W26 - myelodysplastic syndrome

Question 1

What are myelodysplastic syndromes (MDS)

Answer 1

Biologically heterogeneous group of acquired haemopoietic stem cell disorders, characterised by the development of a clone of marrow SCs with abnormal maturation

Question 2

What are the 3 end results of myelodysplstic syndromes?

Answer 2

functionlly defective blood cells and numerical reduction leads to:

1. cytopaenia(s)
2. Functional abnormalities of erythroid, myeloid, and megakaryocyte maturation
3. Increased risk of transformation to leukaemia

Question 3

Myelodysplastic synromes - do they typically affect young/elderly?

Answer 3

Elderly

Question 4

Symptoms of myelodysplastic syndromes

Answer 4

similar to BM failure

• low red cells (fatigue, SOB, anaemia, pallor)
• low WCC (recurrent infections)
• low platelets (recurrent bleeds)

Question 5

5 blood and BM features of MDS

Answer 5

1. Pelger-Huet anomaly (bilobed neutrophils)
2. Dysgranulopoieses of neutrophils
3. Dyserythropoiesis of red cells
4. Dysplastic megakaryocytes – e.g. (micro-megakaryocytes in BM)
5. Increased proportion of blast cells in marrow (normal < 5%)

Question 6

What does peripheral blood here show?

Answer 6

Pelger-Huet anomaly (bilobed neutrophil) => MDS

Question 7

What does this BM slide show?

Answer 7

desgranulopoiesis (only 4-5 granules, should be much more) => MDS

Question 8

What do these 2 show?

Answer 8

left = red cell precursors joined by cytoplastic bridge

right = red cell precusor where cytoplsm is blebbing

= dyserythropoiesis => MDS

Question 9

What does this BM slide show?

Answer 9

Ringed sideroblasts - iron loaded mitochondria stained with Prussian Blue => MDS

Question 10

Peripheral smear - what do you see?

Answer 10

2 blast cells with auer rods (rod-like structure) = ACUTE MYELOID LEUKAEMIA (AML)

Question 16

How is MDS prognosis determined? Name the 5 criteria

Answer 16

using the IPSS - International Prognostic Scoring System

1. BM blast %
2. Karyotype
3. Hb (g/L)
4. Platelet count
5. Neutrophil count

Question 17

Name 1 driver mutation in MDS? what is the importance of identifying these?

Answer 17

TP53

carry prognostic significance

Question 18

Rule of thumb for outcome of MDS

Answer 18

1/3 die from infection

1/3 die from bleeding

1/3 die from acute leukaemia

Question 19

Treatments (4) for MDS

Answer 19

1. Supportive (blood products, abx, growth factors like epo for RBC, GCSF for neutrophil)
2. Biological modifiers (immunosuppressive therapy)
3. Allogeneic SCT (if young + matched donor)
4. Intestive chemotherapy (if residual healthy stem cell)
   - or low dose if intensive is unsuitable

Question 20

Which one of the following is true?

1. Myelodysplasia has a bi-modal age distribution
2. The primary modality of treatment of MDS is by intensive chemotherapy
3. One third of MDS patients can be expected to die from leukaemic transformation
4. There is no good correlation between the severity of the cytopenias and the overall life expectancy
5. White cell function is frequently well preserved in MDS

Answer 20

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

Question 21

describe the right and left BM

Answer 21

left = normal BM (50% is fat, the other pink stuff are cells, bigger cells are megakaryocytes)

right = aplastic BM (hypocellular)

Question 22

Aplastic anaemia

• incidence
• peak incidence (age)

Answer 22

Aplastic anaemia

• incidence:

2-5 cases/million/yr

• peak incidence (age):

2 peaks: 15-24 yrs, >60 yrs

Question 23

4 classifications of aplastic anaemia

Answer 23

1. Idiopathic (most common, 70-80%)

2. Inherited (Dyskeratosis congenita, Fanconi anaemia, etc)

3. Secondary:

• Radiation
• Drugs (i.e. cytotoxic drugs, chlorampheniocol)
• Viruses (i.e. hepatitis)
• Immune (i.e. SLE)

4. Miscellaneous (i.e. Paroxysmal nocturnal haemoglobinuria, thymoma)

Question 24

Idiopathic aplastic anaemia pathophysiology

Answer 24

Failure of BM to produce blood cells

Thought to be an immune attack = B or T cell attack against multipotent HSCs

Question 25

Clinical presentation (3) of aplastic anaemia

Answer 25

1. Anaemia = Fatigue, breathlessness
2. Leucopenia = Infections
3. Platelets = Easy bruising/bleeding

Question 26

How is aplastic anaemia diagnosed?

Answer 26

1. Blood shows cytopaenias
2. BM showed hypocellularity

Question 28

What is the criteria used for diagnosing the severity of aplastic anaemia?

