1. Myelodysplastic Syndrome
Dr. Mohammad Nurul Azam
HMO, Department of Haematology
CMCH

2. What Is Myelodysplastic Syndrome?
 Heterogeneous group of clonal hematopoietic stem cell
disorders.
 In MDS the bone marrow cannot produce blood cells
effectively, and many of the blood cells formed are
defective.
 MDS is best considered a preleukemic disorder in which
the neoplastic clone that has been established may or may
not fully progress to acute leukemia.

3. Characteristics
Varying degree of tri-lineage
cytopenia ( red blood cells,
white blood cells and platelets).
Dysplasia
Normocellular or hypercellular
B.M
May progress to acute leukaemia
Incidence
1- Disease of elderly.
2- Median age 65 years.
3- <10% are younger
than 50 years.
4- Incidence rates
1/100,000 pop./ years.
5- Incidence rise to
1/1000 / years in > 60
years old.
6- Male slightly higher
than female

4. Predisposing Factors

5. HEREDITARY ACQUIRED
A) Constitutional genetic disorders
Downs Syndrome
Trisomy 8
Monosomy 7
B) Neurofibromatosis
C) Congenital neutropenia
syndrome
Kostmann Agranulocytosis
Shwachman Diamond syndrome
D) DNA repair defects
Fanconi anemia,
Ataxia telangiectasia
Bloom syndrome
E) Mutagen detoxification
a)Mutagen exposure
Genotoxic therapy- alkylating agents
Beta-emitter phosphorus; Used in the
treatment of Polycythemia Vera- 10-15%
increased risk.
Topoisomerase(Topo-II) interactive agents
like anthracycline, etoposide.
Autologous stem cell transplantation- long
term survivors
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

6. Morphological dysplasia in MDS
Dyserythropoiesis
Dysmyelopoiesis
Dysmegakaryopoiesis
Ring Sideroblast
Type I, II & III blasts

7. Dyserythropoiesis
 Peripheral blood:
 Anemia
 Reticulocytopenia
 Anisocytosis
 Poikilocytosis
 Basophilic stippling
 Macrocytosis
 Bone Marrow:
 Ineffective erythropoiesis
 Erythroid hyperplasia
 Ringed sideroblasts
 Megaloblastoid maturation:
 Multinuclearity
 Nuclear fragments
 Cytoplasmic abnormalities
Bizarre erythroid precursors
Ring sideroblast

8.  Peripheral blood:
 Neutropenia
 Decreased or abnormal neutrophil granules
 Neutrophil nuclear changes with:
 Hyposegmentation (pseudo-Pelger-Huet anomaly)
 Hypersegmentation
 Bizarre shapes
 Bone Marrow:
 Granulocytic hyperplasia
 Abnormal or decreased granules in neutrophil precursors
 Increased numbers of blast cells <20%
 Type I and type II blasts
Dysgranulopoiesis

9. Hyposegmented/
hypogranular neutrophil
Pelger-Huet
hyposegmentation
Dysgranulopoiesis ( contd…)

10. Blasts in MDS
Dysgranulopoiesis ( contd…)

11. Dysmegakaryocytopoiesis
 Peripheral Blood:
Thrombocytopenia
Large platelets with abnormal or decreased granularity
Abnormal platelet function
 Bone Marrow:
 Reduced numbers of megakaryocytes
 Micromegakaryocytes
 Megakaryocytes with large, single nuclei or multiple small
nuclei

12. Abnormal platelets
Micromegakaryocyte
Dysmegakaryocytopoiesis

13. FAB Classification
Refractory Anemia (RA)
Refractory Anemia with Ringed Sideroblasts (RARS)
Refractory Anemia with Excess Blasts (RAEB)
Refractory Anemia with Excess Blasts in Transformation
(RAEB-T)
Chronic Myelomonocytic Leukemia (CMML)

14. MDS: FAB Classification 1982
FAB
subtype
Blast % RS% Monocyte
s >1x109/l
Survival
(months)
PB BM
RA <1 <5 <15 - 50
RARS <1 <5 >15 - 75
RAEB <5 5-20 variable - 11
CMML <5 <20 variable + 11
RAEB-T >5;
Auer rods
20-30;
Auer rods
variable +/- 5

