Myelodysplastic Syndromes and Bone Marrow Failure Flashcards
What are myelodysplastic syndromes (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.
What is the epidemiology of MDS?
Typically a disorder of the elderly.
Symptoms/signs are those of general marrow failure.
Develops over weeks & months.
What are some blood and bone marrow morphological features of MDS?
- Pelger-Huet anomaly (bilobed neutrophils)
- Dysganulopoieses of neutrophils
- Dyserythropoiesis of red cells
- Dysplastic megakaryocytes – e.g. micromegakaryocytes
- Increased proportion of blast cells in marrow (normal < 5%)
What is this?
Normal neutrophils
What is this?
Pelger-Heut anomaly
What is this?
Refractory anaemia dysgranulopoiesis
What is this?
Myelokathexis
What is this?
Refractory anaemia-dyserythropoiesis
What is this?
Refractory anaemia-dyserythropoiesis
What is this?
Ringed sideroblasts
What is this?
Auer rods
What are Auer rods a sign of?
AML
Which prognostic variables are included in the Revised International Prognostic Scoring System (IPSS-R) in MDS (2012)?
BM blasts (%)
Karyotype
Hb (g/L)
Platelets (x10^9/L)
Neutrophils (x10^9/L)
How is the IPSS-R score interpreted?
The higher the score, the lower the survival and time to progress to AML.
Which driver mutations in MDS carry prognostic significance?
TP53, EZH2, ETV6, RUNX1, ASXL1
Others: SF3B1, TET2, DNMT3A
What is the sequelae of disease in MDS?
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
What is the treatment of MDS?
Allogeneic stem cell transplantation (SCT)
Or
Intensive chemotherapy
(Only minority of patients can benefit from this)
How do patients with MDS usually die?
1/3 die from infection
1/3 die from bleeding
1/3 die from acute leukaemia
What are congenital causes of primary bone marrow failure?
Fanconi’s anaemia (multipotent stem cell)
Diamond-Blackfan anaemia (red cell progenitors)
Kostmann’s syndrome (neutrophil progenitors)
What are acquired causes of primary bone marrow failure?
Idiopathic aplastic anaemia (multipotent stem cell)
What are secondary causes of bone marrow failure?
Marrow infiltration
Haematological (leukaemia, lymphoma, myelofibrosis)
Non-haematological (Solid tumours)
Radiation
Drugs
Chemicals (benzene)
Autoimmune
Infection (Parvovirus, Viral hepatitis)
Which drugs can cause bone marrow failure?
PREDICTABLE (dose-dependent, common): Cytotoxic drugs.
IDIOSYNCRATIC (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 pathophysiology of idiopathic 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 triad of bone marrow failure findings?
Anaemia: Fatigue, breathlessness.
Leucopenia: Infections
Platelets: Easy bruising/bleeding
What is this?
Normal bone marrow
What is this?
Aplastic bone marrow
What are treatments for aplastic anaemia?
Immunosuppressive therapy – older patient:
- Anti-Lymphocyte Globulin (ALG)
- Ciclosporin
- Eltrombopag
Androgens – oxymethalone
Stem cell transplantation:
- Younger patient with donor (80% cure)
- VUD/MUD for > 40 yrs (50% survival)
What are complications associated with aplastic anaemia?
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?
A. Immunosuppressive therapy is only used to treat a minority of patients with aplastic anaemia.
B. If treated with immunosuppression, then relapse of Aplastic Anaemia occurs in less than 15% of cases.
C. The cure rate of AA treated by sibling-related allogeneic stem cell transplantation in a patient under 40 years old is > 70%.
D. Severe aplastic anaemia is differentiated from non-severe aplastic anaemia on the basis of the acquired cytogenetic abnormalities in the bone marrow.
E. Leucodepletion of cellular blood products is only exceptionally undertaken for patients with aplastic anaemia.
C. The cure rate of AA treated by sibling-related allogeneic stem cell transplantation in a patient under 40 years old is > 70%.
What is Fanconi Anaemia?
The most common form of inherited aplastic anaemia.
Autosomal recessive or X-linked inheritance.
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 congenital abnormalities associated with Fanconi Anaemia?
- Short Stature
- Hypopigmented spots and café-au-lait spots
- Abnormality of thumbs
- Microcephaly or hydrocephaly
- Hyogonadism
- Developmental delay
- No abnormalities 30%
What is Dyskeratosis Congenita (DC)?
An inherited disorder characterised by:
- Marrow failure
- Cancer predisposition
- Somatic abnormalities
What is the classical triad of dyskeratosis congenita?
Skin pigmentation
Nail dystrophy
Leukoplakia
What is the association between telomeres and dyskeratosis congenita?
Telomere length is reduced in marrow failure diseases (especially short in patients with DC).
What is the genetic basis of dyskeratosis congenita?
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.
Which one of the following is true?
A. Telomeric shortening is a feature of both idiopathic aplastic anaemia and dyskeratosis congenita.
B. Development of malignancy is an uncommon complication of Fanconi Anaemia.
C. A single genetic defect has been identified as the underlying cause for Fanconi Anaemia.
D. Fanconi Anaemia is usually inherited in an autosomal dominant fashion.
E. Telomeric function is considered to be unimportant in the pathophysiology of Dyskeratosis Congenita.
A. Telomeric shortening is a feature of both idiopathic aplastic anaemia and dyskeratosis congenita.
Which one of the following about MDS is true?:
A. Myelodysplasia has a bi-modal age distribution.
B. The primary modality of treatment of MDS is by intensive chemotherapy.
C. One third of MDS patients can be expected to die from leukaemic transformation.
D. There is no good correlation between the severity of the cytopenias and the overall life expectancy.
E. White cell function is frequently well preserved in MDS.
C. One third of MDS patients can be expected to die from leukaemic transformation.
