Myelodysplastic Syndromes and Aplastic Anaemia

Question 1

What are myelodysplastic syndromes?

Answer 1

Biologically heterogeneous groups of acquired haemopoietic stem cell disorders

Question 2

What characterises myelodysplastic syndromes?

Answer 2

The development of a clone of marrow stem cells with abnormal maturation resulting in functionally defective blood cells AND numerical reduction
Is also associated with increased risk of transformation to leukaemia

Question 3

What are the presenting features of myelodysplasia?

Answer 3

Typically a disorder of the elderly
Symptoms/signs are those of general marrow failure
Develops over weeks & months

Question 4

What are the morphological features of blood and bone marrow in myelodysplastic syndrome?

Answer 4

Pelger-Huet anombaly (bilobed neutrophils)
Dysganulopoiesis of neutrophils
Dyserythropoiesis of red cells
Dysplastic megakaryocytes e.g. micro-megakaryocytes
Increased proportion of blast cells in marrow

Question 5

What is the normal proportion of blast cells in bone marrow?

Answer 5

<5%

Question 6

What is the classification of MDS based on?

Answer 6

Number of dysplastic lineages
Percentage of blasts in bone marrow and peripheral blood
Cytogenetic findings
Percentage of ringed sideroblasts
Number of cytopenias

Question 7

What is an important gene mutation in MDS?

Answer 7

TP53

EZH2, ETV6, RUNX1, ASXL1

Question 8

What increases the chance of MDS developing into acute myeloid leukaemia?

Answer 8

High blast cells

Question 9

What is the rule of 1/3rds in MDS?

Answer 9

1/3 die from infection
1/3 die from bleeding
1/3 die from acute leukaemia

Question 10

Why is AML that has progressed from MDS hard to treat?

Answer 10

No functioning stem cell

Question 11

What are the treatment options for MDS?

Answer 11

Allogenic stem cell transplantation (SCT)
Intensive chemotherapy
However, as majority of patients are elderly they are unlikely to tolerate these

Question 12

What supportive care is given to patients with MDS?

Answer 12

Blood product support
Antimicrobial therapy
Growth factors (Epo, G-CSF), TPO-Receptor Agnoist)

Question 13

What biological modifiers can be used in treatment of MDS?

Answer 13

Immunosuppressive therapy
Hypomethylating agents
Lenalidomide (for del(5q) variant)

Question 14

What chemotherapies can be used in MDS?

Answer 14

Oral: hydroxyurea

Low dose sub cut cytarabine

Question 15

What is bone marrow failure?

Answer 15

Results from damage or suppression of stem or progenitor cell

Question 16

What are the types of bone marrow failure?

Answer 16

Pluripotent haematopoietic cell - impairs production of all peripheral blood cells - RARE
Committed progenitor cells - results in bi-or unicytopenias

Question 17

What are the primary causes of bone marrow failure?

Answer 17

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)

Question 18

What are the secondary causes of bone marrow failure?

Answer 18

Marrow infiltration
Haematological (leukaemia, lymphoma, myelofibrosis)
Non-haematological (solid tumours)
Radiation
Drugs
Chemicals (benzene)
Autoimmune
Infection (Parvovirus, viral hepatitis)

Question 19

How can we break down the types of drugs that cause marrow failure?

Answer 19

Predictable e.g. cytotoxic
Isiosyncratic - rare
Antibiotics
Diuretics
Antithyroid drugs

Question 20

What antibiotics can cause marrow failure?

Answer 20

Chloramphenicol

Sulphonamide

Question 21

What diuretics can cause marrow failure?

Answer 21

Thiazides

Question 22

What antithyroid drug can cause marrow failure?

Answer 22

Carbimazole

Question 23

What is the epidemiology of aplastic anaemia?

Answer 23

2-5cases/million/yr
All age groups can be affected
Peak incidence: 15-24yrs and >60yrs

Question 24

What is the classification of aplastic anaemias?