15. MDS: Limitations of FAB Classification
 Multilineage cytopenia with <5% BM blasts
 Rough prediction of prognosis
 Cytogenetics not given importance
 Ill defined entities: childhood MDS, T-MDS & other
secondary MDS
 Immunophenotyping and genetic techniques not included

16. WHO Classification System( 2001)
 Refractory Anemia (RA)
 Refractory Anemia with ringed sideroblasts
 Refractory Cytopenia (MDS) with Multilineage Dysplasia
(RCMD) – with & without sideroblasts
 Refractory Anemia with Excess Blasts (RAEB)
 5q- syndrome
 Myelodysplastic syndrome, unclassifiable

17. WHO CLASSIFICATION OF
MDS (2008)

18. SUBTYPE BLOOD BONE MARROW
RCUD:
1.RA 2.RN 3.RT
ANEMIA;
NO OR RARE BLASTS
UNICYTOPENIA
BICYTOPENIA
UNILINEAGE DYSPLASIA > 10% CELLS IN ONE
MYELOID LINE WITH < 5% BLASTS
<15%RINGED SIDEROBLASTS
REFRACTORY ANEMIA WITH RINGED
SIDEROBLASTS
ANEMIA;
NO OR RARE BLASTS
>15%RINGED SIDEROBLASTS; ERYTHROID
DYSPLASIA; <5%BLASTS;
REFRACTORY CYTOPENIA WITH
MULTILINEAGE DYSPLASIA (RCMD)
BI / PAN CYTOPENIAS;
NO OR RARE BLASTS; NO AUER RODS;
<1X109/L MONOCYTES
DYSPLASIA IN >10% OF THE CELLS >2
MYELOID LINES <5%BLASTS IN BM
>15%RINGED SIDEROBLAST NO AUER
RODS
RAEB - 1 BI / PAN CYTOPENIAS; < 5%BLASTS;
NO AUER RODS;
<1X109/L MONOCYTES
UNI OR MULTILINEAGE DYSPLASIA;
5-9%BLASTS;
NO AUER RODS
RAEB – 2 CYTOPENIAS;
5-19%BLASTS;
AUER RODS PRESENT;
<1X109/L MONOCYTES
UNI OR MULTILINEAGE DYSPLASIA;
10-19%BLASTS;
AUER RODS PRESENT
MYELODYSPLASTIC SYNDROME,
UNCLASSIFIED(MDS-u
CYTOPENIAS; NO OR RARE BLASTS;
NO AUER RODS;
UNILINEAGE DYSPLASIA;
<5% BLASTS;
NO AUER RODS
5q-SYNDROME ANEMIA;
NORMAL/INCREASED PLATELET COUNT;
<5%BLASTS
NORMAL/INCREASED MEGAKARYOCYTES;
<5%BLASTS;
NO AUER RODS
CHILDHOOD MDS < 2 % BLASTS
DYSPLASTIC CHANGES IN >10 % NEUTROPHILS
DYSPLASTIC CHANGES IN > 10 % ERYTHROID
PRECURSORS
DYSPLASTIC CHANGES IN > 10 %
GRANULOCYTE PRECURSORS
MICROMEGAKARYOCYTES,DYSPLASTIC
CHANGES IN MGKS

19. Comparison of MDS Classifications
FAB
classification
WHO Classsification
2001
WHO Classification 2008
RA RA Refractory cytopenia with unilineage dyplasia
• Refractory anemia
• Refractory neutropenia
• Refractory thrombocytopenia
RARS RARS Refractory anemia with ring sideroblasts (RARS)
RCMD RCMD
RCMD-RS RCMD-RS
RAEB RAEB I and 2 RAEB I and 2
RAEB-T RAEB II/ AML RAEB II/ AML
CMML MDS-UC MDS-UC
MDS associated with
isolated del(5q)
MDS associated with isolated del(5q)
Childhood myelodysplastic syndrome
• Refractory cytopenia of childhood

