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?
- Left: Normal
- Right: Aplastic BM
What are the ddx of pancytopenia and hypocellular marrow?
Hypoplastic MDS / Acute Myeloid Leukaemia Hypocellular Acute Lymphoblastic Leukaemia Hairy Cell Leukaemia
Mycobacterial (usually atypical) infection
Anorexia Nervosa
Idiopathic Thrombocytopenic Purpura
What is the criteria of severe AA?
How should we manage BN failure?
- Seek and remove a cause (detailed drug & occupational exposure history).
- Supportive:
- Blood/platelet transfusions (leucodepleted, CMV neg, irradiated)
- Antibiotics
- Iron Chelation Therapy
- Immunosuppressive therapy (anti-thymocyte globulin, steroids, eltrombopag, cyclosporine A)
- Drugs to promote marrow recovery
- Oxymethone, TPO receptor agonists (eltrombopag), ??G-CSF (prob not).
- Stem cell transplantation
- Other treatments in refractory cases – e.g. alemtuzumab (anti-CD52, high dose cyclophosphamide)
What is the specific treatment for idiopathic AA? What does it depend on?
What are the late complications following immunosuppressive therapy for AA?
The cure rate of AA treated by sibling-related allogeneic stem cell transplantation in a patient under 40 years old is > 70%.
