20.06.19 Myelodysplastic syndromes

Question 1

What are myelodysplastic syndromes (MDS)

Answer 1

• Heterogenous group of hematologic malignancies characterised by
  1. Clonal expansion of bone marrow myeloid cells with impaired differentiation
  2. development of peripheral cytopenias due to ineffective haemopoiesis and dysplasias of one or more myeloid lineages
  3. Increased risk of transformation to AML

Question 2

Characteristics of MDS

Answer 2

• Hypercelluar bone marrow
• Imparied morphology and maturation leading to ineffective blood cell production and cytopenias.
• Clinically heterogenous

Question 3

Clinical manifestations of MDS

Answer 3

• Anaemia, thrombocytopenia and/or neutropenia.

- Treated with transfusions, chemotherapy and bone marrow transplantation.

Question 4

Prevalence of MDS

Answer 4

• 3-5/ 100,000

- Increases to 20/100,00 over 70 years

Question 5

Median age of diagnosis

Answer 5

70 years. (90% over 50yrs at diagnosis)

Question 6

Causes of MDS

Answer 6

• De novo (viral, smoking, inherited disorders e.g. Fanconi anaemi, Down syndrome)
• Secondary MDS: Due to prior cytotoxic chemotherapy (10-15%). e.g alkylating agents

Question 7

Percentage of patients with clonal chromosomal abnormalities

Answer 7

• 50%
• Balanced translocations are rare
• CNVs of part or all of chromosome 5, (36%), 7 (21%) or 8 (16%) are most commonly seen.

Question 8

5q deletion syndrome

Answer 8

• More common in females
• Haploinsufficiency of several genes including RPS14.
• Treated with lenolidomide. Presence of a TP53 mutation predicts poor response.

Question 9

Monosomy 7 and 7q

Answer 9

• Seen in 5-10% of primary MDS, 55% of secondary MDS.

- Poor prognosis

Question 10

Trisomy 8

Answer 10

• 8% of MDS
• Only recurrent amplification in MDS
• Treated with immunosuppressant therapy.

Question 11

20q

Answer 11

• Seen in 5% of MDS

- Low risk of progression to AML

Question 12

Complex karyotypes

Answer 12

• 3 or more abnormalities
• in 10-20% of primary MDS, up to 90% of secondary MDS.
• High risk

Question 13

What 5 functional categories are genes found to be frequently mutated in MDS

Answer 13

1. Spliceosomal (U2AF1, SF3B1, SRSF2)
2. Epigenetic (DNMT3A, BCOR, ASXL1)
3. Cohesins (STAG2, RAD21, SMC3)
4. Transcription factors (RUNX1, WT1)
5. Signalling molecules (NF1, NRAS, JAK2)

Question 14

Which functional group are most commonly mutated in MDS

Answer 14

-Spliceosomal (50% patients)

Question 15

What proportion of patients with MDS will develop AML

Answer 15

• AML= Acute myeloid leukemia
• Due to the acquisition of an additional driver mutation leading to proliferation of a subclonal population, which are unable to differentiate and mature.

Question 16

What does the term “clonal haematopoiesis of indeterminate potential” mean

Answer 16

• Used to describe patients whose haemopoietic tissues have detectable (2%) somatic clonal driver mutations in genes associated with haemtologic malignancies.
• I.e. do not meet the definitive diagnostic criteria for haemtologic malignancy.
• Higher rate of progression to neoplasia (0.5-1%)
• DNMT3A, ASXL1 and TET2 most commonly reported but require cooperating mutations to manifest clinically

Question 17

Diagnostic strategies for MDS

Answer 17

• Karyotyping is gold standard according to WHO classification guidelines.
• ArrayCGH and SNP arrays have been used in research basis as they do not require dividing cells. Detects 80% of abnormalities. Cannot distinguish individual clones or detect balanced translocations.
• SNP arrays can detect somatic UPD which occurs in 20% of cases
• Combination of karyotype and array increases diagnostic yield.
• DNA methylation may be predictive of outcomes for patients, no used clinically yet
• NGS. Single variant detection interpreted with caustion as it could be ‘clonal haematopoiesis of indeterminate potential’

Question 18

What are the current therapies available for MDS

Answer 18

• azacitidine (hypomethylating), lenalidomide (induces tumour cell apoptosis and anti-angiogenic), decitabine (Nucleic Acid Synthesis Inhibitor).
• Stem cell transplantation is only curative therapy.