Answer 24

Idiopathic - vast majority
Inherited
Secondary
Miscellaneous

Question 25

Give examples of inherited aplastic anaemia

Answer 25

``` Dyskeratosis congenita (DC) Fanconi anaemia (FA) Shwachman-Diamond syndrome ```

Question 26

What are some secondary causes of aplastic anaemia?

Answer 26

Radiation Drugs e.g. cytotoxic agents, chloramphenicol, NSAIDs Viruses e.g. hepatitis Immune: SLE

Question 27

What are the miscellaneous causes of aplastic anaemia?

Answer 27

PNH (Paroxysmal nocturnal haemoglobinuria) | Thymoma

Question 28

What is the pathophysiology of idiopathic AA?

Answer 28

Failure of BM to produce blood cells 'Stem cell' problem (CD35, LTC-IC) [Long-Term Culture-Initiating Cells] Immune attack: Humoural or cellular (T cell) attack against multipotent haematopoietic stem cell

Question 29

What are the clinical findings of aplastic anaemia?

Answer 29

Anaemia - fatigue, breathlessness Leucopenia - infections Platelets - easy bruising/bleeding

Question 30

How is aplastic anaemia diagnosed?

Answer 30

Blood - cytopenia | Marrow - hypocellular

Question 31

What are some differential diagnoses for pancytopenia and hypocellular marrow

Answer 31

Hypoplastic MDS / AML Hypocellular acute lymphoblastic leukaemia Hairy cell leukaemia Mycobacterial (usually atypical) infection Anorexia nervosa Idiopathic thrombocytopenic purpura

Question 32

What is the Camitta criteria for severe aplastic anaemia?

Answer 32

``` 2 out of 3 peripheral blood features: 1. Reticulocytes <1% (<20 x 10^9/L) 2. Neutrophils <0.5 x 10^9/L 3. Platelets <20 x 10^9/L + Bone marrow <25% cellularity ```

Question 33

What are the steps to bone marrow failure treatment?

Answer 33

``` Seek and remove cause Supportive Immunosuppressive Drugs to promote recovery of marrow Step cell transplantation ```

Question 34

What immunosuppressive therapy is given in bone marrow failure?

Answer 34

Anti-thymocyte globulin Steroids Eltrombopag Cyclosporine A

Question 35

What drugs are given to promote marrow recovery?

Answer 35

Oxymethone, TPO receptor agonists

Question 36

What specific treatment is there for aplastic anaemia?

Answer 36

``` Immunosuppressive therapy - older patient ○ Anti-lymphocyte globulin (ALG) ○ Ciclosporin ○ Eltrombopag • Androgens - oxymethalone • Stem cell transplantation ○ Younger patient with donor (80% cure) VUD/MUD >40 years (50% survival) ```

Question 37

What are the features of supportive aplastic anaemia treatment?

Answer 37

Blood products Antimicrobials Iron chelation therapy

Question 38

What late complications may occur following immunosuppressive therapy for AA?

Answer 38

Relapse of AA Clonal haematological disorders: myelodysplasia, leukaemia Solid tumours

Question 39

What congenital malformations may occur in 60-70% of children with Fanconi's Anaemia?

Answer 39

``` Short stature Hypopigmented spots and café-au-lait spots Abnormality of thumbs Microcephaly or hydrocephaly Hypogonadism Developmental delay No abnormalities in 30% ```

Question 40

What are the complications of Fanconi's anaemia?

Answer 40

``` Aplastic anaemia Leukaemia Liver disease Myelodysplasia Cancer ```

Question 41

What is dyskeratosis congenita?

Answer 41

An inherited disorder characterised by: bone marrow failure, cancer predisposition and somatic abnormalities

Question 42

What is Fanconi's anaemia?

Answer 42

Most common form of inherited aplastic anaemia | Autosomal recessive or X-linked inheritance

Question 43

What is the presentation of dyskeratosis congenita?

Answer 43

Skin pigmentation Nail dystrophy Leukoplakia