Myelodysplatic Syndromes/Bone Marrow Failure Flashcards
What are myelodysplastic syndromes
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.
Key features of MDS
Typically a disorder of the elderly
Symptoms/signs are those of general bone marrow failure
Develops over weeks and months
Blood film 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 a Pelger-Huet anomaly
Neutrophils with bilobed nuclei. The two lobes are connected by a thin strand giving a ‘ince-nez’ appearance.
What is myelokathexis
Pyknotic nuclei with lengthening and thinning of intrasegmented filaments and vacuoles
Ringed sideroblasts
Blue-stain ed haemosiderin (Prussian blue stain) deposits in the mitochondria of erythroid precursors to form an apparent ring around the nucleus
Myeloblasts with aurer rods
Large cells with high nuclear-to-cytoplasm ratio and nucleoli.
Aurer rod = a pink/red rod like structure in the cytoplasm
WHO classification of MDS
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
Prognostic scoring system in MDS
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)
Clinical course of MDS
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
Treatment of MDS
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
Chemotherapy treatments for MDS
Oral chemotherapy: hydroxyurae
Low dose chemotherapy: sucbutaneous low dose cytarbine
Intensive chemotherapy/SCT: AML type regimens, Allo/VUD standard/reduced intensity
How is bone marrow failure causes classified
Primary
Secondary
Primary causes of bone marrow failure
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 causes of bone marrow failure
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
Pathophysiology of primary bone marrow failure syndromes
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
Drugs and bone marrow failure
Predictable (dose-dependent, common): cytotoxic drugs
Idiosynchratic (not dose-dependent, rare) - phenylbutazone, gold salts
Antibiotics: chloramphenicol, sulphanamide
Diuretics: thiazides
Antithyroid drugs: carbimazole
When does aplastic anaemia occur
2-5 cases/million/year
Bi modal age incidence:
15-24 years
Over 60 years
Classification of aplastic anaemia
Idiopathic: vast majority
Inherited: dyskeratosis congenita, fanconi anaemia, shwachman-diamond syndrome
Secondary: radiation, drugs (cycotoxic agents, chloramphenicol, NSAIDs), viruses (hepatitis), SLE
Pathophysiology of aplastic anaemia
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.
Clinical presentation of aplastic anaemia
Triad of bone marrow failure findings:
Anaemia: fatigue, breathlessness
Leucopenia: infections
Platelets: easy bruising, bleeding.
How is aplastic anaemia diagnosed
Blood: cytopenia
Marrow: hypocellular
How is aplastic anaemia classified
Severe aplastic anaemia
Non-severe aplastic anaemia
Differentail diagnoses of pancytopenia and hypocellular marrow
Hypoplastic MDS / Acute Myeloid Leukaemia
Hypocellular Acute Lymphoblastic Leukaemia
Hairy Cell Leukaemia
Mycobacterial (usually atypical) infection
Anorexia Nervosa
Idiopathic Thrombocytopenic Purpura
Severe aplastic anaemisa
2 out of 3 peripheral blood features:
Reticulocytes <1%
Neutrophils <0.5 (very severe <0.2)
Platelets <20
Bone marrow: <25% cellularity
Management of bone marrow failure
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
Specific treatment of aplastic anaemia
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
Complications of aplastic anaemia (due to immunosuppression)
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
Name some causes of pancytopenia
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)
Name some causes of single cytopenias
Diamond-Blackfan syndrome Kostman’s syndrome Shwachman-Diamond syndrome Reticular dysgenesis Amegakaryocytic thrombocytopenia with absent radii (TAR)
Pathophysiology of 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)
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.
Clinical features of fanconi anaemia
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
Treatment of fanconi anaemia
Supportive
Androgens can transiently improve counts but side-effects (hepatic toxicity)
Complications of fanconi anaemia
10% terminate in acute leukaemia
Aplastic anaemia in 90%
Others: liver disease, myelodysplasia, cancer
Features of dyskeratosis congenita
An inherited disorder characterised by:
Marrow failure
Cancer predisposition
Somatic abnormalities
Clinical features of dyskeratosis congenita
Patients may present with the classical triad of:
Skin pigmentation
Nail dystrophy
Leukoplakia
Complications of dyskeratosis congenita
Abnormal skin pigmentation
Bone marrow failure
Leucoplakia
Nail dystrophy
Management of bone marrow failure in dyskeratosis congenita
Supportive:
Blood/platelet transfusions
Antibiotics
Drugs to promote marrow recovery:
Oxymetholone
Growth factors
Haematopoietic stem transplantation
? Autologous marrow transplantation
Future ? haematopoietic gene therapy
Genetic pathophysiology of dyskeratosis congenita
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
Management of bone marrow failure
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
Treatment algorithm for severe apastic anaemia
<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
