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Year 5 - Pathology > HAEM: Myelodysplastic syndromes/ Bone marrow failure > Flashcards

HAEM: Myelodysplastic syndromes/ Bone marrow failure Flashcards

1
Q
A

Platelet count

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2
Q

Define myelodysplastic syndromes (MDS).

A

Biologically heterogeneous group of acquired haemopoietic stem cell disorders

Characterised by development of a clone of marrow stem cells with abnormal maturation resulting in functionally defective blood cells AND a numerical reduction

(~ 4 per 100,000 persons)

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3
Q
A
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4
Q

Who is most affected by myelodysplasia?

A

Elderly

Symptoms of BM failure

Over weeks/months

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5
Q

What are the main 3 features of MDS?

A
  1. Cytopenia
  2. Qualitative (i.e. functional) abnormalities of erythroid, myeloid and megakaryocyte maturation.
  3. Increased risk of transformation to leukaemia
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6
Q

What is Pelger-Huet anomaly in MDS?

A

bilobed neutrophils - joined together by thin rim of nuclear substance

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7
Q

What feature of MDS is this?

A

Refractory anaemia dysgranulopoiesis

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8
Q

What feature of MDS is this?

A

Myelokathexis

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9
Q

What feature of MDS is this?

A

Refractory anaemia-dyserythropoiesis

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10
Q

What feature of MDS is this?

A

Ringed Sideroblasts

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11
Q

What feature of MDS is this?

A

Myeloblasts (with Auer Rods)

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12
Q

What is the WHO classification of MDS?

A

Based on:

  1. Number of dysplastic lineages
  2. Percentage of blasts in bone marrow and peripheral blood
  3. Cytogenetic findings
  4. Percentage of ringed sideroblasts
  5. Number of cytopenias (based on criteria from the International Prognostic Scoring System - IPSS)
    • 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)
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13
Q

What are the prognostic factors taken into account in MDS?

A
  • BM blast %
  • Karyotype
  • Hb
  • Platelets
  • Neutrophils
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14
Q

Summarise the prognostic factors of IPSS-R in MDS.

A

The higher the score the lower the survival and the lower the time to progression to AML.

  • Very low risk = _<_1.5
  • Low risk = 1.5-3.0
  • Intermediate risk = >3.0-4.5
  • High risk = >4.5-6.0
  • Very high risk = >6
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15
Q
A
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16
Q

Name some mutatins of prognostic significance in MDS.

A

Driver mutations in MDS - carry prognostic significance:

  • TP53, EZH2, ETV6, RUNX1, ASXL1
  • Others: SF3B1, TET2, DNMT3A

More commonly found in high risk rather than low risk MDs.

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17
Q

Describe the progression/evolution of MDS.

A
  1. Deterioration of blood counts
    • Worsening consequences of marrow failure
  2. Development of acute myeloid leukaemia
    • 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
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18
Q

What is the prognosis with AML post MDS?

A

Extremely poor

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19
Q

What are the causes of death in MDS?

A

As a rule of thumb

  • 1/3 die from infection
  • 1/3 die from bleeding
  • 1/3 die from acute leukaemia
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20
Q

What are the two main treatments for MDS which prolong survival?

A

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

1. allogeneic stem cell transplantation (SCT)

2. intensive chemotherapy - but most are not good candidates for this due to their age

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21
Q

What supportive care is offered in MDS?

A

Supportive care

  1. Blood product support
  2. Antimicrobial therapy
  3. Growth factors (Epo, G-CSF, TPO-Receptor Agonist)
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22
Q

What biological modifiers can be used in MDS?

A
  • Immunosuppressive therapy
  • Azacytidine (Hypomethylating agent)
  • Decitabine (Hypomethylating agent)
  • Lenalidomide (for del(5q) variant)
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23
Q
A

3

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24
Q

What oral therapy and what low dose chemotherapy may be used in MDS?

A

Oral chemotherapy: Hydroxyurea

Low dose chemotherapy: Subcutaneous low dose cytarabine

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25
Q

What intensive chemotherapy is available for high risk MDS?

