Myelodysplatic Syndromes/Bone Marrow Failure

Question 1

What are myelodysplastic syndromes

Answer 1

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

The development of a clone of marrow stem cells with abnormal maturation resulting in:
Functionally defective blood cells AND a numerical reduction.

Resulting in:
Cytopenias
Qualitiative (i.e. functional) abnormalities or erythroid, myeloid and megakaryocyte maturation.
Increased risk of transformation to leukaemia.

Question 2

Key features of MDS

Answer 2

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

Question 3

Blood film features of MDS

Answer 3

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%)

Question 4

What is a Pelger-Huet anomaly

Answer 4

Neutrophils with bilobed nuclei. The two lobes are connected by a thin strand giving a ‘ince-nez’ appearance.

Question 5

What is myelokathexis

Answer 5

Pyknotic nuclei with lengthening and thinning of intrasegmented filaments and vacuoles

Question 6

Ringed sideroblasts

Answer 6

Blue-stain ed haemosiderin (Prussian blue stain) deposits in the mitochondria of erythroid precursors to form an apparent ring around the nucleus

Question 7

Myeloblasts with aurer rods

Answer 7

Large cells with high nuclear-to-cytoplasm ratio and nucleoli.
Aurer rod = a pink/red rod like structure in the cytoplasm

Question 8

WHO classification of MDS

Answer 8

Refractory anaemia (RA):
with ringed sideroblasts (RARS) or without ringed sideroblasts

Refractory cytopenia with multilineage dysplasia (RCMD)

Refractory anaemia with excess of blasts (RAEB): RAEB-I (BM blasts 5-10%), RAEB-II (BM blasts 11-20%)

5q- syndrome

Unclassified MDS: MDS with fibrosis, childhood MDS, others

Question 9

Prognostic scoring system in MDS

Answer 9

International Prognostic Scoring System:
BM blasts %
Karyotype 
Hb 
Platelets 
Neutrophils 

Very low risk = <1.5 (median survival 8.8 years)
Low risk =1.5-3
Intermediate risk 3-4.5
High risk 4.5-6
Very high risk >6 (median survival 0.8 years)

Question 10

Clinical course of MDS

Answer 10

Deterioration of blood counts:
Worsening consequences of marrow failure

Development of acute myeloid leukaemia:
Develops in poor prognostic cases in <1 year
Some cases of MDS are much slower to evolve
AML from MDS has an extremely poor prognosis and is usually not curable

As a rule of thumb:
1/3 die from infection
1/3 die from bleeding
1/3 die from acute leukaemia

Question 11

Treatment of MDS

Answer 11

Only two treatments can currently prolong survival:
Allogenic stem cell transplantation (SCT)
Intensive chemotherapy

But only a minority of MDS patients can really benefit from them (mostly because patients cannot tolerate these treatments due to age-related co-morbidities

Supportive care: blood product support, antimicrobial therapy, growth factors (Epo, G-CSF)

Biological modifiers: immunosuppressive therapy, azacytidine/decitabine, lenalidomide

Question 12

Chemotherapy treatments for MDS

Answer 12

Oral chemotherapy: hydroxyurae

Low dose chemotherapy: sucbutaneous low dose cytarbine

Intensive chemotherapy/SCT: AML type regimens, Allo/VUD standard/reduced intensity

Question 13

How is bone marrow failure causes classified

Answer 13

Primary

Secondary

Question 14

Primary causes of bone marrow failure

Answer 14

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)

Question 15

Secondary causes of bone marrow failure

Answer 15

Marrow infiltration:
Haematological ( leukaemia, lymphoma, myelofibrosis)
Non-haematological (Solid tumours)
Radiation
Drugs (e.g. chemotherapy, antibiotics, anti-thyroid, diuretics, etc.)
Chemicals (benzene)
Autoimmune
Infection (Parvovirus, Viral hepatitis

Question 16

Pathophysiology of primary bone marrow failure syndromes

Answer 16

Results from damage or suppression of stem or progenitor cells

PLURIPOTENT HAEMATOPOIETIC CELL
Impairs production of ALL peripheral blood cells
- rare

COMMITTED PROGENITOR CELLS
- results in bi- or uni-cytopenias

Question 17

Drugs and bone marrow failure

Answer 17

Predictable (dose-dependent, common): cytotoxic drugs
Idiosynchratic (not dose-dependent, rare) - phenylbutazone, gold salts
Antibiotics: chloramphenicol, sulphanamide
Diuretics: thiazides
Antithyroid drugs: carbimazole

Question 18

When does aplastic anaemia occur

Answer 18

2-5 cases/million/year
Bi modal age incidence:
15-24 years
Over 60 years

Question 19

Classification of aplastic anaemia

Answer 19

Idiopathic: vast majority
Inherited: dyskeratosis congenita, fanconi anaemia, shwachman-diamond syndrome
Secondary: radiation, drugs (cycotoxic agents, chloramphenicol, NSAIDs), viruses (hepatitis), SLE

Question 20

Pathophysiology of aplastic anaemia

Answer 20

Acquired idiopathic aplastic anaemia (AA) is an immune-mediated bone marrow failure disorder linked to clonal haematopoiesis.