20. DIFFERENCES BETWEEN WHO AND FAB
The WHO system…
 Makes use of cytogenetic findings.
 The category of RAEB-t was eliminated as it got included
within AML(>20%blasts).
 CMML was removed and put in a new category of
myelodysplastic/ myeloproliferative diseases.
 Adds the subtypes 5q syndrome and unclassifiable MDS.
 Recognizes the prognostic importance of % of bone marrow
blasts

21. PATHOGENESIS

22. MDS : a stem cell disorder
 The abnormal cells in MDS are clones derived from an abnormal stem cell
Apoptosis in MDS
 Mechanism appears to be one of increased apoptosis of haemopoietic precursors in
the marrow,
 For those patients undergoing leukaemic transformation,the cytopenias arise due to
maturation block of the malignant cells
 Apoptosis is more prominent in early MDS, such as RA and RARS, than in
advanced MDS with excess myeloblasts
Ineffective Hematopoiesis
 Colony forming capacities of pleuripotent stem cells and their progeny are low or
absent
 Lower level of GM-CSF, M-CSF,IL 6 .IL 3,
 CFU- GM less responsive to both G-CSF & GM-CSF
 More dramatic in pts with RAEB or RAEB –t

23. Immunological abnormalities in MDS
 Commonly encountered in MDS, suggesting that they may play a role in the
aetiology and pathogenesis of the disease.
 Particularly apparent in cases of hypoplastic MDS that share a number of features in
common with aplastic anaemia, notably clinical presentation with macrocytosis and
varying levels of dyserythropoiesis
 Acquired mutations in the PIG-A gene characteristic of paroxysmal nocturnal
haemoglobinuria (PNH) are also encountered
Angiogenesis
 Autocrine production of angiogenic molecules promotes expansion of leukemic
clone
 Vascular endothelial growth factor(VEGF) and its receptor VEGFR-1 And VEGFR-2
is overexpressed

24. Molecular basis of MDS
 The common chromosomal abnormalities
found in MDS include loss of Y,
monosomy 5, monosomy 7,trisomy 8,
20q – , abnormalities of 11q23, and
deletions of 17p, 12p, 13q and 11q among
others.
Genetic abnormalities in MDS
 Mutations of the AML1 gene (also known as RUNX1 ) have recently been recognized to occur
in MDS, particularly where it is treatment - related or radiation - induced.
 Activating mutations of RAS , usually involving NRAS , are found in up to 20% of cases of
MDS
 Class 1 mutation-mutation involving Tyrosine kinase GATA1 , PU.1 ( SPI1 ), CEBPA , MLL
and TP53 .
 Class 2 mutation –mutation involving Transcription factors FMS (now called CSF1R ), KIT ,
FLT3 , PDGFRB and GCSFR
 Association of both Class 1 &2 – highly predisposed to MDS & AML

25. Epigenetic abnormalities
 Refers to alteration of gene expression without altering the DNA sequence
 Two important epigenetic modifications relevant to MDS, are DNA methylation and
histone modification.
 Promoter methylation of p15INK4B – t-MDS
 methylation of p15INK4B also seen in loss of Chr 7 and in pts who progresses from
RA to RAEB

26. MDS
ENVIRONMENTAL
EPIGENETIC
APOPTOSIS
STEM CELL
DEFECT
GENETIC
LOSS OF
SIGNAL
ANGIOGENESI
S
IMMUNOLOGICAL
MOLECULAR
GAIN OF
FUNCTION

27. Signs and Symptoms
 Excessive tiredness, shortness of breath, and pale skin
can be caused by anemia.
 Serious infections with high fevers can be caused by
leukopenia and, in particular, by having neutropenia or
granulocytopenia.
 Excessive bruising and bleeding, for example, frequent
or severe nosebleeds and/or bleeding from the gums,
can be due to thrombocytopenia.

