Myelodysplastic syndrome and aplastic anaemia Flashcards
Define myelodysplastic syndrome.
biologically heterogenous group of acquired haematopoietic stem cell disorders (~4 per 100,000)
What is MDS characterised by?
- • Characterised by:
o Development of a clone of marrow stem cells with abnormal maturation resulting in:
Functionally defective blood cells
Numerical reduction
o Resulting in…
Cytopaenia
Qualitative (functional) abnormalities of erythroid, myeloid and megakaryocyte maturation
Increased risk of transformation to leukaemia
Describe the presentation of MDS.
Elderly; develops over weeks-months
Bone marrow failure – WL, fatigue, infections, bleeding
What are some blood morphological features of MDS?
- Pelger-Huet anomaly (bilobed neutrophils)
- Dysgranulopoiesis of neutrophils (low granule number)
- Dyserythropoiesis of red cells
- There is a lack of separation between red cell precursors
- There is an abnormal ring of cytoplasm around the nucleus on the right
- Dysplastic megakaryocytes – e.g. micro-megakaryocytes
- Increased proportion of blast cells in marrow (normal < 5%)
- Ringed sideroblasts (iron granules in red cell precursors) – ferritin may be elevated – ineffective erythropoiesis
Pelger-Huet anomaly
Refarctory anaemia dysgranulopoeisis
Myelokathexis
Refractory anaemia-dyserythropoiesis
Ringed sideroblasts
Myeloblasts (with Auer Rods) → AML
What is the MDS classification based on?
- This classification is based on:
- Number of dysplastic lineages
- Percentage of blasts in bone marrow and peripheral blood
- Cytogenetic findings
- Percentage of ringed sideroblasts
- Number of cytopenias (based on criteria from the International
- Prognostic Scoring System - IPSS) - the higher the score, the Lower the survival and time to progress to AML
- Hb < 100 g/L
- Platelets < 100 x 10^9/L
- Neutrophils < 1.8 x10^9/L
- Monocytes < 1.0 x 10^9/L (if > 1.0 x 10^9/L then diagnosis is CMML)
What are the gene mutations in MDS?
- Driver mutations in MDS - carry prognostic significance:
- TP53, EZH2, ETV6, RUNX1, ASXL1
- Others: SF3B1, TET2, DNMT3A
- Majority of common mutations are found more frequently in high risk MDS than in low risk MDS
Describe the evolution of myelodysplasia?
- (1) Deterioration of blood count
- Worsening consequences of marrow failure
- (2) Development of acute myeloid leukaemia (AML)
- Develops in 5-50% <1 year (depends on subtype)
- Some cases of MDS are much slower to evolve
- AML from MDS has an extremely poor prognosis and is usually not curable
- (3) Death:
- 1/3 die from infection
- 1/3 die from bleeding
- 1/3 die from acute leukaemia
What is the tx of MDS?
At present, the only two treatments that can prolong survival are:
- allogeneic stem cell transplantation (SCT) - of young enough
- intensive chemotherapy
but only a minority of MDS patients can really benefit from them - elderly cannot have
What other tx is available for MDS?
- Care pathway for MDS:
- (1) Supportive care:
- Blood products
- Antimicrobial therapy
- Growth factors (EPO, G-CSF)
- (2) Biological modifiers:
- Immunosuppressive therapy
- Hypomethylating agents (Azacytidine, Decitabine)
- Lenalidomide (IMiD = Immunomodulatory -imide Drugs)
- (3) Oral Chemotherapy:
- Oral → hydroxyurea
- Low dose → SC low dose cytarabine
- Intensive chemotherapy / A-SCT:
- AML-type regimens
- Allo/VUD standard/reduced intensity
- 4 Low dose chemotherapy
- Subcutaneous low dose cytarabine
- 5 Intensive Chemotherapy/SCT (for high risk MDS)
- AML type regimens
- Allo/VUD standard/ reduced intensity
- (1) Supportive care:
One third of MDS patients can be expected to die from leukaemic transformation
What causes BM failure?
- Results from damage or suppression of stem or progenitor cell
- PLURIPOTENT HAEMATOPOIETIC CELL (impairs production of all peripheral blood cells; rare)
- COMMITTED PROGENITOR CELLS (results in bi- or uni-cytopenias)
What are the types of BM Failure?
- PRIMARY
- Congenital: Fanconi’s anaemia (multipotent stem cell)
- Diamond-Blackfan anaemia (red cell progenitors)
- Kostmann’s syndrome (neutrophil progenitors)
- Acquired: Idiopathic aplastic anaemia (multipotent stem cell)
- SECONDARY
- Marrow infiltration:
- Haematological (leukaemia, lymphoma, myelofibrosis) 3. Non-haematological (Solid tumours, )
- Radiation
- Drugs
- Chemicals (benzene)
- Autoimmune
- Infection (Parvovirus, Viral hepatitis
What drugs cause BM failure?
- PREDICTABLE (dose-dependent, common)
* 1. Cytotoxic drugs - IDIOSYNCRATIC (NOT dose-dependent, rare)
- Phenylbutazone
- Gold salts
- ANTIBIOTICS
- Chloramphenicol
- Sulphonamide
- DIURETICS
* 1. Thiazides - ANTITHYROID DRUGS
* 1. Carbimazole
Describe the epidemiology of aplastic anaemia.
- 2-5 / million / year (world-wide) much rarer than MDS
- All age groups but with bimodal peaks:
- 15-24yo
- >60yo
How do we classify aplastic anaemia?
What is the payhophsyiology of aplastic anaemia?
Failure of BM to produce blood cells
“Stem cell” problem (CD34, LTC-IC) [Long-Term Culture-Initiating Cells]
Immune attack:
Humoral or cellular (T cell) attack against multipotent haematopoietic stem cell.
What is the clinical presentation of AA?
- Clinical presentation of AA → classic triad of BM failure:
- Anaemia – fatigue, breathlessness
- Leucopaenia – infections
- Thrombocytopaenia – bleeding/bruising
How do we diagnose and classify AA?
