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pathy5 > Myelodysplastic syndromes and aplastic anaemia > Flashcards

Myelodysplastic syndromes and aplastic anaemia Flashcards

1
Q

Which one result of the follow falls within the normal reference range?
Hb 29.0 g/L
Total White Cell Count 109.3 x 10^9/L
Platelet count 273 x 10^9/L
Neutrophil count 0.34 x 10^9/L
Blood urea 29.5 mmol/l

A

Platelet count 273 x 10^9/L

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2
Q

What is MDS?

A

Biologically heterogeneous group of acquired haemopoietic stem cell disorders (~ 4 per 100,000 persons)

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3
Q

What is MDS characterised by?

A

The development of a clone of marrow stem cells with abnormal maturation resulting in -
functionally defective blood cells AND
a numerical reduction
This results in:
i. Cytopenia(s).
ii. Qualitative (i.e. functional) abnormalities of erythroid, myeloid and megakaryocyte maturation.
iii. Increased risk of transformation to leukaemia

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4
Q

What is the general clinical picture of myelodysplasia?

A

Typically a disorder of the elderly.

Symptoms/signs are those of general marrow failure

Develops over weeks & months

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5
Q

What are Some Blood & Bone Marrow Morphological Features of MDS?

A

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

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6
Q

What is this?

A

Refractory anaemia dysgranulopoiesis

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7
Q

What is myelokathexis?

A

Myelokathexis is a congenital disorder of the white blood cells that causes severe, chronic leukopenia (a reduction of circulating white blood cells) and neutropenia (a reduction of neutrophil granulocytes). The disorder is believed to be inherited in an autosomal dominant manner.

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8
Q

What is this?

A

Ringed sideroblasts

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9
Q

What is this?

A

Myeloblast with Auer Rods

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10
Q

What is the WHO classification of MDS?

A

Refractory anaemia (RA)​

with ringed sideroblasts (RARS)​

without ringed sideroblasts​

Refractory cytopenia with multilineage dysplasia (RCMD)​

Refractory anaemia with excess of blasts (RAEB)​

RAEB-I (BM blasts 5-9%)​

RAEB-II (BM blasts 10-19%)​

5q- syndrome​

Unclassified MDS: MDS with fibrosis, childhood MDS, others

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11
Q

What is the Revised International Prognostic Scoring System (IPSS-R) in MDS (2012)​?

A
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12
Q

How do you use IPSS R for prognosis?

A
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13
Q

What is the evolution of myelodysplasia?

A
  1. Deterioration of blood counts​

• Worsening consequences of marrow failure​

  1. 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​

  1. 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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14
Q

What is the treatment of MDS?

A

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

allogeneic stem cell transplantation (SCT)​

intensive chemotherapy​

but only a minority of MDS patients can really benefit from them

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15
Q

What are the specific treatments of MDS?

A

​

1 Supportive care​

Blood product support​

Antimicrobial therapy​

Growth factors (Epo, G-CSF)​

​

2 Biological Modifiers​

Immunosuppressive therapy​

Azacytidine ) Hypomethylating​

Decitabine ) agents​

Lenalidomide

​

3 Oral chemotherapy​

Hydroxyurea​

​

4 Low dose chemotherapy​

Subcutaneous low dose cytarabine​

​

5 Intensive Chemotherapy/SCT (for high risk MDS)​

AML type regimens​

Allo/VUD standard/ reduced intensity

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16
Q

Which one of the following about MDS is true?:

Myelodysplasia has a bi-modal age distribution​

The primary modality of treatment of MDS is by intensive chemotherapy​

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

There is no good correlation between the severity of the cytopenias and the overall life expectancy​

White cell function is frequently well preserved in MDS

A

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

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17
Q

Draw out the haematopoietic cell lines

A
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18
Q

What is Bone Marrow Failure?

A

Results from damage or suppression of stem or progenitor cell ​

​

PLURIPOTENT HAEMATOPOIETIC CELL Impairs production of all peripheral blood cells​

Rare​

​

COMMITTED PROGENITOR CELLS​

Result in bi- or unicytopenias

19
Q

What are the types of BM failure?

