HAEM: Myelodysplastic syndromes/ Bone marrow failure

Question 1

Answer 1

Platelet count

Question 2

Define myelodysplastic syndromes (MDS).

Answer 2

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)

Question 4

Who is most affected by myelodysplasia?

Answer 4

Elderly

Symptoms of BM failure

Over weeks/months

Question 5

What are the main 3 features of MDS?

Answer 5

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

Question 6

What is Pelger-Huet anomaly in MDS?

Answer 6

bilobed neutrophils - joined together by thin rim of nuclear substance

Question 7

What feature of MDS is this?

Answer 7

Refractory anaemia dysgranulopoiesis

Question 8

What feature of MDS is this?

Answer 8

Myelokathexis

Question 9

What feature of MDS is this?

Answer 9

Refractory anaemia-dyserythropoiesis

Question 10

What feature of MDS is this?

Answer 10

Ringed Sideroblasts

Question 11

What feature of MDS is this?

Answer 11

Myeloblasts (with Auer Rods)

Question 12

What is the WHO classification of MDS?

Answer 12

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)

Question 13

What are the prognostic factors taken into account in MDS?

Answer 13

• BM blast %
• Karyotype
• Hb
• Platelets
• Neutrophils

Question 14

Summarise the prognostic factors of IPSS-R in MDS.

Answer 14

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

Question 15

Question 16

Name some mutatins of prognostic significance in MDS.

Answer 16

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.

Question 17

Describe the progression/evolution of MDS.

Answer 17

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

Question 18

What is the prognosis with AML post MDS?

Answer 18

Extremely poor

Question 19

What are the causes of death in MDS?

Answer 19

As a rule of thumb

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

Question 20

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

Answer 20

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

Question 21

What supportive care is offered in MDS?

Answer 21

Supportive care

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

Question 22

What biological modifiers can be used in MDS?

Answer 22

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

Question 23

Answer 23

3

Question 24

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

Answer 24

Oral chemotherapy: Hydroxyurea

Low dose chemotherapy: Subcutaneous low dose cytarabine

Question 25

What intensive chemotherapy is available for high risk MDS?

Answer 25

Intensive Chemotherapy/SCT (for high risk MDS): * AML type regimens * Allo/VUD standard/ reduced intensity

Question 26

Reminder:

Question 27

What is the aetiology of BM failure?

Answer 27

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

Question 28

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

Answer 28

PLURIPOTENT HAEMATOPOIETIC CELL --\> impairs production of all peripheral blood cells (rare) COMMITTED PROGENITOR CELLS --\> result in bi- or unicytopenias

Question 29

What are the primary causes of BM failure?

Answer 29

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)

Question 30

What are the secondary causes of BM failure?

Answer 30

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

Question 31

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

Answer 31

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

Question 32

What is the peak incidence of aplastic anaemia?

Answer 32

All age groups can be affected Peak incidence: 15 to 24 yrs AND over 60 yrs

Question 33

What is the classification of causes of aplastic anaemia?

Answer 33

* Idiopathic * Inherited * Secondary * Miscellaneous

Question 34

What is the problem in idiopathic AA?

Answer 34

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.

Question 35

What is the triad of clinical features of AA?

Answer 35

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

Question 36

How is AA diagnosed?

Answer 36

DIAGNOSIS: 1. Blood = Cytopenia 2. Marrow= Hypocellular

Question 37

What are the two types of AA?

Answer 37

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

Question 38

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

Answer 38

Camitta criteria = BM biopsy necessary and peripheral blood **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 39

What are the differentials for pancytopenias/hypocellular marrow?

Answer 39

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

Question 40

What are the differences in these BM samples?

Answer 40

1. normal 2. aplastic BM

Question 41

What is the management of BM failure?

Answer 41

* **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 recover**y * 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)

Question 42

Answer 42

3

Question 43

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

Answer 43

35% over 15 yrs

Question 44

What are the late complications following immunosuppressive therapy for AA?

Answer 44

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

Question 45

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

Answer 45

May be transient

Question 46

Treatment algorithm for severe aplastic anaemia:

Question 47

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

Answer 47

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)

Question 48

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

Answer 48

Fanconi anaemia Autosomal recessive or X-linked inheritance Heterozygote frequency may be 1:300

Question 49

What are the genetic problems in Fanconi's anaemia?

Answer 49

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)

Question 50

What somatic/congenital abnormalities may also occur in FA?

Answer 50

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

Question 51

How common are congenital malformations in FA?

Answer 51

Congenital malformations may occur in 60-70% of children with FA: No abnormalities in 30%

Question 52

What are the most common complications of FA?

Answer 52

Question 53

What is dyskeratosis congenita?

Answer 53

Inherited disorder characterised by: * Marrow failure * Cancer predisposition * Somatic abnormalities

Question 54

What is the classical triad of dyskeratosis congenita?

Answer 54

1. Skin pigmentation 2. Nail dystrophy 3. Leukoplakia

Question 55

What are the most common complications of DC?

Answer 55

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

Question 56

What is the management of BM failure in DC?

Answer 56

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

Question 57

What is the MAIN genetic basis of DC?

Answer 57

Telomere shortening

Question 58

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

Answer 58

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

Question 59

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

Answer 59

_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.**

Question 60

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

Answer 60

Question 61

Answer 61

1