Myleodysplastic syndromes and Aplastic anaemia

Question 1

1. What are myelodysplastic syndromes?
2. What are they characterized by?

Answer 1

1. Biologically heterogeneous group of acquired haemopoietic stem cell disorders approx 4 per 100,000 persons
2. Characterized by:

• The development of a clone of marrow stem cells with abnormal maturation resulting in
  
  • functionally defective blood cells AND
  • a numerical reduction in blood cells
• Cytopenia
• Qualitative/functional abnormalities of erythroid, myeloid and megakaryocyte maturation
• Increased risk of transformation to leukemia

Question 2

What is myelodysplasia?

Answer 2

• Typically a disorder of the elderly
• Symptoms/signs are those of general marrow failure
• Develops over weeks and months

Question 3

What are some blood and bone marrow morphological features in myelodysplatic syndromes?

Answer 3

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

Question 4

What does this image show?

Answer 4

Pelger-Huet anomaly - bilobed neutrophils

Question 5

What does this image show?

Answer 5

Refractory anaemia dysgranulopoiesis

irregular production of granulocytes and causing refractory anemia

Question 6

What does this image show?

Answer 6

Myelokathexis

Question 7

What does this image show?

Answer 7

Ringed sideroblasts

Question 8

What does this image show?

Answer 8

Myeloblasts with Auer rods

Question 9

What is the prognostic scoring system for MDS?

Answer 9

International Prognostic Scoring system (IPSS-R)

Scores for risk categories:

• <1.5 - very low risk
• 1.5-3.0 - Low risk
• >3-4.5 - Intermediate risk
• >4.5-6.0 - High risk
• >6 - very high risk

median survival decreases with increased risk score

Question 10

What is the evolution of myelodysplasia?

Answer 10

1. Deterioation of blood counts
   * Worsening consequences of marrow failure
2. Development of acute myeloid leukemia (depends on subtype)

• Develops in 5-50% <1 year (depends on subtype)
• Some cases of MDS are much slower to evolve
• AML from MDS has an extremelt poor prognosis and is usally not curable

3. As a rule of thumb:

• 1/3 die from infection
• 1/3 die from bleeding
• 1/3 die from acute leukemia

Question 11

Describe the WHO classification of MDS

Answer 11

• Refractory anaemia
  
  • 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 and others

Question 12

What are the treatments for MDS that prolong survival?

Answer 12

There are only two treatments at the moment that prolong survival:

• Allogenic cell transplantation (SCT)
• Intensive chemotherapy

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

Question 13

What are the main types of treatment for MDS?

Answer 13

1. Supportive care

• Blood product support
• Antimicrobial therapy
• Growth factors (Epo, G-CSF)

2. Biological modifiers:

• Immunosuppressive therapy
• Azacytidine and Decitabine (hypomethylating agents)
• Lenalidomide (given in combination with dexamethasone)

3. Oral chemotherapy
   * Hydroxyurea
4. Low dose chemotherapy
   * Subcutaenous low dose cytrabine
5. Intensive chemotherapy/SCT (for high risk MDS)

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

Question 14

Which one of the following about MDS is true?

1. Myelodysplasia has a bi-modal age distribution
2. The primary modality of treatment of MDS is by intesnive 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 14

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

Question 15

Describe the haematopoietic cell lines

Answer 15

Multipotential haematopoietic stem cell (hemocytoblast) which can become a common myeloid progenitor or a common lymphoid progenitor.

Common myeloid progenitor can evolve into:

• Megakarocytes –> breakdown into thrombocytes
• Erythrocytes
• Mast cells
• Myleoblasts –> granulocytes such as basophils, neutrophils, eosinophils, monocytes

Common lymphoid progenitor cells can evolve into:

• Small lymphocyte into
  
  • B lymphocyte –> plasma cell or
  • T lymphocyte
• Natural killer cell

Question 16

What is bone marrow failure and what happens?

Answer 16

• Bone marrow failure resulst from damage of suppression of stem cell progenitor cell
• Pluripotent haemtopoietic cell affected - impairs production of all peripheral blood cells - but this is rare
• Committed progenitor cells down the line affected will result in bi- or unictopenias

Question 17

1. What are the causes of primary bone marrow failure and what cells are affected?
2. What are the causes of secondary bone marrow failure?

Answer 17

1. Primary bone marrow failure

• Congenital - Fanconi’s anaemia - multipotent stem cells
• Diamond-Blackfan anaemia - red cell progenitors
• Kostmann’s syndrome - neutrophil progenitors
• Acquired - idiopathic aplastic anaemia - multipotent stem cell

2. Secondary bone marrow failure:

• Marrow infiltration
• Haematological (leukemia, lymphoma, myelofibrosis)
• Non haematological (solid tumours)
• Radiation
• Drugs
• Chemicals e.g. benzene
• Autoimmune
• Infection (parvovirus, viral hepatitis)

Question 18

What classes of drugs can cause marrow failure?

Answer 18

1. Predicatable (dose dependent and common)
   * Cytotoxic drugs
2. Idiosynchratic (dose dependent, rare)

• Phenylbutazone
• Golds salts

3. Antibiotics

• Chloramphenicol
• Sulphonamides

4. Diuretics
   * Thiazides
5. Antithyroid drugs
   * Carbimazole

Question 19

What is the epidemiology of aplastic anaemia?

Answer 19

• 2-5 cases/million/year worldside
• All age groups can be affected
• Peak incidence
  
  • 15-24 years
  • over 60 years

Bimodal distribution

Question 20

What is the classification of aplastic anaemia?

