12. Myelodysplastic syndromes and aplastic anaemia Flashcards
What is the definition of myelodysplastic syndrome (MDS)?
Biologically heterogenous group of acquired haematopoietic stem cell disorders (~4 per 100,000)
What is MDS characterised by?
Cytopaenia; qualitative (functional) abnormalities of erythroid; myeloid and megakaryocyte maturation; increased risk of transformation to leukaemia. Usually a disorder of the elderly. Symptoms/signs of general bone marrow failure.
Summarise what happens in MDS, leading to its symptoms:
Development of a clone of marrow stem cells with abnormal maturation resulting in: functionally defective blood cells and numerical reduction.
Over what time frame does MDS develop?
Develops over weeks and months
What are blood and bone marrow morphological features of MDS?
Pelger-Heut anomaly (bilobed neutrophils), dysgranulopoiesis of neutrophils (failure of granulation), dyserythropoiesis of red cells (lack of separation between red cell precursors, abnormal ring of cytoplasm around the nucleus), dysplastic megakaryocytes (e.g. micro-megakaryocytes), increased proportion of blast cells in the marrow (normally <5%), ringed sideroblasts, myeloblasts with Auer rods.
What are ringed sideroblasts?
If you stain the bone marrow for iron you may see iron granules within the red cell precursors. These are ringed sideroblasts (an accumulation of iron around the nucleus).
What do blast cells with Auer rods look like?
Blast cells have a big nucleus with nucleoli. Rod-like structure in cytoplasm is called an Auer rod. These are a feature of acute myeloid leukaemia.
What is taken into account when classifying MDS?
WHO classification of MDS (2018). Different things are taken into account when classifying MDS (e.g. lineages, blast cell proportions, cytogenetics, presence of ringed sideroblasts
What is used to find out the prognosis of MDS?
Revised International Prognostic Scoring System (PSS-R) in MDS (2012)
What prognostic variables does the Revised International Prognostic Scoring System include?
BM blasts, karyotype, Hb, platelets, neutrophils
What karyotypes in MDS are associated with a poor or very poor prognosis?
Poor: Complex (3 abnormalities, -7, double abnormalities inc. -7 or del(7q). Very poor: > 3 abnormalities
What is the median survival of patients with MDS according to the IPSS-R?
Very low risk category: 8.8 years. Intermediate: 3.0 years. Very high risk: 0.8 years
What is AML evolution in 25% of MDS patients (years)?
Very low risk: >14.5. Intermediate risk: 3.2. Very high risk: 0.7
Describe the evolution of myelodysplasia?
Blood cell counts will decrease as a result of BM failure. Patients may develop AML. 1/3 die from infection; 1/3 die from bleeding; 1/3 die from acute leukaemia.
What percentage of MDS patients develop AML? What is the prognosis?
Develops in 5-50% within 1 year (depending on subtype). Some cases are much slower to evolve. AML on a background of MDS has an extremely poor prognosis.
What is the treatment for MDS?
Only TWO treatments can prolong life: allogenic stem cell transplantation (SCT) and intensive chemotherapy. Other Mx: supportive care (blood product support, antimicrobial support, GFs); biological modifiers; oral chemotherapy; low-dose chemotherapy; and intensive chemotherapy/SCT (AML-type regimens)
What are the issues with MDS treatment?
Only a minority of MDS patients can benefit from them. As a lot of MDS patients are elderly, few can tolerate such aggressive treatments.
What are GFs that can be given as supportive care in MDS?
E.g. EPO, G-CSF
What are examples of biological modifiers that can be given in MDS?
Immunosuppressive agents; azacytidine (hypomethylating agent); decitabine; lenalidomide (used in 5q minus syndrome)
What are examples of oral and low-dose chemotherapies that can be given in MDS?
Oral: Hydroxyurea/hydroxycarbamide. Low-dose: Subcutaneous low-dose cytarabine
Draw out an overview of haemopoietic cell lines:
Start: multipotential haemopoietic stem cell (haemocytoblast). This dividides into common myeloid progenitor and common lymphoid progenitor. Common myeloid progenitor –> megakaryocyte, erythrocyte, mast cell, myeloblast. Megakaryocyte -> thrombocytes. Myeloblast -> basophil, neutrophil, eosinophil, monocyte. Monocyte -> macrophage. Common lymphoid progenitor –> small lymphocytes and NK cells. Small lymphocyte -> B lymphocyte and T lymphocyte. B lymphocyte -> plasma cell.
