Haem - Myelodyplasia and Aplastic anaemia

Question 1

What are myelodysplastic syndromes and what are the characterised by

Answer 1

Heterogeneous group of progressive disorders featuring ineffective proliferation and differentiation of abnormally maturing myeloid stem cells.

1. Cytopenia
2. Qualitative (functional) abnormalities of erythroid, myeloid and megakaryocyte maturation
3. Increased risk of transformation to leukaemia (AML)

Question 2

What are the clinical features of myelodysplasia

Answer 2

Elderly
Symptoms develop over weeks-months
BM failure and cytopenias – infection, bleeding, fatigue

Question 3

What are the features of myelodysplasia in the blood

Answer 3

RBCs:
Dyserythropoiesis of red cells (lack of separation between RBC precursors)
Ringed sideroblasts (iron granules in red cell precursors, iron deposited in mitochondria in a ring around the nucleus)
Ferritin may be elevated– ineffective erythropoiesis

Granulocytes:
Pelger-Huet anomaly (bilobed neutrophils)
Dysgranulopoiesis of neutrophils (low granule number)

Dysplastic megakaryocytes – e.g. micro-megakaryocytes

Increased proportion of blast cells in marrow (5-20%)

Question 4

What is RAEB-T

Answer 4

Refractory anaemia with excess blasts in
transformation
21-30% myeloblasts in the marrow – now
considered as AML.

Question 5

Describe the evolution of myelodyslplasias

Answer 5

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 6

What is the treatment for myelodysplasia

Answer 6

Supportive: transfusion, antimicrobial therapy, growth factors (EPO, G-CSF, TPOr-atagonist)
Biological modifiers: immunosuppressive therapy, hypomethylating agents, lenalidomide
Treatments to prolong survival: allogenic stem cell transplant (A-SCT) OR intensive chemotherapy

Question 7

What is the WHO classification of myelodysplastic syndromes

Answer 7

Refractory anaemia (RA): with (RARS) or without ringed sideroblasts
- anaemia, no blasts, dysplasia <5% blasts OR >15% ringed sideroblasts
Refractory cytopenia with multilineage dyspalsia (RCMD)
- cytopenia and dysplasia (>10% cells) in 2 or more cell lines
Refractory anaemia with excess of blasts (RAEB): RAEB-I (blasts 5-9%) or RAEB-II (blasts 10-19%)
5q syndrome
- anaemia, megakaryocytes with hypolobulated nuclei <5% blasts
Unclassified: with fibrosis, childhood, others

Question 8

What is aplastic anaemia

Answer 8

Bone marrow failure from damage/suppression of stem/progenitor cells
May be committed progenitor cells (bi- or uni-cytopenia) OR pluripotent haematopoeitic cells (pancytopenia)

Question 9

What are the causes of aplastic anaemia

Answer 9

3

Question 10

What drugs can cause aplastic anaemia

Answer 10

Cytotoxic drugs (predictable)
Phenylbutazone, gold salts (idiosyncratic, not dose dependent)
Chloramphenicol, sulphonamides
Thiazides
Carbimazole

Question 11

What is the epidemiology of aplastic anaemia

Answer 11

Rarer than myelodysplasia
Bimodal peaks: 15-24 and >60yo

Question 12

What are the clinical features of aplastic anaemia

Answer 12

Anaemia – fatigue, breathlessness
Leucopaenia – infections
Thrombocytopaenia – bleeding/bruising

Question 13

What is the criteria for severe aplastic anaemia

Answer 13

(Camitta criteria)  2 out of 3 peripheral blood features:
1. Reticulocytes < 1% (<20 x 109/L)
2. Neutrophils < 0.5 x 109 /L
3. Platelets < 20 x 109 /L

+ Bone marrow <25% cellularity

Question 14

What is the management for aplastic anaemia

Answer 14

1. Seek and remove any causes
2. Supportive: transfusions, Abx, iron chelation
3. Immunosuppression: anti-thymocyte globulin, steroids, Eltrombopag, cyclosporine A
4. Drugs for marrow recovery (androgens (oxymetholone), thrombopoietin receptor agonists (Eltrombopag))
5. Stem cell transplantation

Question 15

What is the prognosis for aplastic anaemia

Answer 15

Stem cell transplantation tends to be used in younger patients: <40yo → 80% cure rate
25% risk of relapse
Risk of myelodysplasia, leukaemia and Paroxysmal nocturnal haemoglobinuria (PNH)

Question 16

What is Fanconi anaemia

Answer 16

Congenital aplastic anaemia (most common form of inherited AA)
Autosomal recessive or X-linked
Multiple mutated genes → abnormal DNA repair and chromosomal fragility

Question 17

What are the clinical features of Fanconi anaemia

Answer 17

Presents at 5-10yo
Short Stature
Hypopigmented spots and café-au-lait spots
Abnormality of thumbs
Microcephaly or hydrocephaly
Hypogonadism
Developmental delay
No abnormalities 30%

Question 18

What are the complications of Fanconi anaemia

Answer 18

32% progress to myelodysplasia
10% progress to AML

Question 19

What is dyskeratosis congenita

Answer 19

An inherited disorder characterised by:
- Marrow failure
- Cancer predisposition
- Somatic abnormalities: leukoplakia, nail dystrophy, skin pigmentation

Question 20

What is the genetic basis for dyskeratosis congenita

Answer 20

Due to telomere shortening
X-linked recessive (most common): DKC1 gene mutation
Autosomal dominant: TERC gene
Autosomal recessive

Question 21

Describe Schwachman-Diamond Syndrome

Answer 21

Autosomal recessive
Primarily neutrophilia ± others
Skeletal abnormalities, endocrine and pancreatic dysfunction, hepatic impairment, short stature
AML risk

Question 22

Describe Diamond-Blackfan Syndrome

Answer 22

Pure red-cell aplasia; normal WCC and platelets
Presents at 1yr/neonatal
Dysmorphology

Question 23

What is the treatment for severe aplastic anaemia

Answer 23

<35: ?HLA identical sibling → HLA matched HSCT (if not → unrelated donor HSCT
35-50: either HSCT or horse ATG
>50: horse anti-thymocyte globulin (ATG) + ciclosporin