A
  1. PRIMARY​

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)​

​

  1. SECONDARY​

Marrow infiltration:​

Haematological ( leukaemia, lymphoma, myelofibrosis)​

Non-haematological (Solid tumours, )​

Radiation​

Drugs​

Chemicals (benzene)​

Autoimmune​

Infection (Parvovirus, Viral hepatitis

20
Q

Which drugs cause BMF?

A

PREDICTABLE (dose-dependent, common)​

Cytotoxic drugs​

IDIOSYNCHRATIC (NOT dose-dependent, rare)​

Phenylbutazone​

Gold salts​

ANTIBIOTICS​

Chloramphenicol​

Sulphonamide​

DIURETICS​

Thiazides​

ANTITHYROID DRUGS​

Carbimazole

21
Q

What is the epidemiology of aplastic anaemia?

A

​

• 2-5 cases/million/yr (world-wide)​

​

• All age groups can be affected​

​

• Peak incidence: ​

i. 15 to 24 yrs​
ii. over 60 yrs

22
Q

What is the classification of aplastic anaeamia?

A

IDIOPATHIC: Vast majority (70-80%)​

​

INHERITED: Dyskeratosis congenita (DC)​

Fanconi anaemia (FA)​

Shwachman-Diamond syndrome​

​

SECONDARY: Radiation: Predictable​

Drugs: Predictable: Cytotoxic agents​

Idiosyncratic: Chloramphenicol​

NSAIDS​

Viruses (Idiosyncratic): Hepatitis viruses​

Immune: SLE​

23
Q

What is the pathophysiology of aplastic anaemia?

A

Failure of BM to produce blood cells​

​

• “Stem cell” problem (CD34, LTC-IC) [Long-Term Culture-Initiating Cells]​

​

• Immune attack: ​

Humoral or cellular (T cell) attack against multipotent haematopoietic stem cell.

24
Q

What is the clinical presentation of AA?

A
  1. Anaemia Fatigue, breathlessness​

​

  1. Leucopenia Infections​

​

  1. Platelets Easy bruising/bleeding
25
Q

How do you diagnose AA?

A

​1. Blood Cytopenia​

  1. Marrow Hypocellular
26
Q

What is the classification of AA?

A

​1. Severe aplastic anaemia (SAA)​

  1. Non-severe aplastic anaemia (NSAA)
27
Q

What is severe AA classed as?

A

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

28
Q

What is the management of BMF?

A
  1. Seek and remove a cause (detailed drug & occupational exposure history).​

​

  1. Supportive: Blood/platelet transfusions (leucodepleted, CMV neg, irradiated)​

Antibiotics​

Iron Chelation Therapy​

​

  1. Immunosuppressive therapy (anti-thymocyte globulin, steroids, eltrombopag, cyclosporine A)​

​

  1. Drugs to promote marrow recovery​

Oxymethone, TPO receptor agonists (eltrombopag), ??G-CSF (prob not).​

​

  1. Stem cell transplantation​

​

  1. Other treatments in refractory cases – e.g. alemtuzumab (anti-CD52, high dose cyclophosphamide)
29
Q

What is the treatment of AA?

A
  1. SUPPORTIVE ​

Blood products ​ Leucodepleted​ (CMV negative)​ (Irradiated)​

Antimicrobials​

Iron Chelation Therapy​ (when ferritin > 1000 ug/l)

  1. SPECIFIC TREATMENT – Idiopathic AA​

Based on:​

Severity of illness​

Age of patient​

Potential sibling donor​

A. Immunosuppressive therapy – older patient​

Anti-Lymphocyte Globulin (ALG)​

Ciclosporin​

B. Androgens – oxymethalone​

C. Stem cell transplantation​

Younger patient with donor (80% cure)​

VUD/MUD for > 40 yrs (50% survival)

30
Q

What are the late complications following immunosuppressive therapy for AA?

