Haem: Myelodysplastic syndromes and Aplastic anaemia Flashcards
Define myelodysplastic syndrome.
Biologically heterogenous group of acquired haematological stem cell disorders.
What is the defining pathophysiological characteristics of myelodysplastic syndromes?
- Development of a clone of marrow stem cell with abnormal maturation resulting in functionally defective blood cells and a reduction in cell counts
- This leads to 3 main features:
* cytopaenia
* functional abnormalities of cell maturation
* increased risk of transformation to leukaemia
Typicaly age range does Myelodysplastic syndromes affect
Elderly (>60)
How do myelodysplastic syndromes typically present?
Bone marrow failure (cytopenias) developing over weeks/months
List and describe some blood film and bone marrow features of myelodysplastic syndromes.
- Pseudo-Pelger-Huet anomaly (bilobed neutrophils with decreased granules)
- Dysgranulopoeisis of neutrophils (decreased granules)
- Dyserythropoiesis of red blood cells (lack of separation between red cell precursors - cytoplasmic bridges, presence of abnormal ring of cytoplasm around the nucleus of percursor red cells)
- Increased ring sideroblasts
- Dysplastic megakaryocytes (micro-megakaryocytes)
- Increased proportion of blast cells in the bone marrow BUT NOT over 20% (normally < 5%)
Differentiate between AML and Myelodysplastic Syndrome
BY DEFINITION:
Myelodysplastic < 20% blast cells in bone marrow
Myeloid > 20% blast cells in bone marrow
What does this image show?
Pelger-Huet anomaly
What does this image show?
Dysgranulopoiesis (failure of neutrophil granulation)
What does this image show?
Lack of separation between red cell precursors, presence of abnormal ring of cytoplasm around the nucleus of precursor red cells)
What does this image show?
Ringed sideroblast (accumulation of iron around the nuclei of red blood cell precursors)
What is the presence of myeloblasts with Auer rods suggestive of?
Acute myeloid leukaemia - it is pathognomonic
Diagnostic Criteira for Myelodysplastic Syndrome
- Cytopenia of at least 1 blood cell line
- < 20% blasts in blood and bone marrow
- Either
- characteristic cytogenic or molecular finding
- morphological dysplasia >10% of nucleated cells
What are the four prognostic variables that are used to calculate prognostic risk using the Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes?
Cytogenetics
Molecular Data
Age
Clinical data (BM blast%, cytopaenia, karyotype)
How does myelodysplasia tend to evolve from the time of diagnosis?
Blood counts will decrease (leading to worsening bone marrow failure) - *strong correlation between severity of cytopenia + overall life expectancy *
Then many develop acute myeloid leukaemia (poor prognosis)
Death causes: infection (commonest), bleeding, leukaemia
What are the two treatments that can prolong life in myelodysplastic syndromes?
- Allogeneic stem cell transplantation
- Intensive chemotherapy
NOTE: as most MDS patients are elderly, they often cannot tolerate treatment
List some other treatments that may be used in myelodysplastic syndromes.
- Supportive Care (blood products, antimicrobials, growth factors (e.g. EPO, GM-CSF)
- Biological modifiers
- Immunosuppression
- Azacytidine (hypomethylating agent)
- Decitabine
- Lenalidomide (used in 5q minus syndrome)
- Oral chemotherapy (e.g. hydroxyurea)
- Low-dose chemotherapy (SC low-dose cytarabine)
Define Aplastic Anaemia
Inability of BM to produce adequate blood cells - damage or suppresion of stem cell or committed progenitor cell.
Note = aplastic anaemia refers to anaemia but may also include failure to produce all types of blood cells.
List some causes of primary bone marrow failure.
CONGENITAL
* Fanconi anaemia (multipotent stem cell)
* Diamond-Blackfan syndrome (red cell progenitor)
* Kostmann syndrome (neutrophil progenitor)
ACQUIRED:
* idiopathic aplastic anaemia (multipotent stem cell)
List some secondary causes of bone marrow failure.
