mylodysplastic syndrome narmada

1. MODERATOR – Prof. DR. - ANIL KAPOOR

2. What Is Myelodysplastic Syndrome?
The myelodysplastic syndromes are a group of disorders
characterized by one or more peripheral blood cytopenias
secondary to bone marrow dysfunction.
 In MDS the bone marrow cannot produce blood cells
effectively, and many of the blood cells formed are
defective.
These abnormal blood cells are usually destroyed before
they leave the bone marrow or shortly after entering the
bloodstream.
As a result, patients have shortages of blood cells, which
are reflected in their low blood

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

4. Incidence
1- Disease of elderly.
2- Median age is 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

5. MDS Etiology
Two etiologic categories of MDS:
1.) De Novo:
Associated with:
-benzene exposure (gasoline)
-cigarette smoking
-viruses -Fanconi’s anemia
2.) Therapy related:
Associated with:
-alkylating agent chemotherapy
-radiation

6. Aetiological Agents
 Tobacco smoke.
 Ionizing radiation.
 Organic chemicals (such as benzene, toluene, xylene, and
chloramphenicol).
 Heavy metals.
 Herbicides.
 Pesticides.
 Fertilizers.
 Stone and cereal dusts.
 Exhaust gases.
 Nitro-organic explosives.
 Petroleum and diesel derivatives.
 Alkylating agents.
 Marrow-damaging agents used in cancer chemotherapy.

7. Pathophysiology: Contributing Factors
Immune
Apoptosis
dysfunction
Stem cell
Stem Cell
dysfunction
Epigenetic Dysfunction Environmental
changes direct toxicity
/Stromal
/Mutations
angiogenic
factors
MDS DNA damage
. With Permission of J. Maciejewski, M.D
Taussig Cancer Center/ Cleveland Clinic Foundation

8. Myelodysplastic Syndrome
Dyserythropoiesis
Dysmyelopoiesis
Dysmegakaryopoiesis
Ring Sideroblast
Type I and II blasts

9. Dyserythropoiesis
Anemia
Normocytic or macro-ovalocytes
Low retic count
NRBC
Megaloblastic changes
Ringed sideroblast
Pappenheimer bodies
Basophilic stippling

13. Dyserythropoiesis
Ringed sideroblast

14. Dysmyelopoiesis
Neutropenia
Monocytosis
Pseudo Pelger-Huet
Hypogranular PMN
<20% blasts in BM
Type I and type II blasts

17. Blasts in MDS
Type I blasts Promyelocyte
No granules Many 1o granules
Prominent Less prominent
nucleoli nucleoli
Central nucleus Eccentric nucleus
Type II and III blasts
Few 1o granules
Prominent
nucleoli
Central nucleus

18. Type I Blast
Type III Blast

19. Dysmegakaryopoiesis
Low platelet count
Giant Platelet
Dwarf (micro) megakaryocyte

20. Micromegakaryocyte
Abnormal platelets

21. Chromosomal abnormalities and MDS
Chromosomal abnormalities are present in up to
50%of de novo cases of MDS and in virtually all
cases of secondary MDS. The most common are:
 Abnormality -7 +7 +8 5q- 7q- 11q- 12q- 13q- 20q- inv3 i(17q) t(1;3) t(1;7) t(3;3)
 Frequency(%) 15 5 19 27 4 7 5 2 5 1 5 1 2 1

22. Deletion of the long arm of chromosome 5
(5q- syndrome )
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.

23. Monosmy 7 and 7q-
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.

24. Deletion of the q arm of chromosome 11
(11q-)
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 H-
subunit of ferritin at chromosome 11 , may explain
this

25. Abnormalities of chromosome 17 (i17q)
It involves the loss or disruption of the Р53 tumor
suppressor gene are seen in CML in association with
transformation to the blastic phase and in up to 5%
of cases of primary MDS.
 This predisposes to certain dysplastic features and
neutrophil vaculation.

26. Abnormalities of chromosome 3
Dysmegakaryopiesis and thombocytosis appear to be
associated with Abnormalities of chromosome 3

27. The importance of indication of chromosomal
abnormalities
To confirm diagnoses .
 To know the stage of disease.
To know the direction of progression of disease.
Multiple genetic abnormalities indicate late events in
MDS.

28. Abnormal localization of immature
precursors
Presence of 3 or more small clusters of myeloblasts
and promyelocytes (5 – 8 cells) in marrow trephine
biopsy in the central portion of the marrow away
from the vascular structure and the endosteal
surface of the bone trabeculae

29. Abnormal localization of immature
precursors

30. Signs and Symptoms
Excessive tiredness, shortness of breath, and pale skin can
be caused by anemia (shortage of red blood cells).
Serious infections with high fevers can be caused by
leukopenia (not having enough normal white blood cells)
and, in particular, by having neutropenia or
granulocytopenia (too few mature granulocytes).
Excessive bruising and bleeding, for example, frequent or
severe nosebleeds and/or bleeding from the gums, can be
due to thrombocytopenia (not having enough of the blood
platelets needed for plugging holes in damaged blood
vessels).

