<5% blasts; No Auer rods; ±15% ring sideroblasts

5-9% blasts; No Auer rods

10–19% blasts; ± Auer rods

<5% blasts;

abnormality; No Auer rods

<5% blasts; No Auer rods

≥10% of the cells of the affected lineage

Dysplasia in ≥10% of cells in two or

Unilineage or multilineage dysplasia;

Unilineage or multilineage dysplasia;

Normal to increased megakaryocytes

Dysplasia in <10% of the cells in one or

with hypolobated nuclei;

more myeloid lineages;

Isolated del(5q) cytogenetic


This classification was based on morphological characteristics and the percentage of blasts in the bone marrow and peripheral blood (Table 1) (Bennett et al., 1982).

Table 1. Classification of Myelodysplastic Syndrome according to the FAB Group in 1982.

As we can notice, this classification suggests multiple steps during the evolution from MDS to acute leukemia, being the initial stages the RA and RARS and the advanced stages the RAEB, RAEB-t and CMML. Since it was introduced, several studies have shown the usefulness of the FAB classification, both for monitoring a large number of patients with primary MDS, allowing comparisons between different studies, as for the treatment of patients. However, to determine a precise prognosis this classification still has some problems especially within initial subgroups, RA and RARS. The term "refractory anemia" is not always adequate, and anemia is only one of the three cytopenias in MDS. The CMML presents features of MDS and myeloproliferative diseases, so their inclusion in MDS classification has been discussed in more recent classifications like the World Health Organization (WHO) (Harris et al., 2000; Malcovati & Nimer, 2008).

### **3.1.2 WHO classification**

The classification of the World Health Organization (WHO) was established in 2000 and used many concepts and definitions of the FAB classification and also the knowledge of the cytogenetic and molecular features to improve the definition of subgroups, as well as clinical relevance in order to improve diagnostic criteria and improve the prognosis definition (Harris et al., 2000). The main difference between the two classifications is the disappearance of the subgroup RAEB-t, considered the evolution to AML from 20%of blasts in the bone marrow. The classification system proposed by WHO was reviewed in 2008 and consider the subgroups described in Table 2. In this new classification the subgroup CMML is regarded as a myeloproliferative disorder. The WHO categories have several important clinical implications (Brunning et al., 2008). Patients with unilineage dysplasia have a favorable outcome compared to patients with multilineage dysplasia (Jadersten & Hellstrom, 2008). The presence of del(5q) strongly correlates to the probability of response to lenalidomide (Oliva et al., 2010).

This classification was based on morphological characteristics and the percentage of blasts

**Blast cells (%) Auer** 

bone marrow

peripheral blood

**rods bone marrow** 

**Ringed Sideroblasts (%) bone marrow** 

**RA** No < 15 < 1 < 5 No **RARS** No > 15 < 1 < 5 No **RAEB** No No < 5 5 - 20 No

**RAEB-t** No No > 5 20 - 30 Yes or No

**CMML** > 1000 No < 5 < 20 No

Table 1. Classification of Myelodysplastic Syndrome according to the FAB Group in 1982.

Organization (WHO) (Harris et al., 2000; Malcovati & Nimer, 2008).

As we can notice, this classification suggests multiple steps during the evolution from MDS to acute leukemia, being the initial stages the RA and RARS and the advanced stages the RAEB, RAEB-t and CMML. Since it was introduced, several studies have shown the usefulness of the FAB classification, both for monitoring a large number of patients with primary MDS, allowing comparisons between different studies, as for the treatment of patients. However, to determine a precise prognosis this classification still has some problems especially within initial subgroups, RA and RARS. The term "refractory anemia" is not always adequate, and anemia is only one of the three cytopenias in MDS. The CMML presents features of MDS and myeloproliferative diseases, so their inclusion in MDS classification has been discussed in more recent classifications like the World Health

The classification of the World Health Organization (WHO) was established in 2000 and used many concepts and definitions of the FAB classification and also the knowledge of the cytogenetic and molecular features to improve the definition of subgroups, as well as clinical relevance in order to improve diagnostic criteria and improve the prognosis definition (Harris et al., 2000). The main difference between the two classifications is the disappearance of the subgroup RAEB-t, considered the evolution to AML from 20%of blasts in the bone marrow. The classification system proposed by WHO was reviewed in 2008 and consider the subgroups described in Table 2. In this new classification the subgroup CMML is regarded as a myeloproliferative disorder. The WHO categories have several important clinical implications (Brunning et al., 2008). Patients with unilineage dysplasia have a favorable outcome compared to patients with multilineage dysplasia (Jadersten & Hellstrom, 2008). The presence of del(5q) strongly correlates to the probability of response to

in the bone marrow and peripheral blood (Table 1) (Bennett et al., 1982).

**Subgroup Monocytes (l)** 

**3.1.2 WHO classification** 

lenalidomide (Oliva et al., 2010).

**peripheral blood** 


Table 2. The WHO 2008 Classification of MDS.