Immune attack of stem cells mediated through cytotoxic T-lymphocytes

The majority of AA patients have somatic mutations (i.e. not inherited) and/or structural chromosome abnormalities.

Question 21

Clinical presentation of aplastic anaemia

Answer 21

Triad of bone marrow failure findings:
Anaemia: fatigue, breathlessness
Leucopenia: infections
Platelets: easy bruising, bleeding.

Question 22

How is aplastic anaemia diagnosed

Answer 22

Blood: cytopenia
Marrow: hypocellular

Question 23

How is aplastic anaemia classified

Answer 23

Severe aplastic anaemia

Non-severe aplastic anaemia

Question 24

Differentail diagnoses of pancytopenia and hypocellular marrow

Answer 24

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

Question 25

Severe aplastic anaemisa

Answer 25

2 out of 3 peripheral blood features: Reticulocytes <1% Neutrophils <0.5 (very severe <0.2) Platelets <20 Bone marrow: <25% cellularity

Question 26

Management of bone marrow failure

Answer 26

Seek a cause (detailed drug & occupational exposure history) Supportive: Blood/platelet transfusions (leucodepleted, CMV neg, irradiated) Antibiotics Iron Chelation Therapy (when ferritin >1000ug/L) Drugs to promote marrow recovery: Androgens – Oxymetholone, Danazol Growth factors Immunosuppressive therapy Stem cell transplantation Future ? haematopoietic gene therapy

Question 27

Specific treatment of aplastic anaemia

Answer 27

Based on: Severity of illness Age of patient Potential sibling donor Immunosuppressive therapy – older patient: Anti-Lymphocyte Globulin (ALG) Ciclosporin Androgens: Oxymethalone Danazol Stem cell transplantation: Younger patient with donor (80% cure) VUD/MUD for > 40 yrs (50% survival

Question 28

Complications of aplastic anaemia (due to immunosuppression)

Answer 28

Relapse of AA (35% over 15 yrs) ``` Clonal haematological disorders: Myelodysplasia Leukaemia ~ 20% risk over 10 yrs PNH (Paroxysmal Nocturnal Haemoglobinuria) May be a transient phenomenon ``` Solid tumours ~ 3% risk

Question 29

Name some causes of pancytopenia

Answer 29

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

Question 30

Name some causes of single cytopenias

Answer 30

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

Question 31

Pathophysiology of fanconi anaemia

Answer 31

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) Multiple genes appear to be 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 32

Clinical features of fanconi anaemia

Answer 32

Normal blood count at birth Marrow failure and pancytopenia develops slowly from aged 5 - 10 onwards 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

Question 33

Treatment of fanconi anaemia

Answer 33

Supportive | Androgens can transiently improve counts but side-effects (hepatic toxicity)

Question 34

Complications of fanconi anaemia

Answer 34

10% terminate in acute leukaemia Aplastic anaemia in 90% Others: liver disease, myelodysplasia, cancer

Question 35

Features of dyskeratosis congenita

Answer 35

An inherited disorder characterised by: Marrow failure Cancer predisposition Somatic abnormalities

Question 36

Clinical features of dyskeratosis congenita

Answer 36

Patients may present with the classical triad of: Skin pigmentation Nail dystrophy Leukoplakia

Question 37

Complications of dyskeratosis congenita

Answer 37

Abnormal skin pigmentation Bone marrow failure Leucoplakia Nail dystrophy

Question 38

Management of bone marrow failure in dyskeratosis congenita

Answer 38

Supportive: Blood/platelet transfusions Antibiotics Drugs to promote marrow recovery: Oxymetholone Growth factors Haematopoietic stem transplantation ? Autologous marrow transplantation Future ? haematopoietic gene therapy

Question 39

Genetic pathophysiology of dyskeratosis congenita

Answer 39

3 patterns of inheritance Abnormal telomeric structure and 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 in marrow failure diseases (especially short in patients with DC). Maintenance of telomere length is required for the indefinite proliferation of human cells. 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

Question 40

Management of bone marrow failure

Answer 40

Supportive: Blood/platelet transfusions: Antibiotics Iron Chelation Therapy (possibly) Drugs to promote marrow recovery: Androgens – Oxymetholone, Danazol Growth factors TPO-receptor agonists (e.g. Eltrombopag) Stem cell transplantation Future ? haematopoietic gene therapy

Question 41

Treatment algorithm for severe apastic anaemia

Answer 41

<35 years at presentation --> if HLA identical sibling donor so HLA matched stem cell transplant If not start horse anti-thymocyte globulin + ciclosporin, if not responding or relapse occurs try either unrelated donor HSCT or eltrombopag or ATG