Name the criteria

Answer 28

Camitta criteria:

2 out of 3 peripheral blood features:

1. Reticulocyte
2. Neutrophils
3. Platelets

+ BM <25% cellularity

Question 29

Management (6) of aplastic anaemia (BM Failure)

Answer 29

1. Remove cause, if possible (i.e. radiation)
2. Supportive (blood products, abx, iron chelation therapy if iron overloaded from RBC transfusion)
3. Immunosuppressive therapy
4. Drugs to promote marrow recovery
5. SCT (if young + matched donor)
6. Other tx for refractory cases (biologic therapies)

Question 30

Aplastic anaemia - who would benefit from a SCT?

Answer 30

Younger patient with donor (80% cure)

% falls if match isn’t a sibling donor and patient age >40 y.o.

Question 31

Diagnosis?

Answer 31

Thumb problems Café au lait spots Microcephaly = Fanconi anaemia

Question 32

Regarding Aplastic Anaemia – which one answer is true? 1. Immunosuppressive therapy is only used to treat a minority of patients with aplastic anaemia. 2. If treated with immunosuppression, then relapse of Aplastic Anaemia occurs in less than 15% of cases 3. The cure rate of AA treated by sibling-related allogeneic stem cell transplantation in a patient under 40 years old is \> 70%. 4. Severe aplastic anaemia is differentiated from non-severe aplastic anaemia on the basis of the acquired cytogenetic abnormalities in the bone marrow. 5. Leucodepletion of cellular blood products is only exceptionally undertaken for patients with aplastic anaemia.

Answer 32

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

Question 33

3 complications following immunosuppressive therapy for aplastic anaemia

Answer 33

1. Relapse of AA (35%) 2. Clonal haematological disorders =\> MDS, leukaemia, PNH (may be transient) 3. Solid tumours (3%)

Question 34

Diagnosis?

Answer 34

* Skin pigmentation * Nail dystrophy * Leukoplakia **= Dyskeratosis congenita**

Question 35

Inherited BM syndromes causing pancytopaenia - name 2

Answer 35

1. Fanconi anaemia 2. Dyskeratosis congenita

Question 36

The most common form of inherited aplastic anaemia is...

Answer 36

Fanconi anaemia

Question 37

_Fanconi anaemia:_ 1. mode of inheritance? 2. pathophysiology?

Answer 37

_Fanconi anaemia:_ 1. mode of inheritance = **autosomal recessive or X-linked inheritance** 2. pathophysiology = **multiple genes become mutated =\> abnormalities in DNA repair + chromosomal fragility/breaksage**

Question 38

6 congenital abnormalities seen in children with Fanconi anaemia

Answer 38

Congenital malformations may occur in 60-70% of children with FA: 1. Short Stature 2. Hypopigmented spots and café-au-lait spots 3. Abnormality of thumbs 4. Microcephaly or hydrocephaly 5. Hyogonadism 6. Developmental delay - No abnormalities 30%

Question 40

5 complications of Fanconi anaemia

Answer 40

_Aplastic anaemia (90%)_ Leukaemia (10%) Liver disease Myelodysplasia (32%) Cancer (epithelial)

Question 41

Dyskeratosis Congenita presentation (6)

Answer 41

1. BM failure 2. Cancer predisposition 3. Somaitc abnormalities ^ similar to FA. but also: 4. Skin pigmentation 5. Nail dystrophy 6. Leukoplakia

Question 43

Somatic abnormalities/complications in Dyskeratosis Congenita

Answer 43

1. Abnormal skin pigmentation (90%) 2. Nail dystrophy (90%) 3. BM failure (85%) 4. Leukoplakia (80%) ^ most common features!

Question 44

Dyskeratosis Congenita - pathophysiology

Answer 44

the structrues at the end of the chromosome, called telomeres, are damaged and shortened in length. Temoreres are imp to ensure the longevitiy of the chromosome and proliferation of the cells and without it, the chr becomes very fragile

Question 45

Dyskeratosis Congenita -Name the genetic patterns of inheritance

Answer 45

3 genetic patterns of inheritance: 1. X-linked recessive trait 2. Autosomal dominant trait 3. Autosomal recessive trait

Question 46

Other than dyskeratosis congenita, in what BM failure condition have shortened telomeres been seen?

Answer 46

Idiopathic aplastic anaemia

Question 47

Which one of the following is true? 1. Telomeric shortening is a feature of both idiopathic aplastic anaemia and dyskeratosis congenita 2. Development of malignancy is an uncommon complication of Fanconi Anaemia 3. A single genetic defect has been identified as the underlying cause for Fanconi Anaemia 4. Fanconi Anaemia is usually inherited in an autosomal dominant fashion 5. Telomeric function is considered to be unimportant in the pathophysiology of Dyskeratosis Congenita.

Answer 47

1. Telomeric shortening is a feature of both idiopathic aplastic anaemia and dyskeratosis congenita