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Kat's Pathology > Myelodysplatic Syndromes/Bone Marrow Failure > Flashcards

Myelodysplatic Syndromes/Bone Marrow Failure Flashcards

1
Q

What are myelodysplastic syndromes

A

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.

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2
Q

Key features of MDS

A

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

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3
Q

Blood film 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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4
Q

What is a Pelger-Huet anomaly

A

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

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5
Q

What is myelokathexis

A

Pyknotic nuclei with lengthening and thinning of intrasegmented filaments and vacuoles

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6
Q

Ringed sideroblasts

A

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

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7
Q

Myeloblasts with aurer rods

A

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

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8
Q

WHO classification of MDS

A 
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

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9
Q

Prognostic scoring system in MDS

A 
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)

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10
Q

Clinical course of MDS

A

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

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11
Q

Treatment of MDS

A

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

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12
Q

Chemotherapy treatments for MDS

A

Oral chemotherapy: hydroxyurae

Low dose chemotherapy: sucbutaneous low dose cytarbine

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

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13
Q

How is bone marrow failure causes classified

A

Primary

Secondary

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14
Q

Primary causes of bone marrow failure

A

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)

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15
Q

Secondary causes of bone marrow failure

A 
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
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16
Q

Pathophysiology of primary bone marrow failure syndromes

A

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

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17
Q

Drugs and bone marrow failure

A

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

18
Q

When does aplastic anaemia occur

A

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

19
Q

Classification of aplastic anaemia

A

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

20
Q

Pathophysiology of aplastic anaemia

A

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.

21
Q

Clinical presentation of aplastic anaemia

A

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

22
Q

How is aplastic anaemia diagnosed

A

Blood: cytopenia
Marrow: hypocellular

23
Q

How is aplastic anaemia classified

A

Severe aplastic anaemia

Non-severe aplastic anaemia

24
Q

Differentail diagnoses of pancytopenia and hypocellular marrow

A

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

25
Q

Severe aplastic anaemisa

A

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

Bone marrow: <25% cellularity

26
Q

Management of bone marrow failure

A

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

27
Q

Specific treatment of aplastic anaemia

A

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

28
Q

Complications of aplastic anaemia (due to immunosuppression)

A

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

29
Q

Name some causes of pancytopenia

A

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)

30
Q

Name some causes of single cytopenias

A 
Diamond-Blackfan syndrome
Kostman’s syndrome
Shwachman-Diamond syndrome
Reticular dysgenesis
Amegakaryocytic thrombocytopenia with absent radii (TAR)
31
Q

Pathophysiology of 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)

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.

32
Q

Clinical features of fanconi anaemia

A

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

33
Q

Treatment of fanconi anaemia

A

Supportive

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

34
Q

Complications of fanconi anaemia

A

10% terminate in acute leukaemia
Aplastic anaemia in 90%

Others: liver disease, myelodysplasia, cancer

35
Q

Features of dyskeratosis congenita

A

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

36
Q

Clinical features of dyskeratosis congenita

A

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

37
Q

Complications of dyskeratosis congenita

A

Abnormal skin pigmentation
Bone marrow failure
Leucoplakia
Nail dystrophy

38
Q

Management of bone marrow failure in dyskeratosis congenita

A

Supportive:
Blood/platelet transfusions
Antibiotics

Drugs to promote marrow recovery:
Oxymetholone
Growth factors

Haematopoietic stem transplantation

? Autologous marrow transplantation

Future ? haematopoietic gene therapy

39
Q

Genetic pathophysiology of dyskeratosis congenita

A

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

40
Q

Management of bone marrow failure

A

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

41
Q

Treatment algorithm for severe apastic anaemia

A

<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

Kat's Pathology (105 decks)

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