How does BM failure occur?
Results from damage or suppression of stem or progenitor cells
What happens if there is damage to pluripotent haematopoietic stem cell?
This will impair the production of ALL peripheral blood cells (but this is RARE).
What happens if there is damage to committed progenitor cells?
Results in bi- or unicytopaenias
What are causes of primary BM failure?
Fanconi’s anaemia (multipotent stem cell); Diamond-Blackfan anaemia (red cell progenitors); Kostmann’s syndrome (neutrophil progenitors); acquired: Idiopathic aplastic anaemia (multipotent stem cell).
Which cells does Fanconi’s anaemia affect?
Multipotent stem cells
Which cells does Diamond-Blackfan anaemia affect?
Red cell progenitors
Which cells does Kostmann’s syndrome affect?
Neutrophil progenitors
Which cells does acquired: idiopathic aplastic anaemia affect?
Multipotent stem cell
What are causes of secondary BM failure?
Marrow infiltration; haematological malignancies (leukaemias, lymphomas, myelofibrosis); non-haematological (solid tumours spreading to bone marrow); radiation; drugs; chemicals (e.g. benzene); autoimmune; infection (parvovirus, viral hepatitis)
Which predictable (dose-dependent, common) drug causes BM failure
Cytotoxic drugs
Which idiosyncratic (NOT dose-dependent, rare) drugs cause BM failure?
Phenylbutazone, gold salts
Which ABx cause BM failure?
Chloramphenicol and sulphonamide
Which diuretic causes BM failure?
Thiazides
Which antithyroid drug cause BM failure?
Carbimazole
How many cases of aplastic anaemia are there per year worldwide?
2-5 million cases per year worldwide
Who is affected by aplastic anaemia?
ALL age groups can be affected. Bimodal incidence: 15-24 years and 60+ years. NOTE: this is much more RARE than MDS
What three types can aplastic anaemia be classified into?
Idiopathic, inherited, secondary
What classification of aplastic anaemia is the vast majority?
Vast majority is idiopathic (70-80%)
What are causes of inherited aplastic anaemia?
Dyskeratosis congenita (DC), Fanconi anaemia (FA), Shwachmann-Diamond syndrome
What are secondary causes of aplastic anaemia:?
Radiation (predicable), drugs (predictable: cytotoxic agents, idiosyncratic: chloramphenicol, NSAID), viruses (idiosyncratic: hepatitis virues), immune (SLE)
How is aplastic anaemia characterised and what is the pathophysiology of aplastic anaemia?
Characterised by the failure of bone marrow to produce blood cells. This occurs either because there is a problem with the stem cells or due to immune attack of the stem cells (e.g. humoral or cellular attack against multipotent haematopoietic stem cells).
What is the clinical presentation of BM failure?
Anaemia - fatigue, breathlessness; leucopaenia - infections; thrombocytopaenia - bleeding/bruising
How is aplastic anaemia diagnosed?
Peripheral blood - cytopaenia; bone marrow - hypocellular
How is aplastic anaemia diagnosed?
Peripheral blood - cytopaenia; bone marrow - hypocellular
How is aplastic anaemia classified?
Severe aplastic anaemia (SAA) and non-severe aplastic anaemia (NSAA)
What are differential diagnoses of pancytopaenia and hypocellular marrow?
Hypoplastic MDS/AML; hypocellular ALL; hairy cell leukaemia; mycobacterial (usually atypical) infection; anorexia nervosa; idiopathic thrombocytopaenic purpura** (NOTE: it is unlikely that you will confuse aplastic anaemia with ITP because patients with ITP have normal Hb and normal RBC)
What is the Camitta Criteria for SAA?
2 of 3 peripheral blood features: 1. reticulocytes < 1% (<20 x 10^9/L) 2. neutrophils < 0.5 x 10^9/L 3. Platelets < 20 x 10^9/L. Bone marrow < 25% cellularity
What is the management of BM failure?
Seek and remove cause; supportive (blood/platelet transfusions - leucodepleted, CMV negative and irrafiated; ABx; iron chelation therapy); immunosuppressive therapy; drugs to promote marrow recovery; STC; other Tx in refractory cases; specific Tx of idiopathic AA; immunosuppressive therapy; androgens.
What type of immunosuppressive therapy is given in BM failure?
Anti-thymocyte globulin, steroids, eltrombopag, cyclosporine A
Which drugs promote marrow recovery in BM failure?