Marrow infiltration
* Haematological malignancies (e.g. leukaemia, lymphoma, myelofibrosis)
* Non-haemaetological (e.g. solid tumours, mets)
Aplastic
* Infection (e.g. Parvovirus B19, TB, HIV)
* Radiation
* Drugs
* Chemicals (e.g. benzene)
* Autoimmune (e.g. SLE)
List some drugs that can cause bone marrow failure.
- Cytotoxic drugs (predicatble, dose-dependent)
- Antibiotics - chloramphenicol, sulphonamides
- Diuretics - thiazide
- Antithyroid drugs - carbimazole
Which age groups are affected by aplastic anaemia?
Bimodal distribution: 10-24 and 60+
NOTE: this is much more rare than MDS
What is the most common cause of aplastic anaemia?
Idiopathic (70-80%)
List some inherited causes of aplastic anaemia.
- Fanconi anaemia
- Schwachman-Diamond syndrome
- Dyskeratosis Congenita
Outline the possible pathophysiology of idiopathic aplastic anaemia.
- Characterised by failure of the bone marrow to produce blood cells
- Either due to an inherent issue with the stem cells (CD34, LTC-IC) and/or due to autoimmune attack on stem cells
- Also features short telomeres
What are some investigative features of aplastic anaemia?
- Peripheral blood - cytopaenia
- Bone marrow - hypocellular
How is severe aplastic anaemia classified?
Using the Camitta Criteria
- 2 out of the following in peripheral film
- Reticulocytes = < 1%
- Neutrophils = < 0.5
- Platelets = < 20
- bone marrow biopsy = < 25% cellularity
Outline the management approaches used for bone marrow failure in aplastic anaemia.
- Seek and remove cause
- Supportive (blood products, antibiotics, iron chelation)
- Immunosuppressive therapy (anti-thymocyte globulin, steroids, ciclosporin A)
- Drugs that promote bone marrow recovery (oxymetholone (androgen), thrombopoietin receptor agonist (eltrombopag))
- Stem cell transplantation
- Alemtuzumab (T cell depletion) - for refractory cases
How might the age of the patient influence decisions regarding their management in aplastic anaemia?
- Immunosuppressive therapies tend to be used in older patients
- SCT tends to be used in younger patients (80% cure rate)
List some late complications that occur after immunosuppressive therapy for aplastic anaemia.
- Relapse (35% in 15 years)
- Clonal haematological disorders - 20% risk in 10 years (myelodysplasia, leukaemia, paroxysmal nocturnal haemoglobinuria)
- Solid tumours (3% risk)
What is the most common cause of inherited aplastic anaemia?
Fanconi anaemia
What is the inheritance pattern of Fanconi anaemia?
Autosomal Recessive or X-linked Recessive
What do the gene mutations implicated in Fanconi anaemia tend to result in?
- Abnormalities in DNA repair
- Chromosomal fragility (breakage in the presence of in vitro mitomycin and diepoxybutane)
List some somatic abnormalities that are seen in Fanconi anaemia.
- Short stature
- Hypopigmented spots/café-au-lait spots
- Abnormality of thumbs
- Microcephaly or hydrocephaly
- Hypogonadism
- Developmental delay
NOTE: these are only present in 70% of patients
List some complications of Fanconi anaemia.
- Aplastic anaemia (90%)
- Myelodysplasia
- Leukaemia
- Cancer (epithelial)
- Liver disease
What are the characteristic features of dyskeratosis congenita?
- Bone marrow failure
- Cancer predisposition
- Somatic abnormalities
What are the three main somatic features of dyskeratosis congenita?
- Abnormal skin pigmentation
- Nail dystrophy
- Leukoplakia
Which genes are involved in dyskeratosis congenita and what are the inheritance patterns?
- X-linked recessive (MOST COMMON) - DKC1 gene (defective telomere functioning)
- Autosomal dominant - TERC (RNA components of telomerase)
- Autosomal recessive - no mutation identified
NOTE: abnormal telomeric structure and function is heavily implicated in dyskeratosis congenita