28.  splenomegaly,hepatomegaly
 Cutaneous manifestations:
Uncommon
 Sweet’s syndrome( neutrophilic
dermatosis)
 Granulocytic sarcoma (chloroma):
herald disease transformation into
acute leukemia
Sweet’s syndrome
Signs and Symptoms (contd…)

29. EVALUATION OF SUSPECTED MDS
 HISTORY
Prior exposure to CT/RT
Recurrent infections, bleeding gums
 EXAMINATION
Pallor/ bruising
Splenomegaly
 INVESTIGATION
CBC
PBF:Macrocytosis, cytopenia, neytrophilia, monocytosis, pseudo-pelger huet anomaly,
hypogranular neutrophils
 BONE MARROW ASPIRATE
 BONE MARROW TREPHINE BIOPSY
 BONE MARROW CYTOGENETICS ANALYSIS
 EXCLUSION OF REACTIVE CAUSES OF DYSPLASIA
Megaloblastic anaemia
HIV infection
Recent cytotoxic therapy
Alcoholism
Recurrent intercurrent infection

30. BONE MARROW ASPIRATE
 Well stained BM aspirate smears
 At least 500 cells are to be counted
 At least 30 megakaryocyte to be evaluated
 Dysplastic features should be present in > 10 % cells
TREPHINE BIOPSY IN MDS
Useful for determining
 Cellularity of marrow
 Abnormal localization of immature precursors (ALIP)
 Reticulin fibrosis, Megakaryocytic dysplasia, Lymphoid aggregate
 Hypoplastic MDS
 Increases the diagnostic accuracy & helps in refining the IPSS score
Flowcytometry
 Erythroid abnormalities detected by
H- ferritin , CD71 ,CD105 in Glycophorin A
 Abnormal maturation pattern in Granulocytes
 For borderline dysplasia ,FC is highly suggestive for MDS
only if aberrant features are present in all three lineages

31. OTHER INVESTIGATIONS
 A) Immunophenotyping- do not play a major role in the diagnosis
of MDS and need not be routinely performed
 B) Ferrokinetics- to assess erythropoiesis.
 C) Haemoglobin electrophoresis or HPLC, to detect HbH and
HbF
 D) Granulocyte function tests to demonstrate defective
phagocytosis
 E) Platelet function tests to demonstrate reduced aggregation and
prolonged bleeding time.
 F) Serum protein electrophoresis to assess immunoglobulins
and detect paraprotein.

32. REFRACTORY CYTOPENIA WITH UNILINEAGE
DYSPLASIA
 Includes
 Refractory Anaemia (RA),
 Refractory neutropenia (RN)
 Refractory Thrombocytopenia (RT)
 Majority of RCUD cases are RA. RN and RT are rare
 10-20 % of all cases of MDS
 Older age 65-70 yrs
 M:F equal prediliction
 C/F due to type of cytopenia
 Cytopenia refractory to hematinics , but respond to growth
factors

33. RCUD: Refractory Anaemia
 Dyplasia of the erythroid series only.
 Clinically, anaemia is refractory to hematinic therapy
 Myeloblasts < 1% blood and < 5% marrow
 No Auer rods
 Other etiologies of erythroid abnormalities must be excluded. These
include:
 drug/toxin exposure -vitamin deficiency
 viral infection -congenital disease
 Epidemiology:
 5-10% of MDS cases.
 Older patients
 Morphology:
 Anisopoikilocytosis on peripheral smears
 Dyserythropoiesis with nuclear abnormalities (megaloblastoid change)
 < 15% ringed sideroblasts
 Genetics:
 25% may have genetic abnormalities
 Prognosis:
 Median survival is 66 months
 6% rate of progression to acute leukemia

34. RCUD: Refractory Neutropenia
 Most important to exclude secondary causes eg. drugs ,toxins
 Characteristics of Dysgranulopoiesis
 Nuclear: hypolobation (pseudo-Pelger Huet), irregular
hypersegmentation
 Cytoplasmic: hypogranularity, Auer rods, small or abnormally
large size

35. RCUD: Refractory Thrombocytopenia
 Evaluate >30 mgk’cytes
 D/D from chronic autoimmune thrombocytopenia is critical
 Features: Micromegakaryocytes, hypolobation, multiple widely
separated nuclei

