2. 1. • WHO definition 2008
• A group of clonal hematopoietic stem cell
diseases
characterized by
Cytopenia
Dysplasia in one or more major myeloid cell
lines
Ineffective hematopoiesis
Increased risk of development of AML
• 1982- Myelodysplastic syndrome (Benett
et al )
3.
1- Disease of elderly.
2- Median age is 65 years.
3- <10% are younger than 50 years.
4- Incidence rates 35 per million pop./ years
in gen population.
5- Incidence rise to 150-200 per million/
years in > 60 years old.
6- Male slightly higher than female
4. Primary or idiopathic MDS
T-MDS or secondary MDS :genotoxic drug or
radiation therapy
T-mds appears usually 2-8 yrs after
genotoxic exposure
All forms of MDS can transform to AML ,t-
MDS-highest frequency and rapidly.
5. HEREDITARY
A) Constitutional genetic disorders
Downs Syndrome: 10-30 times more risk
Trisomy 8 ,Monosomy 7
B) DNA repair defects
Fanconi anemia,
Ataxia telangiectasia
Bloom syndrome
C) Congenital neutropenia syndrome
6. • ACQUIRED
These factors play a major role in secondary
MDS/ t-MDS
a)Mutagen exposure
1.Genotoxic therapy- alkylating agents
2. Beta-emitter phosphorus; Used in the
treatment of
Polycythemia Vera- 10-15% increased risk.
3. Topoisomerase(Topo-II) interactive agents like
anthracycline, etoposide.
7. b) Environmental /occupational exposures
Exposure to benzene-5-20 fold increase in risk.
Other agents like solvents,
petrochemicals,Insectide
c) Tobacco
Tobacco smoke contains a number of
leukemogens like
nitrosamines, benzene and polonium-210
d) Senescence
e) Aplastic anemia
8.
9. Theories of
Pathophysiology
involved
in MDS Development
Potential
Targets/Componen
ts Involved
Overall Result of
Abnormality
Aging Increased BM
apoptosis
Decreased
hematopoietic stem cell
pool and ineffective
haematopoesis
Environmental
Exposures
Smoking
Radiation
Benzene
Viral Infections
Chemotherapy
Direct Toxicity to
hematopoietic
stem cells.
Telomere Abnormalities Potential decreased
telomerase and
subsequent
telomere shortening
•Impaired ability to
renew stem cell
pool.
•Genetic Instability
11. Immune Dysregulation •T cell Expansion
•B cell alterations
•Increased T cells
leading
to potential attack on
hematopoietic stem
cells.
•Etiology: Possible
chronic
antigenic stimulation
Abnormal
Differentiation
•Cell Cycle Maturation
arrest.
•Altered Proliferation.
•Transcription Factors
alterations
•Impaired maturation
•Cytopenias
•even Progression to
leukemia
12. The common chromosomal abnormalities found in MDS
include loss of Y, monosomy 5, monosomy 7,trisomy
8,deletion of 5 ,deletion of 7
m/c in ped is monosomy7
m/c in adults and overall is 5q-.
13. Strongly associated with RA.
5q- accounts for up to 70% of cytogenetic
abnormalities in
this subtype.
The q arm of chromosome 5 is particularly rich in
genes,
which encoded haemopoietic growth factors and
their
receptors. For example , IL-3 , IL-4 , IL-5 , GM-
CSF and the
M-CSF receptor are located in this region.
The potential for the loss of any or all of these
genes
contribute to the disruption of ordered
haemopoiesis.
14. Most strongly associated with secondary MDS
Associated with the loss of a major surface
glycoprotein (gp 130) in neutrophile and
susceptibility
to bacterial infection secondary to impaired
granulocyte monocyte chemotatic activity.
15. Account for 20% of the chromosomal
abnormalities
in RAS.
This abnormality is associated with raised
iron stores
and high ring sidroblast counts.
The presence of the gene , which encoded
the Hsubunit of ferritin at chromosome 11 ,
may explain
this
16.
17.
18.
19.
20.
21.
22. Symptoms
Low RBC count (anemia)
Fatigue
Shortness of breath
Weakness
Pale skin
Low WBC count (leukopenia)
Recurrent infections
Fever
Low platelet count (thrombocytopenia)
Excessive bleeding (e.g., nose bleeding)
Easy bruising
Petechiae (tiny reddish spots on the skin)
23. MDS in childhood –rare but when diagnosed
Indicates presence of constitutuinal genetic
disease- Downs syndrome,
Family history: heriditory sideroblastic annemia
,fanconi’s anemia, telomeropathy
24. • Pallor
• Peripheral oedema
• Evidence of heart failure (severe anaemia).
• Petechiae on the lower extremities or on
the buccal mucosa
(if severe thrombocytopenia is present).
• Splenomegaly seen in 20% of MDS pts
25. Cutaneous manifestations:
uncommon
Sweet’s syndrome(febrile neutrophilic
dermatosis): This condition is a reactive process
characterized by the abrupt onset of tender,
red-to-purple papules and nodules that
coalesce to form plaques
transformation to acute leukemia ( IL-6)
26. Granulocytic sarcoma (chloroma): herald
disease
transformation into acute leukemia
In younger patients sterotypical anamolies
point to the constitutional syndromes( short
stature, thumb anamolies in Fanconi’s
anemia,early greying in
telomeropathies,cutaneous warts in GATA2
deficiency
28. CBC findings- there is cytopenia affecting bi
or pancytopenia–
Cytopenias:
Hgb < 10 g/dL
ANC < 1500 cells /mm3
PLT < 100,000 /mm3
Reticulocyte count :may be normal or
decreased
35. Bone Marrow:
– Granulocytic hyperplasia
– Abnormal or decreased granules in
neutrophil precursors
– Increased numbers of blast cells
36.
