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?
Development of a clone of marrow stem cells with abnormal maturation resulting in functionally defective blood cells + a numerical reduction.
What does the development of a clone of marrow cells with abnormal maturation in MDS result in?
Cytopenia(s)
Qualitative (functional) abnormalities of erythroid, myeloid + megakaryocytic maturation
Increased risk of transformation to leukaemia (AML)
What is the epidemiology of MDS?
Typically disorder of elderly.
Sx + signs are those of general marrow failure.
Develops over weeks + months.
List 5 blood and bone marrow morphological features of MDS?
- Pelger-Huet anomaly (bilobed neutrophils)
- Dysgranulopoieses 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
Multilobed with granules in cytoplasm
What is this?
Pelger-Heut anomaly
Only 2 lobules, connected by thin bridge of cytoplasm
What is this?
Refractory anaemia dysgranulopoiesis
Abnormal lack of granules in neutrophils
What is this?
Myelokathexis
Condensed nuclei with thin intrasegmented filaments + vacuoles
What is this?
Refractory anaemia-dyserythropoiesis
What is this?
Refractory anaemia-dyserythropoiesis
What is this?
Ringed sideroblasts
What is this?
Myeloblasts with 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 + time to progress to AML.
Which driver mutations in MDS carry prognostic significance?
TP53, EZH2, ETV6, RUNX1, ASXL1
Others: SF3B1, TET2, DNMT3A
In which group of MDS patients are the majority of common mutations found in?
More frequently in high risk MDS than low risk
What is the sequelae of disease in MDS?
Deterioration of blood counts: Worsening consequences of marrow failure.
Development of AML:
- Develops in 5-50% < 1y (depends on subtype)
- Some cases of MDS are much slower to evolve
- AML from MDS has an extremely poor prognosis + is usually not curable
Why is AML from MDS much harder to treat than those with AML without prior MDS?
Those without prior MDS more likely to have normal stem cells in BM
What is the rule of thumb for outcomes of MDS progression?
⅓ die from infection (low neutrophils, can’t fight)
⅓ die from bleeding (low platelets)
⅓ die from acute leukaemia
What is the treatment of MDS?
Allogeneic stem cell transplantation (SCT)
Or
Intensive chemotherapy
(Only minority of patients can benefit from these, as most are too old/ frail)
What supportive care can be given to those with MDS?
Blood product support: transfusions
Abx for infections
Growth factors to enhance residual BM activity
What growth factors can be given to those with MDS? What cell lineage is each given to enhance?
EPO: Hb
G-CSF: Neutrophils
Thrombopoetin (TPO) receptor agonists: Platelets
What biological modifiers are used in the treatment of MDS?
Immunosuppressive therapy
Hypomethylating agents: Azacytidine + Decitabine
Lenalidomide
Which forms of chemotherapy may be used in MDS?
- Oral Hydroxyurea
- Subcutaneous low dose Cytarabine
- Intensive chemo (for high risk): designed to treat AML
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. ⅓ of MDS patients can be expected to die from leukaemic transformation
D. There is no good correlation between the severity of cytopenias and the overall life expectancy
E. White cell function is frequently well preserved in MDS
C. ⅓ of MDS patients can be expected to die from leukaemictransformation
What can the common myeloid progenitor give rise to?
- RBCs
- Mast cells
- Megakaryocytes which give rise to platelets
- Myeloblasts which give rise to basophils, neutrophils, eosinophils + monocytes
What can the common lymphoid progenitor give rise to?
- Natural killer cells
- B Lymphocytes
- T Lymphocytes
How does stage of maturation in the bone marrow determine the lineages affected?
Pluripotent haematopoeitic cell: impairs production of ALL peripheral blood cells (Rare)
Committed progenitor cells: Bi- or unicytopenias
What are 3 congenital causes of primary bone marrow failure?
Fanconi’s anaemia (multipotent stem cell)
Diamond-Blackfan anaemia (red cell progenitors)
Kostmann’s syndrome (neutrophil progenitors)
These are more commonly seen in kids
What is an acquired causes of primary bone marrow failure?
Idiopathic aplastic anaemia (multipotent stem cell)
Most common primary BM failure syndrome (over congenital)
Which form of bone marrow failure is more common?
Secondary is more common than primary
Primary are relatively rare
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.
Abx: 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: 15-24y + > 60y
Give 2 characteristic test findings in aplastic anaemia
Blood: Cytopenia
BM: Hypocellular
How is aplastic anaemia classified?