36. Refractory Anemia with Ringed Sideroblasts
 Dyplasia of the erythroid series only.
 Clinically, anemia is refractory to hematinic therapy
 Myeloblasts < 5% in marrow, absent in blood
 >15% ringed sideroblasts in marrow
 No Auer rods
 Other etiologies of ringed sideroblasts must be excluded. These
include:
 Anti- tuberculosis drugs
 Alcoholism
 Epidemiology:
 10-12% of MDS cases.
 Older patients
 Males > females
 Morphology:
 Dimorphic pattern on peripheral smears
 Majority RBC’s normochromic, 2nd population hypochromic
 Dyserythropoiesis with nuclear abnormalities (megaloblastoid
change)

37. Refractory Anemia with Ringed Sideroblasts
 Genetics:
 Clonal chromosomal abnormalities in <10%; in fact,
development of such an abnormality should prompt
reassessment of diagnosis.
 Prognosis:
 Median survival 6 years (72 months)
 1-2% rate of progression to acute leukemia
Contd…
Ring sideroblast
Megaloblastoid Change

38. REFRACTORY CYTOPENIA WITH MULTILINEAGE
DYSPLASIA
 MDS with one or more cytopenias and dysplastic changes in two or more of
the myeloid lineage
 ≤ 1% blasts in PBS and ≤ 5% in the BM
 Poor prognosis if even 1% blasts in peripheral blood
 Proposed modified criteria are refractory anemia, >10% pseudo-Pelger-Huet
anomalies, dysmegakaryopoiesis in ≥40% or micromegakaryocytes in
≥10%, and no 5q- syndrome
 Termed RCMD with ringed sideroblasts if ≥15% ringed sideroblasts
Epidemiology
 30 % of cases of MDS
 Slight predominance in males
 Age 70- 79

39. RCMD: contd...
Genetics
 Cytogenetic abnormalities include Trisomy
8,Monosomy 7,del 7q , del 20q as well as complex
karyotype
Prognosis
 Frequency of AML development at 2 yrs – 10 %
 Overall survival – 30 months
 Pts with complex karyotype have survival rate similar
to RAEB

40. Refractory Anemia with Excess Blasts
 Refractory anemia with 5-19% myeloblasts in the bone marrow.
 RAEB-1:
 5-9% blasts in bone marrow and <5% blasts in blood.
 RAEB-2:
 10-19% blasts in the bone marrow
 Auer rods present
 Epidemiology: 40% of MDS cases.
 Older patients (over 50 years)
Morphology:
 Dysplasia of all three cell lines often present
 Neutrophil abnormalities may include:
 Hypogranulation
 Pseudo-Pelger-huet (hyposegmentation/barbells)
 Megkaryocyte abnormalities may include
 Hypolobation -Micromegakaryocytes

41. Refractory Anemia with Excess Blasts:
Contd…
 Morphology (con’t.)
 Erythroid precursor abnormalities may include:
 Abnormal lobulation -megaloblastoid change
 Multinucleation
 0-19% myeloblasts in the blood
 5-19% in the marrow
 Bone marrow:
 Usually hypercellular (10-15% hypocellular)
 Abnormal localization of immature precursors (ALIP) may be present
 Immunophenotype:
 Blasts express CD 13, CD33 or CD117
 Genetics:
 Clonal chromosomal abnormalities found in 30% - 50% of RAEB cases. The
abnormalities include:
 +8 – -5 – del(5q)
– -7 – del(7q) – Complex karyotypes
 Prognosis:
 Median survival, RAEB-1 = 18 months
 Median survival, RAEB-2 = 10 months
 RAEB-1 = 25% rate of progression to acute leukemia
 RAEB-2 = 33% rate of progression to acute leukemia

42. MDS WITH ISOLATED del 5q
 Anaemia with or without other cytopenia and/or thrombocytosis
in which the sole genetic abnormality is del 5q
 Myeloblasts ≤ 5% of nucleated BM cells and ≤ 1% of PB
leucocytes
 Auer rods are absent
 More in women
 Median age 67 yrs
 Anaemia is often severe and usually macrocytic
 Thrombocytosis is seen in majority of cases while
thrombocytopenia is uncommon
 BM is usually hypercellular or normocellular and frequently
exhibits erythroid hyperplasia
 Megakaryocytes are increased in no. and are normal to slightly
decreased in size with conspicuously hypolobated and nonlobated
nuclei