A
  1. Relapse of AA (35% over 15 yrs)​

​

  1. Clonal haematological disorders ​

Myelodysplasia​

Leukaemia ​

~ 20% risk over 10 yrs​

PNH (paroxysmal nocturnal haemoglobinuria)​

May be a transient phenomenon​

​

  1. Solid tumours ~ 3% risk
31
Q

Regarding Aplastic Anaemia – which one answer is true?​

Immunosuppressive therapy is only used to treat a minority of patients with aplastic anaemia.​

If treated with immunosuppression, then relapse of Aplastic Anaemia occurs in less than 15% of cases​

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

Severe aplastic anaemia is differentiated from non-severe aplastic anaemia on the basis of the acquired cytogenetic abnormalities in the bone marrow.​

Leucodepletion of cellular blood products is only exceptionally undertaken for patients with aplastic anaemia.

A
32
Q

What are the inherited BMF syndromes?

A
33
Q

What is Fanconi anaemia?

A

The most common form of inherited aplastic anaemia.​

Autosomal recessive or X-linked inheritance​

Heterozygote frequency may be 1:300​

Multiple mutated genes are responsible. ​

When these genes become mutated, this results in:​

Abnormalities in DNA repair​

Chromosomal fragility ​

(breakage in the presence of in-vitro mitomycin or diepoxybutane)

34
Q

What are the Somatic/congenital abnormalities in FA​?

A

​

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

​

Short Stature​

Hypopigmented spots and café-au-lait spots​

Abnormality of thumbs​

Microcephaly or hydrocephaly​

Hyogonadism​

Developmental delay ​

No abnormalities 30%

35
Q

What are the complications of fanconi syndrome?

A

Aplastic anaemia 90 9​

​

Leukaemia 10 14​

​

Liver disease 4 16​

​

Myelodysplasia 32 17​

​

Cancer (epithelial) 5 23

36
Q

What is DYSKERATOSIS CONGENITA (DC)​?

A

DYSKERATOSIS CONGENITA (DC)​

​

An inherited disorder characterised by:​

Marrow failure​

Cancer predisposition ​

Somatic abnormalities​

​

Patients may present with the Classical Triad of ​

Skin pigmentation​

Nail dystrophy​

Leukoplakia

37
Q

What are the Somatic abnormalities/complications in DC​?

A

Abnormal skin pigmentation

Nail dystrophy

BMF

Leucoplakia

38
Q

What is the management of BMF?

A
  1. Supportive: Blood/platelet transfusions​

Antibiotics​

Iron Chelation Therapy (possibly)​

​

  1. Drugs to promote marrow recovery​

TPO receptor agonists (e.g. eltrombopag)​

?Oxymetholone?​

??Growth factors??​

​

  1. Stem cell transplantation​

​

  1. Future ? haemopoietic gene therapy
39
Q

Why does DC happen?

A

3 patterns of inheritance​

Abnormal telomeric structure & function is implicated.​

Telomeres​

are found at the end of chromosomes​

act to prevent chromosomal fusion or rearrangements during chromosomal replication​

protect the genes at the end of the chromosome from degradation.​

Telomere length is reduced marrow failure diseases (especially short in patients with DC). ​

Maintenance of telomere length is required for the indefinite proliferation of human cells.

40
Q

What genes are involved in DC?

A

X-linked recessive trait — the most common inherited pattern (mutated DKC1 gene - defective telomerase function).​

​

Autosomal dominant trait — (mutated TERC gene - encodes the RNA component of telomerase). ​
​

Autosomal recessive trait — The gene for this form of DC has not yet been identified

41
Q
A
42
Q

Compare DC and AA

A
43
Q

Which one of the following is true?

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

Development of malignancy is an uncommon complication of Fanconi Anaemia​

A single genetic defect has been identified as the underlying cause for Fanconi Anaemia​

Fanconi Anaemia is usually inherited in an autosomal dominant fashion​

Telomeric function is considered to be unimportant in the pathophysiology of Dyskeratosis Congenita.

A

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

44
Q

What’s the treatment algorithm for severe AA?

A

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