Myeloproliferative disease and myelodysplasia

Question 1

Define myeloproliferative disorders and give examples

Answer 1

Clonal proliferation of mature cells

Philadelphia +
CML

Philadelphia -
Polycythaemia vera
Essential thrombocythaemia
Primary myelofibrosis

Question 2

Define primary myelofibrosis and what is it characterised by

Answer 2

a clonal myeloproliferative disease associated with reactive bone marrow fibrosis
Characterised by extramedullary haematopoiesis (i.e. in liver and spleen)
Other MPD (ET and PV) may transform into PMF

Question 3

What is the cause and epidemiology of primary myelofibrosis

Answer 3

Expansion of the clone → produces fibroblast growth stimulating factor → proliferation and collagen deposition in the bone marrow → bone marrow scarring
Epidemiology = 60-70yo, M=F, 0.5-1.5/100,000/year

Question 4

What are the clinical features of primary myelofibrosis

Answer 4

Incidental in 30%
Presentations related to:
- Cytopaenias (anaemia, thrombocytopaenia)
- Thrombocytosis
- Splenomegaly (MASSIVE) → Budd-Chiari syndrome
- Hepatomegaly (extra-medullary haematopoiesis)
- Hypermetabolic state (WL, fatigue and dyspnoea, night sweats, hyperuricaemia)

Question 5

What are the features of primary myelofibrosis on investigation

Answer 5

Blood film:
- Leucoerythroblastic picture
- Tear drop poikilocytosis (dacrocytes)
- Giant platelets
- Circulating megakaryocytes

Bone marrow:
- DRY TAP
- Trephine biopsy: increased reticulin/collagen fibrosis, increased clustering and megakaryocytes, new bone formation
JAK2/CALR mutation
Evidence of extramedullary haematopoeisis (liver, spleen)

Question 6

What is the treatment for primary myelofibrosis

Answer 6

Supportive:
- transfusion of RBC or platelets (often ineffective due to splenomegaly → rapid break down RBCs)

Medical:
- Cytoreductive Therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia)
- Ruxolotinib (JAK2 inhibitor – only used in high prognostic score cases)

HSCT: potentially curative (reserved for high risk eligible cases)
Splenectomy: symptomatic relief but a dangerous operation, often followed by worsening of condition

Question 7

What is the prognosis for myelofibrosis

Answer 7

Prognostic scoring system = DIPPS (1-6)
Median 3-5 years survival (however, very variable)
BAD prognostic signs:
- Severe anaemia < 100 g/L
- Thrombocytopaenia < 100 x 109/L
- Massive splenomegaly
- High DIPPS score (score 4-6: 1.3 years)

Question 8

Which gene mutations are associated with myeloproliferative disorders

Answer 8

JAK2: single point mutation in polycythaemia vera (100%), essential thrombocythaemia and primary myelofibrosis
Calreticulin:
MPL

Question 9

What are myelodysplastic syndromes and what are the characterised by

Answer 9

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 10

What are the clinical features of myelodysplasia

Answer 10

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

Question 11

What are the features of myelodysplasia in the blood

Answer 11

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 12

What is the treatment for myelodysplasia

Answer 12

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 13

What is aplastic anaemia

Answer 13

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 14

What are the causes of aplastic anaemia

Answer 14

Primary:
Acquired: idiopathic aplastic anaemia (70%), familial aplastic anaeamia (pan)
Congenital: Fanconi’s anaemia, dyskeratosis congenita (pan), Diamond-Blackfan anaemia (single)
Kostmann’s syndrome (form of SCID) (single)

Secondary
Marrow infiltration
Haematological (leukaemia, lymphoma, myelofibrosis)
Non-haematological (Solid tumours, secondary fibrosis)
Radiation
Drugs e.g. cytotoxic, chlorampehnicol, thiazides, carbimazole, gold salts
Autoimmune
Infection: Parvovirus, viral hepatitis