43. Contd…
 Genetic abnormality
 Sole cytogenetic abnormality interstitial deletion of Chr 5
 Recent report a small subset of patients with isolated del 5q may
show a concomitant JAK2 V617F mutation.
 Subtype of refractory anemia with good prognosis
 Stable clinical course but often transfusion dependent causing
frequent hemochromatosis
 10% progress to AML
 lenalidomide, a thalidomide analogue and immunomodulating
drug, has high response rate

44. MDS UNCLASSIFIABLE
 Subtype of MDS which lacks findings appropriate for classification
into any other MDS category
 3 possible instances for MDS-U
1. Patients with findings of refractory cytopenia with unilineage
dysplasia (RCUD) or refractory cytopenia with multilineage
dysplasia (RCMD) but with 1% blasts in PB
2. Cases of MDS with unilineage dysplasia which are associated with
pancytopenia
3. Patients with persistent cytopenia with 1 % or fewer blasts in the
blood and fewer than 5% in BM , unequivocal dysplasia in less than
10% of cells in one or more of the myeloid lineage and who have
cytogenetic abnormalities considered as presumptive evidence of
MDS
 Some cases associated with prior aplastic anemia and monosomy 7

45. CHILDHOOD MYELODYSPLASTIC SYNDROME
 MDS in children is very uncommon ,accounting less than 5%
of all hematopoietic neoplasms in patients less than 14 yrs
 This entity should be distinguished from “ secondary MDS”
that follow congenital or acquired BM failure syndromes and
from MDS that follows cytotoxic therapy for a previous
neoplastic or non neoplastic condition
 This entity should be distinguished from MDS with Down
Syndrome

46. Childhood MDS: Contd...
 Most of childhood MDS become symptomatic rather early
and transform to AML in a very short span
 Has an aggressive clinical couse irrespective of WHO
subtype
 Often associated with preexisting BM failure syndromes or
congenital abnormalities like Kostmann Syndrome
Schwachmann Diamond syndrome, Fanconi anaemia, NF 1
down syndrome, juvenile xanthogranuloma
 JMML is the commonest
 Cytogenetic abnormalities- occurs in 60-70% of primary
MDS in children. Monosomy 7 is the most common

48.  DIFFERENCE BETWEEN ADULT AND CHILDHOOD MDS
 Pts may not have increased blasts in their PB or BM
 RARS and MDS with del 5q are exceedingly rare in children
 Neutropenia or Thrombocytopenia is more likely seen
 Hypocellular bone marrow is more commonly observed in childhood MDS
REFRACTORY CYTOPENIA OF CHILDHOOD (RCC)
 It’s a type of MDS characterized by persistent cytopenia with <5% blasts in BM
and < 2% blasts in PB
 BM trephine biopsy specimen is indispensable
 75% of children with RCC shows BM hypocellularity
 Down syndrome related myeloid neoplasms are excluded
 RCC is the most common MDS in childhood accounting for 50% of the cases
 Equal incidence in both sexes

49. MINIMAL DIAGNOSTIC CRITERIA FOR MDS IN
CHILDREN
 At least two of the following
 Sustained unexplained cytopenia( neutropenia,
thrombocytopenia , anemia)
 At least bilineage morphological myelodysplasia
 Acquired clonal cytogenetic abmormality in hematopoietic
cells
 Increased blasts > 5%

50. DIFFERENTIAL DIAGNOSIS
1. Vitamin B 12 and folic acid deficiency
2. AML M6
3. HIV infection
4. Parvo virus B 19 infection
5. Exposure to arsenic and other heavy metals
6. Congenital Dyserythropoietic anemia
7. G- CSF Therapy

51. HYPOPLASTIC MDS
 10-15% of MDS are of hypocellular type
 Higher prevalence in women
 Severe cytopenia and cellularity of the marrow <30% in those
who are <60 yrs of age OR < 20% in those > 60 yrs age
 Majoriy of pt present with refractory anaemia
 BM is hypocellular
 D/D- Aplastic anaemia and hypocellular AML