Severe aplastic anaemia (SAA)
Non-severe aplastic anaemia (NSAA)
Using Camitta criteria based on % reticulocytes, neutrophils + platelets in peripheral blood
+ cellularity of BM
Describe the aetiological classification of aplastic anaemia
Idiopathic: 70-80% (majority)
Inherited: Dyskeratosis congenita, Fanconi anaemia, Scwachman-Diamond syndrome
“Secondary”: Radiation, cytotoxics, SLE
Idiosyncratic: Chloramphenicol, NSAIDs, hepatitis viruses
Paroxysmal Nocturnal Haemaglobinuria
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 in aplastic anaemia?
Anaemia: Fatigue, breathlessness.
Leucopenia: Infections
Platelets: Easy bruising/ bleeding
What is this?
Normal bone marrow
White = fat
What is this?
Aplastic bone marrow
Few cells, majority fat
List 6 differentials to aplastic anaemia for findings of pancytopenia and hypo cellular marrow
Hypoplastic MDS/ AML
Hypocellular ALL
Hairy cell leukaemia
Mycobacterial (usually atypical) infection
Anorexia Nervosa
Idiopathic Thrombocytopenic Purpura
Give 6 approaches to management of aplastic anaemia
- Seek + remove a cause
- Supportive
- Immunosuppressive therapy
- Drugs to promote marrow recovery
- Stem cell transplantation
- Other tx in refractory cases
What supportive treatment can be given to those with aplastic anaemia?
Blood/ platelet transfusions (Leucodepleted, CMV -ve, irradiated)
Abx
Iron Chelation Therapy
What is the specific treatment for idiopathic aplastic anaemia based on?
Severity of illness
Age of patient
Potential sibling donor
What are the specific treatments for aplastic anaemia?
Immunosuppressive therapy – older patient:
- Anti-Lymphocyte Globulin (ALG)
- Ciclosporin
- Eltrombopag
Androgens: oxymethalone
Stem cell transplantation:
- Young with donor (80% cure)
- VUD/MUD for > 40 yrs (50% survival)
What are complications associated with aplastic anaemia?
- Relapse of AA (35% >15y)
- Clonal haematological disorders
- Solid tumours ~3% risk
Which clonal haematological disorders may arise as a complication following immunotherapy for aplastic anaemia?
Myelodysplasia
Leukaemia ~20% risk over 10y
PNH (paroxysmal nocturnal haemoglobinuria): May be a transient phenomenon.
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. Cure rate of AA treated by sibling-related allogeneic stem cell transplantation in a patient <40y is > 70%.
What is Fanconi Anaemia?
Most common form of inherited aplastic anaemia.
Autosomal recessive or X-linked inheritance.
Multiple mutated genes are responsible. When these genes become mutated, results in:
- Abnormalities in DNA repair
- Chromosomal fragility (breakage in the presence of in-vitro mitomycin or diepoxybutane)
What are 6 congenital abnormalities associated with Fanconi Anaemia?
- Short Stature
- Hypopigmented spots + café-au-lait spots
- Abnormality of thumbs
- Microcephaly or hydrocephaly
- Hyogonadism
- Developmental delay
No abnormalities 30%
List 5 complications that arise in fanconis anaemia with their prevalence
Aplastic anaemia: 90%
Myelodysplasia: 32%
Leukaemia: 10%
Cancer (epithelial): 5%
Liver disease: 4%
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 (white patches on tongue)
List 4 somatic abnormalities/ complications in dyskeratosis congenita
Abnormal skin pigmentation: 89%
Nail dystrophy: 88%
BM failure: 85.5%
Leukoplakia: 78%
What is the general approach to management of bone marrow failure e.g. in congenital syndromes?
- Supportive: Blood/platelet transfusions, Abx +/- Iron Chelation Therapy
- Drugs to promote marrow recovery: TPO receptor agonists
(e.g. eltrombopag),
?Oxymetholone,
?Growth factors - Stem cell transplantation
- Future ? haemopoietic gene therapy
What are telomeres?
Found at the end of chr
Act to prevent chr fusion/ rearrangements during chr replication
Protect the genes at the end of the chr from degradation
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 maintenance of telomere length required for?
Indefinite proliferation of human cells
What is the genetic basis of dyskeratosis congenita?
X-linked recessive trait: 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: gene for this form of DC not yet 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.
Why is immunosuppression used in aplastic anaemia?
Most cases of AA have immunological// immune mediated attack on stem cells
Immunesuppression dampens AI attack on stem cells
Allow stem cells to recover
