Myelodysplastic syndromes (MDS) are a group of clonal myeloid neoplasms characterized by ineffective hematopoiesis that present clinically as cytopenia(s), dysplasia in one or more hematopoietic cell lines in the bone marrow, and risk of transformation to acute myeloid leukemia (AML).[1]
See Myelodysplastic Syndromes: Classification, Features, Diagnosis, and Treatment Options, a Critical Images slideshow, to help identify, classify, work up, and treat these disorders.
Evidence of clonality often supports the diagnosis of MDS and may manifest as recurrent karyotypic or molecular genetic abnormalities, although these findings are not necessary to fulfill the diagnostic criteria.
MDS represent several molecularly unique entities whose variation makes constructing a concise and practical framework difficult. However, with ever-increasing knowledge of the biology and molecular heterogeneity of myeloid neoplasms comes the ability to further classify MDS with prognostic and predictive relevance. Furthermore, there is increasing recognition that some higher-risk MDS have considerable biologic and prognostic overlap with MDS-related AML. As such, in 2022, the World Health Organization (WHO) updated its classification of myelodysplastic syndromes, replacing the term "syndromes" with "neoplasms" to reflect the neoplastic biology of these diseases.[2]
While the Revised International Prognostic Scoring System (IPSS-R)[3] remains the prognostic rubric used in most recent MDS clinical trials, an updated Molecular Prognostic Scoring System (IPSS-M) uses somatic mutation status of genes found on most myeloid malignancy next generation sequencing (NGS) panels to refine prognostication for MDS patients[4] .
The WHO classification system of MDS relies on incorporating clinical features, peripheral blood and bone marrow findings, and cytogenetic analysis.[2] This classification of myeloid neoplasms also includes a collection of heterogeneous neoplasms that share features of MDS and myeloproliferative neoplasms.
These "overlap neoplasms" fall under the classification "myelodysplastic/myeloproliferative neoplasms" (MDS/MPN) and include the following:
Although a detailed discussion of the overlap neoplasms is beyond the scope of this review, they share clinical, pathologic, and therapeutic features with MDS and can be treated similarly when they present with more features of MDS than MPN.
The WHO MDS classification comprises three groups, as listed below and detailed in Table 1, below.
MDS with defining genetic abnormalities:
MDS, morphologically defined:
Childhood MDS:
Table 1. World Health Organization criteria for myelodysplastic neoplasms (2022, 5th edition) (Open Table in a new window)
Neoplasm |
Blast percentage |
Cytogenetics by conventional karyotype analysis |
Mutations |
Other features |
|
---|---|---|---|---|---|
MDS with low blasts and isolated 5q deletion (MDS-5q) |
< 5% in bone marrow (BM) and < 2% in peripheral blood (PB) |
5q deletion alone, or with 1 other abnormality (except -7 or del(7q)) |
|
Thrombocytosis may be present |
|
MDS with low blasts and SF3B1 mutation (MDS-SF3B1) |
< 5% in BM and < 2% in PB |
Absence of 5q deletion, monosomy 7 or complex karyotype |
SF3B1 |
Ring sideroblasts often present but are not necessary |
|
MDS with biallelic TP53 inactivation (MDS-biTP53) |
< 20% in BM and PB |
Usually complex | Two or more TP53 mutationsor 1 mutation with evidence of TP53 copy number loss or cnLOH |
|
|
MDS with low blasts (MDS-LB) (morphologically defined) |
< 5% in BM and < 2% in PB |
Any (except isolated 5q deletion) |
Any (except SF3B1) |
||
MDS, hypoplastic (MDS-h) |
< 5% in BM and < 2% in PB |
Any |
|
Marrow hypocellularity for age, oligoclonal expansion of CD8+ T-cells, clonal hematopoiesis | |
MDS with increased blasts (MDS-IB1) |
5-9% in BM or 2-4% in PB |
Any |
|
|
|
MDS with increased blasts (MDS-IB2) |
10-19% in BM or 5-19% in PB, or presence of Auer Rods in blasts |
Any |
|
|
|
MDS with increased blasts, MDS with fibrosis (MDS-f) |
5-19% in BM or 2-19% in PB |
Any |
|
Marrow reticulin or collagen fibrosis |
|
Childhood MDS with low blasts, hypocellular |
< 5% in BM and < 2% in PB |
Any |
|
||
Childhood MDS with low blasts, not otherwise specified |
< 5% in BM and < 2% in PB |
Any |
|
||
Childhood MDS with increased blasts |
5-19% in BM or 2-19% in PB |
Any |
|
||
|
Each of the MDS categories can be qualified as secondary to predisposing risk factors. Patients with MDS post cytotoxic therapy (MDS-pCT), as subcategory of myeloid neoplasm post cytotoxic therapy (MN-pCT), have blood and bone marrow findings of one of the above diagnostic categories (frequently with multilineage dysplasia) and a past history of exposure to cytotoxic chemotherapy and/or radiation therapy administered for treatment of cancer or nonneoplastic disease.
