20.06.19 Myelodysplastic syndromes Flashcards
What are myelodysplastic syndromes (MDS)
- 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
Characteristics of MDS
- Hypercelluar bone marrow
- Imparied morphology and maturation leading to ineffective blood cell production and cytopenias.
- Clinically heterogenous
Clinical manifestations of MDS
- Anaemia, thrombocytopenia and/or neutropenia.
- Treated with transfusions, chemotherapy and bone marrow transplantation.
Prevalence of MDS
- 3-5/ 100,000
- Increases to 20/100,00 over 70 years
Median age of diagnosis
70 years. (90% over 50yrs at diagnosis)
Causes of MDS
- 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
Percentage of patients with clonal chromosomal abnormalities
- 50%
- Balanced translocations are rare
- CNVs of part or all of chromosome 5, (36%), 7 (21%) or 8 (16%) are most commonly seen.
5q deletion syndrome
- More common in females
- Haploinsufficiency of several genes including RPS14.
- Treated with lenolidomide. Presence of a TP53 mutation predicts poor response.
Monosomy 7 and 7q
- Seen in 5-10% of primary MDS, 55% of secondary MDS.
- Poor prognosis
Trisomy 8
- 8% of MDS
- Only recurrent amplification in MDS
- Treated with immunosuppressant therapy.
20q
- Seen in 5% of MDS
- Low risk of progression to AML
Complex karyotypes
- 3 or more abnormalities
- in 10-20% of primary MDS, up to 90% of secondary MDS.
- High risk
What 5 functional categories are genes found to be frequently mutated in MDS
- Spliceosomal (U2AF1, SF3B1, SRSF2)
- Epigenetic (DNMT3A, BCOR, ASXL1)
- Cohesins (STAG2, RAD21, SMC3)
- Transcription factors (RUNX1, WT1)
- Signalling molecules (NF1, NRAS, JAK2)
Which functional group are most commonly mutated in MDS
-Spliceosomal (50% patients)
What proportion of patients with MDS will develop AML
- 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.
What does the term “clonal haematopoiesis of indeterminate potential” mean
- 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
Diagnostic strategies for MDS
- 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’
What are the current therapies available for MDS
- azacitidine (hypomethylating), lenalidomide (induces tumour cell apoptosis and anti-angiogenic), decitabine (Nucleic Acid Synthesis Inhibitor).
- Stem cell transplantation is only curative therapy.