Oxymethone, TPO receptor agonists (eltrombopag)
What are other Tx in refractory cases of BM failure?
Alemtuzumab
What are specific treatments of idiopathic AA based on?
Severity of illness, age of patient, potential sibling donor
Immunosuppressive therapy tends to be used in older patients to treat BM failure, such as:
anti-lymphocyte globulin, ciclosporin
Which androgens can also promote bone marrow recovery in BM failure?
Oxymethalone
Who does STC tend to be used in for BM failure?
Younger patients, 80% cure rate
What are late complications following immunosuppressive therapy for AA?
Relapse of AA (35% over 15 years). Clonal haematological disorders (~20% risk over 10 years): myelodysplasia; leukaemia; paroxysmal nocturnal haemoglobinuria (PNH); solid tumours (3% risk)
What is paroxysmal nocturnal haemoglobinuria (PNH)?
this is a clonal disorder that has a tendency to develop into leukaemia
What is the most common form of inherited aplastic anaemia?
Fanconi anaemia
What is the inheritance pattern of Fanconi anaemia?
Autosomal recessive or X-linked
What is the heterozygote frequency of Fanconi anaemia?
1:300
What do the gene mutations in Fanconi anaemia result in?
Multiple mutated genes are involved. These gene mutations result in: abnormalities in DNA repair; chromosomal fragility; breakage in the presence of in vitro mitomycin or diepoxybutane
What are somatic and congenital abnormalities in FA?
NOTE: congenital malformations occur in 60-70% of children with FA. Short stature; hypopigmented spots and café-au-lait spots; abnormality of thumbs; microcephaly or hydrocephaly; hypogonadism; developmental delay. NOTE: there are NO abnormalities in 30% of patients.
What are complications of Fanconi anaemia and what percentage experience them?
Aplastic anaemia (90%), leukaemia (10%), liver disease (4%), myelodysplasia (32%), cancer - epithelial (5%)
What is the median age in years of the complications of Fanconi anaemia?
Aplastic anaemia (9), leukaemia (14), liver disease (16), myelodysplasia (17), cancer - epithelial (23)
What is dyskeratosis congenita (DC) characterised by?
An inherited disorder characterised by: marrow failure, cancer predisposition, and somatic abnormalities
What is the classical triad of dyskeratosis congenita?
Skin pigmentation, nail dystrophy, leukoplakia
What are somatic abnormalities/complications in DC and what percentage of patients have them?
Abnormal skin pigmentation (89%), nail dystrophy (88%), BM failure (85.5%), leucoplakia (78%)
What are the three patterns of inheritance of DC and how do they occur? NOTE: abnormal telomeric structure and function is implicated
X-linked recessive (MOST COMMON): Mutant DKC1 gene leads to defective telomere functioning.
Autosomal dominant: Mutant TERC gene - encodes the RNA component of telomerase.
Autosomal recessive: Mutant gene has NOT been identified
What are telomeres and what do they do?
Found at the end of chromosomes. Prevent chromosomal fusion or rearrangements during chromosomal replication. Protect genes at the ends of chromosomes from degradation.
What happens to telomere length in BM failure diseases?
Telomere length is reduced in bone marrow failure diseases (they are especially short in DC). Maintenance of telomere length is needed for the indefinite proliferation of human cells.
Physical abnormalities in DC vs idiopathic AA?
DC: yes; idiopathic AA: ?
BM failure in DC vs idiopathic AA?
Present in both
Malignancy in DC vs idiopathic AA?
Present in both
Chromosomal instability in DC vs idiopathic AA?
Present in both
Short telomeres in DC vs idiopathic AA?
Present in both
No. of genes identified in DC vs idiopathic AA?
DC: 2; idiopathic AA:?
Summary of treatment algorithm of SAA in <35 years:
HLA identical sibling donor -> HLA matched SCT. If not, SCT from children. If not, HSCT from unrelated donor
Summary of treatment algorithm of SAA in 35-50 years old
HLA identical sibling donor, if not then child SCT, if not the unrelated donor SCT. OR horse anti-thymocyte globulin (ATG) and ciclosporin. If no response or relapse, either unrelated donor HSCT or eltrombopag+2nd ATG+alternative donor HSCT
Summary of treatment algorithm of SAA in >50 years old
Horse anti-thymocyte globulin (ATG) and ciclosporin. If no response or relapse, either unrelated donor HSCT or eltrombopag+2nd ATG+alternative donor HSCT
