Myelodysplastic syndromes and aplastic anaemia Flashcards
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
Platelet count 273 x 10^9/L
What is MDS?
Biologically heterogeneous group of acquired haemopoietic stem cell disorders (~ 4 per 100,000 persons)
What is MDS characterised by?
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
What is the general clinical picture of myelodysplasia?
Typically a disorder of the elderly.
Symptoms/signs are those of general marrow failure
Develops over weeks & months
What are Some Blood & Bone Marrow Morphological Features of MDS?
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%)
What is this?
Refractory anaemia dysgranulopoiesis
What is myelokathexis?
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.
What is this?
Ringed sideroblasts
What is this?
Myeloblast with Auer Rods
What is the WHO classification of MDS?
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
What is the Revised International Prognostic Scoring System (IPSS-R) in MDS (2012)?
How do you use IPSS R for prognosis?
What is the evolution of myelodysplasia?
- Deterioration of blood counts
• Worsening consequences of marrow failure
- 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
- As a rule of thumb
- 1/3 die from infection
- 1/3 die from bleeding
- 1/3 die from acute leukaemia
What is the treatment of MDS?
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
What are the specific treatments of MDS?
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
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
One third of MDS patients can be expected to die from leukaemic transformation
Draw out the haematopoietic cell lines
What is Bone Marrow Failure?
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
What are the types of BM failure?
- 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)
- SECONDARY
Marrow infiltration:
Haematological ( leukaemia, lymphoma, myelofibrosis)
Non-haematological (Solid tumours, )
Radiation
Drugs
Chemicals (benzene)
Autoimmune
Infection (Parvovirus, Viral hepatitis
Which drugs cause BMF?
PREDICTABLE (dose-dependent, common)
Cytotoxic drugs
IDIOSYNCHRATIC (NOT dose-dependent, rare)
Phenylbutazone
Gold salts
ANTIBIOTICS
Chloramphenicol
Sulphonamide
DIURETICS
Thiazides
ANTITHYROID DRUGS
Carbimazole
What is the epidemiology of aplastic anaemia?
• 2-5 cases/million/yr (world-wide)
• All age groups can be affected
• Peak incidence:
i. 15 to 24 yrs
ii. over 60 yrs
What is the classification of aplastic anaeamia?
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
What is the pathophysiology of aplastic anaemia?
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.
What is the clinical presentation of AA?
- Anaemia Fatigue, breathlessness
- Leucopenia Infections
- Platelets Easy bruising/bleeding
How do you diagnose AA?
1. Blood Cytopenia
- Marrow Hypocellular
What is the classification of AA?
1. Severe aplastic anaemia (SAA)
- Non-severe aplastic anaemia (NSAA)
What is severe AA classed as?
Camitta criteria:
2 out of 3 peripheral blood features
- Reticulocytes < 1% (<20 x 109/l)
- Neutrophils < 0.5 x 109/l
- Platelets < 20 x 109/l
Bone marrow <25% cellularity
What is the management of BMF?
- Seek and remove a 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 recovery
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)
What is the treatment of AA?
- SUPPORTIVE
Blood products Leucodepleted (CMV negative) (Irradiated)
Antimicrobials
Iron Chelation Therapy (when ferritin > 1000 ug/l)
- 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)
What are the late complications following immunosuppressive therapy for AA?
- 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
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.
What are the inherited BMF syndromes?
What is Fanconi anaemia?
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)
What are the Somatic/congenital abnormalities in FA?
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%
What are the complications of fanconi syndrome?
Aplastic anaemia 90 9
Leukaemia 10 14
Liver disease 4 16
Myelodysplasia 32 17
Cancer (epithelial) 5 23
What is DYSKERATOSIS CONGENITA (DC)?
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
What are the Somatic abnormalities/complications in DC?
Abnormal skin pigmentation
Nail dystrophy
BMF
Leucoplakia
What is the management of BMF?
- 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
Why does DC happen?
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.
What genes are involved in DC?
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
Compare DC and AA
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.
Telomeric shortening is a feature of both idiopathic aplastic anaemia and dyskeratosis congenita
What’s the treatment algorithm for severe AA?