A

Intensive Chemotherapy/SCT (for high risk MDS):

  • AML type regimens
  • Allo/VUD standard/ reduced intensity
26
Q

Reminder:

A
27
Q

What is the aetiology of BM failure?

A

Results from damage or suppression of stem or progenitor cell (i.e. top of the diagram)

28
Q

If a pluripotent stem cell is damaged what is the result?

If a committed progenitor cell is damaged what is the result?

A

PLURIPOTENT HAEMATOPOIETIC CELL –> impairs production of all peripheral blood cells (rare)

COMMITTED PROGENITOR CELLS –> result in bi- or unicytopenias

29
Q

What are the primary causes of BM failure?

A

PRIMARY

  1. Congenital: Fanconi’s anaemia (multipotent stem cell)
  2. Diamond-Blackfan anaemia (red cell progenitors)
  3. Kostmann’s syndrome (neutrophil progenitors)
  4. Acquired: Idiopathic aplastic anaemia (multipotent stem cell)
30
Q

What are the secondary causes of BM failure?

A

SECONDARY

  1. Marrow infiltration:
  2. Haematological (leukaemia, lymphoma, myelofibrosis)
  3. Non-haematological (Solid tumours, )
  4. Radiation
  5. Drugs
  6. Chemicals (benzene)
  7. Autoimmune
  8. Infection (Parvovirus, Viral hepatitis
31
Q

Give 3 examples of drugs which can cause BM failure. How are these categorised?

A
  1. PREDICTABLE (dose-dependent, common) e.g. Cytotoxic drugs
  2. IDIOSYNCRATIC (NOT dose-dependent, rare) e.g. Phenylbutazone, Gold salts
  3. ANTIBIOTICS e.g. Chloramphenicol, sulphonamide
  4. DIURETICS e.g. Thiazides
  5. ANTITHYROID DRUGS e.g. Carbimazole
32
Q

What is the peak incidence of aplastic anaemia?

A

All age groups can be affected

Peak incidence: 15 to 24 yrs AND over 60 yrs

33
Q

What is the classification of causes of aplastic anaemia?

A
  • Idiopathic
  • Inherited
  • Secondary
  • Miscellaneous
34
Q

What is the problem in idiopathic AA?

A

Failure of BM to produce blood cells

  • “Stem cell” problem (CD34, LTC-IC) [Long-Term Culture-Initiating Cells]
  • OR Immune attack: Humoral or cellular (T cell) attack against multipotent haematopoietic stem cell.
35
Q

What is the triad of clinical features of AA?

A
  1. Anaemia = Fatigue, breathlessness
  2. Leucopenia = Infections
  3. Platelets = Easy bruising/bleeding
36
Q

How is AA diagnosed?

A

DIAGNOSIS:

  1. Blood = Cytopenia
  2. Marrow= Hypocellular
37
Q

What are the two types of AA?

A
  1. Severe aplastic anaemia (SAA)
  2. Non-severe aplastic anaemia (NSAA)
38
Q

What criteria is used for severe aplastic anaemia diagnosis? What sample is necessary to use this?

A

Camitta criteria = BM biopsy necessary and peripheral blood

2 out of 3 peripheral blood features

    1. Reticulocytes < 1% (<20 x 109/L)
    1. Neutrophils < 0.5 x 109/L
    1. Platelets < 20 x 109/L

Bone marrow <25% cellularity

39
Q

What are the differentials for pancytopenias/hypocellular marrow?

A
  • Hypoplastic MDS / Acute Myeloid Leukaemia
  • Hypocellular Acute Lymphoblastic Leukaemia
  • Hairy Cell Leukaemia
  • Mycobacterial (usually atypical) infection
  • Anorexia Nervosa
  • Idiopathic Thrombocytopenic Purpura
40
Q

What are the differences in these BM samples?

A
  1. normal
  2. aplastic BM
41
Q

What is the management of BM failure?

A
  • Treat + remove 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)
42
Q
A

3

43
Q

What is the risk of relapse in AA following immunosuppressive therapy?

A

35% over 15 yrs

44
Q

What are the late complications following immunosuppressive therapy for AA?