52. MDS-F (MDS with Myelofibrosis)
 Significant marrow fibrosis in 10-15% MDS
 Most cases: excess blasts, aggressive course
 Unclear whether fibrosis has independent prognostic value
 Blast % from aspirate smears alone may understage the disease
 CD34 on BMB may help
 Cytogenetic abnormalities +ve
 JAK2 - negative

53. SECONDARY/THERAPY RELATED MDS
 Occur post-chemotherapy or post-radiation therapy, benzene
toxins
 Mean age of presentation is 10 yrs earlier than primary
 Most cases are or RAEB type
 t- MDS are of 2 types
a) MDS occuring many years after alkylating drugs use.
b) MDS occuring 2 yrs after Topoisomerase II inhibitors
 Both subtypes frequently evolve into AML

54. IPSS: Prognostic Variables
0 0.5 1.0 1.5 2.0
Marrow blasts % <5 5-10 — 11-20 21-30
Karyotype Good Intermediate Poor
Cytopenias 0/1 2/3 - - -
Overall score is the sum of the scores for following parameters:
BM blasts %: score 0 =< 5%; 0.5=5-10%; 1.5=11-19%; 2.0=20-30%.
Cytopenias: score 0 = no/ one cytopenia; 0.5 = 2 or 3 cytopenias.
Cytogenetics: score 0 (good)= Normal karyotype, -Y, 5q- or 20q-;
score 1.0 (poor)= 7q- or -7, complex translocations;
score 0.5 (intermediate)= all others.
Risk group Overall score Median survival (years)
Low 0 5.7
Intermediate 1 0.5 or 1.0 3.5
Intermediate 2 1.5 or 2.0 1.2
Poor >/= 2.5 0.4
Greenberg P et al. Blood 1997;89:2079-2088.

55. 2012 Revised IPSS
Schanz J, et al. J Clin Oncol. 2012;30:820-829. Greenberg PL, et al. Blood. 2012;120:2454-2465.
Prognostic
Subgroup
Cytogenetic Abnormality Median OS,
Mos
Median
Time to
AML, Mos
Very good del(11q), -Y 60.8 NR
Good Normal, del(20q), del(5q) alone or double, del(12p) 48.6 NR
Intermediate
+8, del(7q), i(17q), +19, any other single or double,
independent clones
26.0 78.0
Poor
inv(3)/t(3q)/del(eq), -7, double including del(7q),
complex (3)
15.8 21.0
Very poor complex (≥ 3) 5.9 8.2
Fine tune the prognostic impact of
•Cytogenetic abnormalities
•Depth of cytopenia

56. IPSS-R
Risk Category Risk Score
Very low ≤ 1.5
Low >1.5 - 3
Intermediate >3 – 4.5
High >4.5 - 6
Very High >6
Variable 0 0.5 1 1.5 2 3 4
Cytogenetics V. good - Good - Int Poor V. poor
BM blast% ≤2 - >2 - <5 - 5-10 >10 -
Hb ≥10 - 8-<10 <8 - - -
Platelets ≥100 50-100 <50 - - - -
ANC ≥0.8 <0.8 - - - - -

57. WHO Prognostic Scoring System
*BM fibrosis grade 2-3 shifts risk group by one step

58. Advances in therapy of
MDS

59. Treatment considerations
 Treatment considerations must take into account many
factors, including the
 Pathologic diagnosis
 The prognosis based on the IPSS-R or WPSS
 Cell line /s affected
 Feasibility of performing a clinical trial

60. Tools to treat MDS
 Supportive therapy (Transfusions)
 Hematopoietic growth factors ( Epo, G-CSF )
 Iron chelation
 Lenalidomide (Revlimid, Lenalid)
 Hypomethylating agents
 Azacitidine
 Decitabine
• Immunosuppression (Antithymocyte globulin (ATG),
Cyclosporin, Thalidomide )
• Chemotherapy (High/low Dose AraC, Topotecan + AraC)
 Allogeneic stem cell transplantation ( only curative Rx )
 Newer agents

