myelodysplastic syndrome Flashcards
what are myelodysplastic syndromes
Biologically heterogeneous group of acquired haemopoietic stem cell disorders
what are myelodysplastic syndromes characterised by
development of a clone of marrow with abnormal maturation ->
* functionally defective nlood cells
* numerical reduction in blood cells ->
cytopenia
functional abnormalities of erythroid, myeloid and megakaryocyte maturation
increased risk of transfromation into leukaemia because stem cell disorder
summarise myelodysplasia
disorder of elderly
sx - general marrow failure
slow developing - over wks/mos
blood and bone marrow features of myelodysplasia
- Pelger-Huet anomaly (bilobed neutrophils)
- Dysganulopoieses of neutrophils (abnormal number of granules)
- Dyserythropoiesis of red cells (not nice and round)
- Dysplastic megakaryocytes – e.g. micro-megakaryocytes (bone marrow biopsy – make plts look abnormal)
- Increased proportion of blast cells in marrow (normal < 5%) – normally only have a small number of. In AML – blast cells proliferate, don’t differentiate and eradicate normal marrow
normal neutrophils
Pelger-Huet anomaly
(myelodysplasia)
refractory anaemia dysgranulopoiesis
myelodysplasia
myelokathexis - pyknotic nuclei and lengthening and thinning of intrasegmented filaments and vacuoles
it is an increased number of mature adn hypersegmented neutrophils
refractory anaemia dyserythropoeisis
(myelodysplasia)
ringed sideroblasts in bone marrow
stain bone marrow for iron
some of red cell precurser contain siderotic granules around nucleus - here there are two many ie ringed sideroblast
myelodysplastic syndrome
myeloblasts with Auer rods
precurser of AML
Primative cells with no granules
Auer rods – long red purple intracytoplasmic bodies – only AML
classification of myelodysplastic syndrome
- 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)
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)
importance of classifcation of myleodysplastic syndromes
has prognostic significance
note - started to take into account molecular changes
prognostic scoring system for myelodysplastic syndromes
how does the prognostic score lead to outcomes for myelodysplastic syndrome
what are the driver mutations in myelodysplastic syndrome
Driver mutations - carry prognostic significance:
TP53, EZH2, ETV6, RUNX1, ASXL1
Others: SF3B1, TET2, DNMT3A
most common mutations are more in high risk MDS than in low risk
natural evolution of myelodysplasia
deterioration of blood counts -> worsening consequences of marrow failure
development of AML (depends on risk) - worse Px than spontaneous AML presumably because all stem cells have been effected
1/3 die from infection
1/3 die from bleeding
1/3 die from acute leukaemia
treatment of myelodysplastic syndrome that prolonges survival
allogenic stem cell transplant (SCT)
intensive chemo
only a minority get them - most are too old, there is high mortality from SCT
treatment of MDS
supportive care:
* blood product support
* antimicrobial therapy
* growth factors - (Epo (for RBC), G-CSF (for neutrophils), TPO-Receptor Agonist (for plts))
Biological modifiers
* immunosuppressive therapy
* Azacytidine and decitabine - Hypomethylating agents, enhance marrow function
* Lenalidomide (for del(5q) variant of MDS) – biological response modifier
* oral chemo - if white cell is high (unusual) - use hydroxyurea/hydroxycarbamide
* low dose chemo in past
* intensive chemo/SCT for high risk MDS - give AML like regimen. Allo/VUD standard/ reduced intensity
summarise the haematopoietic cell lines
multipotent stem cell - in very small numbers in marrow. - give rise to progenitor cells
progenitor cells have proliferative ability
summarise how where in the cell lineage that the marrow failure effects alters the outcome
marrow failure is from damage/suppression of a stem/progenitor cell
pluripotent haematopoietic cell impairs production of all peripheral blood cells - rare
committed progenitor - results in bi- or unicytopenias
causes of primary bone marrow failure
Congenital: Fanconi’s anaemia (multipotent stem cell)
Diamond-Blackfan anaemia (red cell progenitors) - children
Kostmann’s syndrome (neutrophil progenitors) - children
Acquired: Idiopathic aplastic anaemia (multipotent stem cell) – most common
causes of secondary bone marrow failure (more common than primary)
Marrow infiltration:
Haematological (leukaemia, lymphoma, myelofibrosis)
Non-haematological (Solid tumours, secondary fibrosis)
Radiation
Drugs
Chemicals (benzene)
Autoimmune
Infection (Parvovirus, Viral hepatitis, HIV)
drugs that can cause bone marrow failure
PREDICTABLE bone marrow suppression (dose-dependent, common) - Cytotoxic drugs
IDIOSYNCRATIC (NOT dose-dependent, rare)
* Phenylbutazone (NSAID)
* Gold salts (for rheumatoid arth)
ANTIBIOTICS
* Chloramphenicol
* Sulphonamide – often when already unwell with haem disease
DIURETICS - Thiazides
ANTITHYROID DRUGS - Carbimazole