Answer 20

1. Idiopathic
   * Vast majority (70-80%)
2. Inherited

• Dyskeratosis congenita (DC)
• Fanconi anaemia (FA)
• Schwachman-Diamond syndrome

3. Secondary

• Radiation - predictable
• Drugs - cytotoxic agents (predictable), chloramphenicol and NSAIDs (idiosyncratic)
• Viruses - Hepatitis
• Immune - SLE

Question 21

What is the pathophysiology of idiopathic anaplastic anaemia?

Answer 21

• Failure of bone marrow to produce blood cells
• Stem cell problem
• Immune attack
  
  • Humoral or cellular (T cell) attack against multipotent haematopoietic stem cell

Question 22

What is the clinical presentation of anaplastic anaemia?

Answer 22

The triad of bone marrow failure findings

1. Anaemia - Fatigue, breathlessness
2. Leucopenia - increased infections
3. Platelets - easy bruising/bleeding

Question 23

How is aplastic anaemia diagnosed?

Answer 23

• Blood - cytopenia
• Marrow - hypocellular

Question 24

What do the images show?

Answer 24

• Left = normal bone marrow
• Right = Aplastic bone marrow

Question 25

What are some differential diagnoses of pancytopenia and hypocellular marrow?

Answer 25

* Hypoplastic MDS/AML * Hypocellular acute lymphoblastic leukemia * Hairy cell leukemia * Mycobacterial (usually atypical) infection * Anorexia nervosa * Idiopathic thrombocytopenic purpura

Question 26

What is the Camitta criteria?

Answer 26

Diagnostic criteria for aplastic anaemia 2 out of 3 peripheral blood features: * Reticulocytes \<1% (\<20x10⁹/l) * Neutrophils \<0.5 x10⁹/l * Platelets \<20x10⁹/l Bone marrow \<25% cellularity

Question 27

What is the management of bone marrow failure?

Answer 27

* Seek and remove a cause of the bone marrow failure * Supportive * Blood/platelet transfusions * Antibiotics * Iron chelation therapy * Immunosuppressive therapy (steroids, anti-thymocyte, cyclosporin A) * Drugs to promote marrow recovery - oxymethone, TPO receptor agonists (eltromobopag) * Stem cell transplantation

Question 28

What is the treatment for aplastic anaemia?

Answer 28

1. Supportive * Blood products - leucodepleted, C,V negative, irradiated * Antimicrobials * Iron Chelation therapy when ferritin is \>1000ug/l 2. Specific treatment - Idiopathic AA * Immunosuppressive therapy - older patient * Anti-lymphocyte globulin * Ciclosporin * Androgens - oxymethalone * Stem cell transplantation - younger patient with a donor available (80% cure)

Question 29

What are late complications following immunosuppressive therapy for AA?

Answer 29

1. Relapse of AA (35% over 15 years) 2. Clonal haematological disorders * Myelodysplasia * Leukaemia * 20% risk over 10 years * Paroxysmal nocturnal haemoglobinuria (PNH) may be a transient phenomenon 3.Solid tumours - 3% risk

Question 30

Regarding aplastic anaemia, which one is true? 1. Immunosuppressive therapy is only used to treat a minority for patients with anaplastic 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 allogenic 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 cytogenic abnormalities in the bone marrow 5. Leucodepletion of cellular blood products is only exceptionally undertaken for patients with aplastic anaemia

Answer 30

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

Question 31

Describe Fanconi Anaemia

Answer 31

* The most common form of inherited aplastic anaemia * Autosomal recessive or X linked inheritance * Heterozygous frequency may be 1:300 * Multiple mutated genes are responsible * When genes become mutated this results in:​ * Abnormalities in DNA repair * Chromosomal fragility (breakage in the presence of in vitro mitomycin or diepoxybutane)

Question 32

Describe the somatic/congenital abnormalities in Fanconi anaemia

Answer 32

* Short stature * Hypopigmented spots and cafe au lait spots * Abnormality of thumbs * Microcephaly or hydrocephaly * Hypogonadism * Developmental delay * However, No abnormalities in 30%

Question 33

What genes are associated with Fanconi's anaemia?

Answer 33

* Multiple genes appear responsible for this illness * It has been suggested that the genes for FA-A, -B, -C and -D act through a final common pathway involved with DNA repair mechanisms

Question 34

Describe Dyskeratosis congenita 1. What is it characterised by? 2. Presentation triad?

Answer 34

1. An inherited disorder characterized by: * Marrow failure * Cancer predisposition * Somatic abnormalities 2. Presents with the classical triad of: * Skin pigmentation * Nail dystrophy * Leukoplakia - thick white plaques in the mouth and tounge

Question 35

What drugs can be used to promote bone marrow recovery?

Answer 35

* TPO receptor agonists e.g. eltrombopag * Oxymetholone * Growth factors

Question 36

What is the genetic basis of dyskeratosis congenita? * Inheritance * Genes involved * Underlying pathophysiology

Answer 36

* Telomere shortening * 3 patterns of inheritance * 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 * Abnormal teleomeric structure and function is implicated * Telomeres: * Are found at the end of chromosomes * Act to prevent chomosomal fusion or rearrangements during chromosomal replication * Protect the genes at the end of the chromosome from degradation * In DC the telomere length is reduced due to marrow failure diseases * Maintenance of telomere length is required for the indefinite proliferation of human cells * X

Question 37

Which 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 37

1. Telomeric shortening is a feature of both idioplastic aplastic anaemia and DC

Question 38

Describe the treatment of algorithim for severe aplastic anaemia

Answer 38