Myelodysplastic Syndrome

Question 1

What are the diagnostic criteria for MDS?

Answer 1

1) Persistent cytopenia (> 4 months) affecting at least one cell lineage
2) Dysplastic changes present in at least 1 lineage and in at least 10% of cells within that lineage

OR the presence of an MDS defining cytogenetic abnormality

OR the presence of 5-19% blasts

3) No alternative reason for cytopenia/ dysplasia

Question 2

List some of the MDS defining cytogenetic abnormalities

Answer 2

Del(7p), monosomy 7
Del(5q), t(5q)
Isochromosome 17q or t(17p)
Inv(3), t(3;3)

Question 3

What cytogenetic abnormalities are considered not to be MDS defining?

Answer 3

Trisomy 8
Del(20q)
-Y

Question 4

How can a myeloid panel be used to determine the likelihood of an underlying myeloid disorder such as MDS?

Answer 4

• No mutations found: high negative predictive value

- ≥2 mutations or VAF >10%= highly predictive of an underlying myeloid malignancy.

Question 5

What cytogenetic abnormalities are commonly seen in therapy related MDS?

Answer 5

• Abnormalities of chromosome 7 in ~50%
• Abnormalities of chromosome 5 in ~40%
• Abnormalities of chromosome 17 in ~30%
• Complex karyotype (often involving the above three chromosomes)

Question 6

What is CHIP

Answer 6

The presence of a somatic mutation associated with malignancy in the absence of any clinical signs of malignancy

• The mutation must be in a known leukaemic driver with a VAF ≥2%
• Most common= “DTA”= DNMT3A, TET2, ASXL1
• There must be no cytopenia

Question 7

What are some of the consequences of CHIP?

Answer 7

• Risk of progression to haematological malignancy= 0.5-1% / year. Generally requires acquisition of additional mutations
• Significantly increased risk of tAML or tMDS when exposed to cytotoxic medications for non-haematological malignancy
• Increased risk of cardiovascular disease (more predictive of risk than traditional risk factors with a higher HR for MI than BP, cholesterol levels and smoking) with a doubled risk of MI.

Question 8

What is CCUS?

Answer 8

• Clonal cytopenia of uncertain significance
• The presence of a somatic mutation and cytopenia BUT the diagnostic criteria for MDS is not met
• VAF must be ≥2%
• Risk of progression is relative to the VAF, number and type of mutations present.
• Thorough bone marrow investigation is necessary to exclude a haematological malignancy.

Question 9

What is ICUS?

Answer 9

• Idiopathic cytopenia of uncertain significance
• The presence of persistent cytopenia with unknown or negative mutation status and no other criteria present to diagnose a myeloid neoplasm.
• In some patients with ICUS, a small clone with a VAF <2% may be detected.

Question 10

What is IDUS?

Answer 10

• Idiopathic dysplasia of uncertain significance
• Significant dysplasia present in at least one cell line without any other features of a haematological malignancy
• Dysplasia present in >10% of precursor ≥1 cell line
• No associated cytopenia
• No MDS-defining mutation present

Question 11

When should the MDS-U category be used?

Answer 11

• When MDS does not fit into any of the other categories
• Presence of unexplained cytopenia with an MDS defining chromosomal abnormality in the absence of any morphological dysplasia
• MDS with pancytopenia but only single lineage dysplasia
• MDS with the presence of 1% blasts in the PB on 2 occasions

Question 12

What is MDS with ring sideroblasts?

Answer 12

• Characterised by cytopenia, morphological dysplasia and ring sideroblasts usually constituting ≥15% of bone marrow erythroid precursors.
• There is an association with the SF3B1 mutation (80-90% in SLD, 30-70% in MLD)
• Where this is present, MDS-RS can be diagnosed with ≥5% ring sideroblasts.
• In SLD, dysplasia is confined to the erythroid line
• The prognosis is generally good in those with SLD with the majority of patients having low or very low R-IPSS scores.

Question 13

What are some non-neoplastic causes of ring sideroblasts?

Answer 13

Alcohol, toxins (benzene), drugs (isoniazid), copper deficiency and congenital sideroblastic anaemia

Question 14

What are the recommended values for defining cytopenia as per the original IPSS?

Answer 14

• Hb <100
• Plts <100
• ANC <1.8

Question 15

What is the definition of MDS with excess blasts?