Myeloid neoplasms with germ line predisposition may present as MDS and are classified into three major categories, as follows:
Like the fitfth edition WHO Classification, the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias was published in 2022 with the goal of classifying myeloid neoplasms among categories with prognostic and therapeutic relevance.[5] With regard to MDS, the classification rubrics are highly similar. Key differences in the ICC with regard to MDS are listed below.
Three categories of low-blast MDS (< 2% in PB, < 5% in BM) grouped accoring to extent of dysplastic morphology, absent genetic findings (5q deletion, multi-hit TP53 mutation/loss, mutated SF3B1):
The designation "MDS/AML" recognizes the simlar biology, prognosis, and therapeutic considerations between AML and MDS with increased blasts as defined by the following:
In recognition of the unique, aggressive biology and therapeutic unmet need associated with TP53 mutation/loss, separate categories of myeloid neoplasms with mutated TP53 are designated, as follows:
Although several prognostic scoring systems have been developed,[6, 7] the most widely used has been the revised IPSS. Compared with the original IPSS,[8] the IPSS-R[3] refined cytogenetic prognostic categorization and weighted the prognostic score according to the severity of cytopenias in addition to the bone marrow blast percentage. The sum of the assigned points yields a prognostic score, which estimates survival and risk of progression to AML.
In addition to the clinical and pathologic variables included in the IPSS-R, point mutations in genes such as TP53, EZH2, ETV6, RUNX1, and ASXL1 have been consistently shown to identify patients at risk for shortened survival or transformation to acute leukemia.[9] Due to the emerging prognostic relevance of mutations and the increasing availability of next-generation sequencing (NGS) assays, the IPSS-M was developed.[4]
The IPSS-M combines clinical, cytogeneti,c and somatic mutational variables and can be calculated using online calculators. Compared with the IPSS-R, the IPSS-M stratifies patients into six (rather than five) prognostic categories: very low, low, moderate low, moderate high, high and very high risk, each discriminating risk of leukemia-free survival, overall survival and leukemic transformation (see Tables 2-4, below). Using somatic mutation data, almost half of patients are re-categorized from one IPSS-R risk stratum to a different higher or lower risk stratum in IPSS-M. For this reason, broad NGS panels that include mutations used in the development of IPSS-M is standard-of-care testing for all newly diagnosed MDS patients.
Table 2. IPSS-R assignment of score (Open Table in a new window)
|
Score Value |
||||||
Prognostic variable |
0 |
0.5 |
1 |
1.5 |
2 |
3 |
4 |
Marrow blasts (%) |
< 2 |
- |
2 - < 5 |
- |
5-10 |
> 10 |
- |
Karyotype† |
Very Good |
- |
Good |
– |
Intermediate |
Poor |
Very Poor |
Hemoglobin (g/dL) |
≥10 |
- |
8 - < 10 |
< 8 |
- |
- |
- |
Absolute neutrophil count (× 109/L) |
≥0.8 |
< 0.8 |
- |
- |
- |
- |
- |
Platelet count (× 109/L) |
≥100 |
50 - < 100 |
< 50 |
- |
- |
- |
- |
† Very good karyotype: del(11q), -Y; good karyotype: 46XX, 46XY, del(5q), del(20q); poor karyotype: complex (≥3 unrelated abnormalities) or chromosome 7 abnormalities; intermediate karyotype: karyotypes not defined as good or poor. |
|
|
Table 3. IPSS-R risk groups, by sum of score [3] (Open Table in a new window)
Risk Category (% IPSS-R population) |
Overall Score |
Median Survival (years) |
Time for 25% of patients to progress to AML |
Very low (19) |
≤1.5 |
8.8 |
Not reached |
Low (38) |
2-3 |
5.3 |
10.8 |
Intermediate (20) |
3.5-4.5 |
3.0 |
3.2 |
High (13) |
5-6 |
1.6 |
1.4 |
Very high (10) |
> 6 |
0.8 |
0.73 |
AML = acute myeloid leukemia; IPSS-R = Revised International Prognostic Scoring System. |
Table 4. Prognosis of IPSS-M risk groups (Open Table in a new window)
Risk Category (% IPSS-M population) |
Median Overall Survival, years (25-75% range) |
Median Leukemia-free Survival, years (25-75% range) |
Risk of AML (%) at 4 years |
---|---|---|---|
Very low (14%) | 10.6 (5.1-17.4) | 9.7 (5.0-17.4) | 2.8 |
Low (33%) | 6.0 (3.0-12.8) | 5.9 (2.6-12.0) | 5.1 |
Moderate low (11%) | 4.6 (2.0-7.4) | 4.5 (1.6-6.9) | 11.4 |
Moderate high (11%) | 2.8 (1.2-5.5) | 2.3 (0.91-4.7) | 18.9 |
High (14%) | 1.7 (1.0-3.4) | 1.5 (0.80-2.8) | 29.2 |
Very high (17%) | 1.0 (0.5-1.8) | 0.76 (0.33-1.5) | 42.8 |