37. Peripheral Blood:
– Thrombocytopenia
– Large platelets with abnormal or
decreased granularity
– Abnormal platelet function
38.
39. Bone Marrow:
– Reduced numbers of megakaryocytes
– Micromegakaryocytes
– Megakaryocytes with large, single nuclei
or multiple small nuclei[(pawn ball
megakaryocytes)
40.
41.
42. Cytogenetics or chromosomal studies
Interphase fluorescence in situ
hybridization testing- offers rapid detection of
several chromosome abnormalities associated with
MDS, including del 5q, -7, +8, and del 20q.
Flow cytometry is helpful to establish the
presence of any lymphoproliferative disorder
in the marrow,distiguishing types of MDS,PNH
43. Serum vit B12 and folatelevels
TIBC
Serology for HIV,parvovirus,brucellosis
Fanconi anemia: diepoxybutane (DEB) test for
chromosomal breakage in
peripheral blood lymphocytes
Paroxysmal nocturnal hemoglobinuria (PNH):
peripheral blood
immunophenotyping for deficiency of
phosphatidylinositol-glycan-linked
molecules on peripheral blood cells (e.g., CD55,
CD59)
45. IPSS Risk-Based Classification
System
Overall IPSS Risk Score is Based on:
1 – Marrow Blast Percentage
2 – Cytogenetic Features:
Good Prognosis
– -Y, 5q-, 20q-, normal
Intermediate Prognosis
– +8, single misc. abnormality, double abnormalities
Poor Prognosis
– any chrom. 7 abn, complex (≥3)
3 – Cytopenias:
Hgb < 10 g/dl
ANC < 1500 /mm3
PLT < 100,000 /mm3
46.
47. Supportive care
infections must be agressively treated
with-parenteral broad spectrum
antibiotics,antifungals
Platelet transfusion- once or twice weekly to
maintain >10,000 c/cmm
PRBC transfusions to maintain Hb-7g%in
normal individuals and 8-9g%in pulmonary or
cardiac disorders
2 units every 2 weekly will replace normal
losses in a patient without functioning BM
48. Iron chelation is only recommended in adult
patients for whom long term transfusion
therapy is likely .after 50th transfusion
Monitoring iron chelation: • The target
Ferritin level is <1000microg
DFO treatment • 40 mg/kg (20-50 mg) by
subcutaneous infusion over 8-12 hours 5-7
days per week
Vitamin C 2-3 mg/kg/d should be started 4
weeks after the onset of DFO therapy to
improve iron excretion
49. Allogenic stem cell transplantation
curative modality
The current survival rate in selected patient
cohorts is ~50% at 3 years and is improving.
high-risk patient, for whom the procedure is
most obviously indicated, has a high probability
of a poor outcome from transplantrelated
mortality or disease relapse, whereas the low-
risk patient, who is more likely to tolerate
transplant, also may do well for years
with less aggressive therapies.
50. Moa: it acts through a demyelinating
mechanism to alter gene regulation and allow
blood cell differentiation
Azatitidine is usually administered
subcutaneously daily for 7 days at 4
weekinterval for 4 cycles before acessing for
response
Overall increase in blood counts and decrease
in transfusion requirements occurred in 50%
pts
51. Decitabine is a more potent drug
30-50%showed responses in blood counts
and resposes lasted for year
Its given in continuousiv infusionsin regimens
of varying doses for 3-10 dys in repeated
cycles
52. Linalidomide : thalidomde derivative with more
favorable toxicity profile ,ts effective in reversing
anemia in mds pts with5q- syndrome
Inhibits angiogenesis by
reducing levels of VEGF,
TNF-α, and IL-61,2
A higher proportion of people become
transfusion independent and cytogenetics also
become normal
s/e : myelosuppression ,DVT, pulmonary
embolism
53. HGFs ;EPO alone or in combination with G-
CSF can improve hemoglobin levels, but
mainly in those with low serum EPO levels
who have no or only a modest need for
transfusions. Survival does not appear to be
improved by G-CSF treatment alone but may
be enhanced by erythropoietin and
amelioration of anemia
54. Immunosuppression, as used in aplastic
anemia, also may produce sustained
independence from transfusion and improve
survival. ATG, cyclosporine, and
alemtuzumab are especially effective in
younger MDS patients (<60
years old) with more favorable IPSS scores.
55. Algorithm for treatment of
symptomatic low-risk MDS.
High-quality transfusion therapy, and chelation
therapy,
. Evaluate patients with IPSS INT-1 for curative
treatment (allogeneic stem cell transplantation)
For patients with anemia, consider Epo ± G-CSF
Lenalidomide treatment for patients with IPSS low
and INT-1-risk MDS with del(5q), who have failed
growth factor treatment
56. Evaluate for curative treatment, allogeneic
stem cell transplantation. 2. Evaluate patient
for azacitidine treatment 3. Evaluate patient
for AML like chemotherapy; especially
younger patients with good risk features for
response. 4. Evaluate patient for low dose
chemotherapy. 5. Supportive care