Answer 15

• MDS-EB-1= 2-4% blasts in the peripheral blood and/or 5-9% blasts in the bone marrow
• MDS-EB-2= 5-19% blasts in the peripheral blood and/or 10-19% blasts in the bone marrow

OR the presence of Auer rods in blast cells irrespective of the blast percentage (EB2).

Question 16

Describe the features of MDS with del(5q)

Answer 16

• Usually effects elderly women
• Present with macrocytic anaemia and thrombocytosis
• Bone marrow may be normocellular or even hypocellular (in contrast to most cases of MDS)
• Erythroid hypoplasia is frequently present
• Single lineage dysplasia with small hypolobated and nonlobated megakaryocytes predominating
• Ring sideroblasts may be present
• A single additional chromosomal abnormality may be present, as long as it does not involve chromosome 7
• Mutations in SRSF3, and JAK2 may be present
• TP53 mutations are seen in 20% are and associated with resistance to lenalidomide
• Good long term prognosis with low rates of progression to AML

Question 17

List the poor and very poor cytogenetic abnormalities seen in MDS

Answer 17

Poor

• Monosomy 7
• Inv(3), t(3q), del(3q)
• Double including -7 or del(7q)
• Complex with 3 abnormalities

Very poor
- Complex with >3 abnormalities

Question 18

List the factors which are associated with a poor prognosis in MDS

Answer 18

Presence of poor and very poor risk cytogenetics
Increased bone marrow blast %
Haemoglobin <100
Platelets <100
ANC <0.8

Question 19

What parameters are used in the MDS flow score?

Answer 19

• Myeloblast related cluster size (≥2% of all nucleated cells)
• B progenitor related cluster size (≤5% of all CD34+ cells)
• Lymphoblast to myeloblast CD45 ratio
• Granulocyte to lymphocyte side scatter ratio
• Each given 1 point. A score ≥2 is considered positive with a 70% sensitivity and 93% specificity.

Question 20

What changes are seen in the CD34 progenitor compartment in MDS?

Answer 20

• Increase of the myeloid-committed CD34+ population
• Decreased B-cell progenitors.
• Co-expression of stem cell and late stage myeloid antigens.
• Expression of lymphoid antigens.
• Abnormal CD45 expression

Question 21

What is RNA splicing? List some of the spliceosome mutations seen in MDS

Answer 21

The spliceosome is a complex protein structure that is responsible for excising introns from primary mRNA and aligning exons to form the mature mRNA that is transcribed.

Common mutations in MDS:
SF3B1
SRSF2
U2AF1
ZRZR2

With the exception of SF3B1, all spliceosome mutations are likely associated with a poor prognosis in MDS

Question 22

What is epigenetic regulation?

Answer 22

Epigenetics refers to various molecular modifications of chromatin that, without altering the DNA sequence, play an important role in genomic regulation and control of gene expression

Question 23

What is DNA methylation? What are some of the mutations seen in MDS that affect DNA methylation?

Answer 23

• Addition of a methyl group to a cytosine residue, where cytosine is followed by guanine (called a CpG dinucleotide pair).
• If the CpG islands are unmethylated then transcription can occur.
• If they are methylated then transcription is blocked (often permanently) and the gene is silenced.
• Mutations in the regulators of DNA methylation lead to hypermethylation.

Common mutations in MDS:
TET2 (intermediate prognosis)
IDH1/2 (intermediate prognosis)
DNMT3A (poor prognosis)

Question 24

What is histone modification? What are some of the mutations in MDS that affect histone modification

Answer 24

• Histones form the chromatin scaffold and closely regulate whether DNA exists in a repressed or permissive state for transcription to occur.
• Biochemical alterations to the tails of the histones influence the degree of nucleotide compaction in a given area of DNA. If the nucleotides are too compact, transcription cannot occur and vice versa.
• This can occur though acetylation/ deacetylation of the lysine residues of histones.
• If acetylated, chromatin becomes less compact and transcription can occur
• If deacetylated (i.e. when the acetylated groups are removed), chromatin becomes condensed and transcription cannot occur.

Common mutations in MDS
ASXL1 (poor prognosis)
EZH2 (poor prognosis)

Question 25

What mutations affect transcription in MDS?

Answer 25

RUNX1 (poor prognosis)

TP53 (poor prognosis)