A
  1. Relapse 35% over 15yrs
  2. Clonal haematological disorders e.g. myelodysplasia, leukaemia, 20% risk over 10 years of PNH (paroxysmal hnocturnal haemoglobinuria)
  3. Solid tumours 3% risk
45
Q

Is the 20% risk over 10yrs of PNH going to cause permanent problems?

A

May be transient

46
Q

Treatment algorithm for severe aplastic anaemia:

A
47
Q

Name 2 inherited causes of BM failure causing (a) pancytopenias (b) single cytopenias.

A

PANCYTOPENIAS

  • Fanconi anaemia (FA)
  • Dyskeratosis congenita (DC)
  • Shwachman-Diamond syndrome (SDS)
  • Familial aplastic anaemia (autosomal and X-linked forms)
  • Myelodysplasia
  • Non-haematological syndromes (Down’s, Dubowitz’s)

SINGLE CYTOPENIAS

  • Diamond-Blackfan syndrome
  • Kostman’s syndrome
  • Shwachman-Diamond syndrome
  • Reticular dysgenesis
  • Amegakaryocytic thrombocytopenia with absent radii (TAR)
48
Q

What is the most common inherited form of AA? What is the inheritance?

A

Fanconi anaemia

Autosomal recessive or X-linked inheritance

Heterozygote frequency may be 1:300

49
Q

What are the genetic problems in Fanconi’s anaemia?

A

Several genes responsible. When these genes become mutated, this results in:

  1. Abnormalities in DNA repair
  2. Chromosomal fragility (breakage in the presence of in-vitro mitomycin or diepoxybutane)
50
Q

What somatic/congenital abnormalities may also occur in FA?

A
  • Short Stature
  • Hypopigmented spots and café-au-lait spots
  • Abnormality of thumbs
  • Microcephaly or hydrocephaly
  • Hyogonadism
  • Developmental delay
  • No abnormalities 30%
51
Q

How common are congenital malformations in FA?

A

Congenital malformations may occur in 60-70% of children with FA:

No abnormalities in 30%

52
Q

What are the most common complications of FA?

A
53
Q

What is dyskeratosis congenita?

A

Inherited disorder characterised by:

  • Marrow failure
  • Cancer predisposition
  • Somatic abnormalities
54
Q

What is the classical triad of dyskeratosis congenita?

A
  1. Skin pigmentation
  2. Nail dystrophy
  3. Leukoplakia
55
Q

What are the most common complications of DC?

A

Abnormal skin pigmentation is the most common feature but BM failure is also extremely common

56
Q

What is the management of BM failure in DC?

A

Supportive:

  • Blood/platelet transfusions
  • Antibiotics
  • Iron Chelation Therapy (possibly)

Drugs to promote marrow recovery:

  • TPO receptor agonists (e.g. eltrombopag)
  • ?Oxymetholone?
  • ??Growth factors??

Stem cell transplantation

Future ? haemopoietic gene therapy

57
Q

What is the MAIN genetic basis of DC?

A

Telomere shortening

58
Q

How many patterns of inheritance are there for DC? What are they?

A

3

  1. X-linked recessive trait — the most common inherited pattern (mutated DKC1 gene - defective telomerase function).
  2. Autosomal dominant trait — (mutated TERC gene - encodes the RNA component of telomerase).
  3. Autosomal recessive trait — The gene for this form of DC has not yet been identified
59
Q

What is the normal function and importance of telomeres? What is the length of telomeres important for?

A

Telomeres are found at the end of chromosomes and act to:

  1. prevent chromosomal fusion or rearrangements during chromosomal replication
  2. protect the genes at the end of the chromosome from degradation.

Maintenance of telomere length is required for the indefinite proliferation of human cells. This is reduced significantly in DC.

60
Q

Compare and contrast whether these features are present in DC and idiopathic aplastic anaemia:

  • Physical abnormalities
  • BM failure
  • Malignancy
  • Chromosomal instability
  • Short telomeres
  • No. of genes identified
A
61
Q
A

1

Year 5 - Pathology (89 decks)

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