61. Role of Growth Factors
GCSF Support improves ANC (75% patients)
Has no impact on overall survival.
Not recommended for routine infection prophylaxis
Thrombopoietic
agents
Most have no significant impact on transfusion needs:
Main utility
–Fewer dose modifications of disease modifying agents
–Romiplostim: 500/750mcg weekly
–Eltrombopag: under study
Erythropoiesis
stimulating agents
(ESA)
–First line therapy for IPSS low or Int-1 risk MDS with
EPO <500U/L (NCCN guidelines)
–Response rates; 20-30%, durability:2 years
–Epoeitin alpha: 60,000-80,000 U once per week
–Darbopoietin alpha: 500mcg once 3 weekly
Most widely prescribed class of medications for MDS (55%)

63. Immunosuppressants
 Immunologic suppression of normal BM function, similar to the situation in
aplastic anemia, has been postulated to account for cytopenias in some MDS
patients
 Specific candidates- Refractory anemia with relatively
hypoplastic marrow
 Predictor of Response to Immunosuppressant
 HLA-DR-15-positivity
 RA (<5% blasts)
 IPSS Low/Int-1
 Age <60 years
 Brief transfusion history
 Trisomy 8 abnormality
 Normal cytogenetics
 Marrow cellularity <30%

64. Biological response modifiers
( Lenalidomide)
del(5q)
IPSS low or Int-1
platelets > 50K/mm3
neutrophils > 500/mm3
transfusion dependent

65. Study Design
Dose Reduction
5 mg qd
5 mg qod
Week: 0 4 8 12 16 20 24
Eligible
Patients
R
e
g
i
s
t
e
r
R
e
s
p
o
n
s
e
10 mg po x 21
NO Off study
YES Continue

66. Results
Frequency of Cytogenetic Response According to Karyotype Complexity

67. Lenalidomide in non del(5q) MDS
 Can be considered for low risk, adequate ANC and platelet
counts
 Expected response rates are similar to other treatment
alternatives
 Use in high risk MDS remains investigational
Raza et al. Blood 2008

68. Hypomethylating agents
• Azacytidine and decitabine are potent DNMT
inhibitors
• This leads to hypomethylation of CpG dinucleotides in
gene promoters and reactivation of previously silent
genes
• Cytotoxic activity similar to cytarabine

69. 5 Azacytidine
AZA Controls
Median survival 24.5 months 15 months
Progression to AML 27 months 13 months
Transfusion independence 45% 11%
Fennaux et al. Lancet Oncol 2009
Decitabine
DAC Controls
Overall survival 10 months 8.5 months
Progression to AML at 1 yr 22% 33%
CR/ PR/ HI 13/6/5% 0/0/2%
Lubbert et al . JCO 2011

70. Hypomethylating agents
When to start
– Int/ high risk MDS (IPSS)
– Transfusion dependent/
EPO failure
– Not yet known if early
treatment is better than
late treatment in MDS
Which drug
– NCCN recommends Azacitidine
preference over Decitabine
– MDACC regimen (5 day
20mg/m2/d) highest CR
– Aza vs Decitabine head to head
trial results awaited
Optimal dose, schedule, route
– Azacitidine:
– 7 day 75mg/m2/d sc 28 days
(5-2-2 or 50mg/m2 5-2-5
schedule)
– Decitabine:
– 3 day 15mg/m2/dose IV 8 hrly
(total dose 135mg/m2)
inpatient
– 5 day 20mg/m2 /d over 1 hr
(total dose 100mg/m2)
outpatient
Duration
– Optimal duration- not known
– To treat responding pts till disease
progression, as long as tolerated
– At least 4 cycles recommended for
adequate response

71. MDS
Low risk
(low or Int 1, BM blasts <10%)
Any age
Iron Chelation
Growth factors
DMT Inhibitors
Lenolidomide
Immunomodulation
Clinical trial
Progression/ failure
HSCT
High Risk
(Int 2, High risk, blasts>10%)
Age <60 Age≥60
Intensive chemo
DMTI
Clinical trial
DMTI
Clinical trial
Intensive Chemo
Failure
Attallah: Cancer Therap 2008;26:208-16
Failure

72. Take Home Message
Myelo-dysplastic syndromes are
heterogeneous disorders
Prognostic scores are evolving with use of
cyto-genetics and molecular markers
Treatment depends upon the prognostic and
host factors
HSCT is the only curative treatment
Treatment paradigms are evolving