Myelodysplastic syndrome and aplastic anaemia

Question 1

Define myelodysplastic syndrome.

Answer 1

biologically heterogenous group of acquired haematopoietic stem cell disorders (~4 per 100,000)

Question 2

What is MDS characterised by?

Answer 2

• • 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

Question 3

Describe the presentation of MDS.

Answer 3

Elderly; develops over weeks-months

Bone marrow failure – WL, fatigue, infections, bleeding

Question 4

What are some blood morphological features of MDS?

Answer 4

• 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

Question 5

Answer 5

Pelger-Huet anomaly

Question 6

Answer 6

Refarctory anaemia dysgranulopoeisis

Question 7

Answer 7

Myelokathexis

Question 8

Answer 8

Refractory anaemia-dyserythropoiesis

Question 9

Answer 9

Ringed sideroblasts

Question 10

Answer 10

Myeloblasts (with Auer Rods) → AML

Question 11

What is the MDS classification based on?

Answer 11

• 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)

Question 12

What are the gene mutations in MDS?

Answer 12

• 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

Question 13

Describe the evolution of myelodysplasia?

Answer 13

• (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

Question 14

What is the tx of MDS?

Answer 14

At present, the only two treatments that can prolong survival are:

1. allogeneic stem cell transplantation (SCT) - of young enough
2. intensive chemotherapy

but only a minority of MDS patients can really benefit from them - elderly cannot have

Question 15

What other tx is available for MDS?

Answer 15

• 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

Question 16

Answer 16

One third of MDS patients can be expected to die from leukaemic transformation

Question 17

What causes BM failure?

Answer 17

• 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)

Question 18

What are the types of BM Failure?

Answer 18

1. PRIMARY
2. Congenital: Fanconi’s anaemia (multipotent stem cell)
3. Diamond-Blackfan anaemia (red cell progenitors)
4. Kostmann’s syndrome (neutrophil progenitors)
5. Acquired: Idiopathic aplastic anaemia (multipotent stem cell)
6. SECONDARY
7. Marrow infiltration:
8. Haematological (leukaemia, lymphoma, myelofibrosis) 3. Non-haematological (Solid tumours, )
9. Radiation
10. Drugs
11. Chemicals (benzene)
12. Autoimmune
13. Infection (Parvovirus, Viral hepatitis

Question 19

What drugs cause BM failure?

Answer 19

1. PREDICTABLE (dose-dependent, common)
   * 1. Cytotoxic drugs
2. IDIOSYNCRATIC (NOT dose-dependent, rare)

• 1. Phenylbutazone
• 2. Gold salts

3. ANTIBIOTICS

• 1. Chloramphenicol
• 2. Sulphonamide

4. DIURETICS
   * 1. Thiazides
5. ANTITHYROID DRUGS
   * 1. Carbimazole

Question 20

Describe the epidemiology of aplastic anaemia.

Answer 20

• 2-5 / million / year (world-wide)  much rarer than MDS
• All age groups but with bimodal peaks:
  
  • 15-24yo
  • >60yo

Question 21

How do we classify aplastic anaemia?

Answer 21

Question 22

What is the payhophsyiology of aplastic anaemia?

Answer 22

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.

Question 23

What is the clinical presentation of AA?

Answer 23

• Clinical presentation of AA → classic triad of BM failure:
  
  • Anaemia – fatigue, breathlessness
  • Leucopaenia – infections
  • Thrombocytopaenia – bleeding/bruising

Question 24

How do we diagnose and classify AA?

Answer 24

Question 25

Answer 25

• Left: Normal
• Right: Aplastic BM

Question 26

What are the ddx of pancytopenia and hypocellular marrow?

Answer 26

Hypoplastic MDS / Acute Myeloid Leukaemia Hypocellular Acute Lymphoblastic Leukaemia Hairy Cell Leukaemia
Mycobacterial (usually atypical) infection

Anorexia Nervosa

Idiopathic Thrombocytopenic Purpura

Question 27

What is the criteria of severe AA?

Answer 27

Question 28

How should we manage BN failure?

Answer 28

• 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)

Question 29

What is the specific treatment for idiopathic AA? What does it depend on?

Answer 29

Question 30

What are the late complications following immunosuppressive therapy for AA?

Answer 30

Question 31

Answer 31

The cure rate of AA treated by sibling-related allogeneic stem cell transplantation in a patient under 40 years old is > 70%.