31. Physical Exam
Hepatomegaly, splenomegaly, LAD:
uncommon
Except CMML
Cutaneous manifestations: uncommon
Sweet’s syndrome( neutrophilic dermatosis):
transformation to acute leukemia ( IL-6)
Granulocytic sarcoma (chloroma): herald disease
transformation into acute leukemia

32. Sweet’s syndrome


33. FAB classification scheme in 1985 for MDS

34. Refractory Anemia
RA Definition:
Dyplasia of the erythroid series only.
Clinically, anemia is refractory to hematinic
therapy
Myeloblasts < 1% blood and < 5% marrow
<15% ringed sideroblasts in marrow
No Auer rods
Other etiologies of erythroid abnormalities must
be excluded. These include:
drug/toxin exposure -vitamin deficiency
viral infection -congenital disease

35. Refractory Anemia
Epidemiology:
5-10% of MDS cases.
Older patients
Morphology:
Anisopoikilocytosis on peripheral smears
Dyserythropoiesis with nuclear abnormalities
(megaloblastoid change)
< 15% ringed sideroblasts

36. Refractory Anemia
Genetics:
25% may have genetic abnormalities
Prognosis:
Median survival is 66 months
6% rate of progression to acute leukemia

37. Peripheral Smear - Anisopoikilocytosis

38. Megaloblastoid Change on Bone Marrow
Aspirate

39. Refractory Anemia with Ringed Sideroblasts
RARS definition:
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

40. Refractory Anemia with Ringed Sideroblasts
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)

41. 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

42. Dimorphic Red Cell Population

43. Ringed Sideroblasts

44. Ringed Sideroblasts

45. Megaloblastoid Change

46. Refractory Anemia with Excess Blasts
RAEB definition:
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

47. Refractory Anemia with Excess Blasts
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

48. Refractory Anemia with Excess Blasts
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

49. Refractory Anemia with Excess Blasts
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

50. Hypercellular Bone Marrow

51. Auer Rods

52. Refractory Anemia with Excess Blasts in
Transformation (RAEB-t)
•
21-30 percent blasts in the marrow; more than
5 percent in the bloodstream
•
normal or hypercellular (filled with cells)
marrow
•
accounts for about 25 percent of cases

53. Chronic Myelomonocytic Leukemia
(CMML)
•
5-20 percent blasts in the marrow; less than 5
percent in the bloodstream
•
cytopenia of at least two cell lines
•
normal or hypercellular (filled with cells)
marrow
•
accounts for 15 to 20 percent of cases.

54. CMML
 Splenomegaly (10%)
 Maculopapular skin infiltration
 Monocytic pleural or pericardial effusion
 JMML (MPD/MDS)
1. Pallor, bleeding, hepatosplenomegaly, skin
involvement

55. WHO
Refractory anemia
Refractory anemia e ringed siderblast
Refractory cytopenia e multilineage dysplasia
Refractory cytopenia e multilineage dysplasia &
ringed sideroblasts
Refractory anemia e excess blast-1
Refractory anemia e excess blast-2
Myelodysplastic syndrome unclassified
MDS associated e isolated del (5q)

56. WHO
Subtype Blood Bone Marrow
RA Anemia Erythroid
dysplasia only
RARS Anemia Erythroid dys
>15% ringed
RCMD Bi- pancytopenia >10%Dysp in 2
or more cell
lineage
RCMD-RS Bi-pancytopenia >10%Dys 2 or
more cell lineage
>15% ringed

57. WHO
subtype Blood Bone Marrow
RAEB-1 Cytopenia Uni-multilineage
<5% blast dys, 5-9%blast
RAEB-2 Cytopenia, Uni-multi dys
5-19%blast or Auer 10-19%blast
rods Or Auer rods
MDS-U cytopenia Myeloid or
megakaryocte dys
MDS with 5q Anemia,nor or Mega e hypolobated
increased PLT nuclei, <5%blast

58. Prognostic Groups
Two groups based on survival and evolution to acute
leukemia
1.) “Good” group
 Refractory anemia (RA)
 Refractory anemia with ringed sideroblasts (RARS)
 5q - syndrome
2.) “Bad” group
 Refractory anemia with excess blasts (RAEB)
 Refractory anemia with excess blasts in transformation (RAEB-t)
 CMML
MDS unclassified can be either

59. International Prognostic Scoring System
(IPSS) Factors
(1) the percentage of blasts in the bone
marrow.
(2)whether chromosome abnormalities are
present and, if so, which ones.
(3)how low the patient's blood counts are. These
are given a score; the lowest scores have the
best outlook for survival.

60. Prognostic Scoring
The International Myelodysplastic Syndrome Working
Group developed a scoring system based on 3 variables:
0 0.5 1.0 1.5 2.0
% Blasts
<5 5-10 -- 11-20 20-30
Karyotyp Normal, -Y, Single ≥3
abnormalities,
e del(5q), karyotypic
chr 7
del(20q) anomaly, abnormalities
Double Chr 3 abn.
abnormaliy
Cytopeni
a
0-1 2-3

61. Median Survival in MDS

62. MDS: Differential Diagnosis
B12/folate deficiency
Heavy metals (Arsenic)
Congenital dyserythropoietic anemia
Parvovirus B19
GCSF therapy (increased blasts)

63. Treatment
o Chemotherapy.
o Supportive therapy, such as WBCs, RBCs,
Platelets transfusions.
o B.M transplantation in young patients.

65. SPEAKER- DR. Narmada Prasad Tiwari
THANK YOU

66. Prevention & Treatment
of Infections
Prevention
Prophylactic antibiotics  no role
Patient education  know your nadir
report a fever
recognize signs of infection
avoid illness, crowds
update vaccinations
Treatment  Febrile neutropenia guidelines
www.nccn.org/MDS v1..2008

67. Iron Chelation Options
Deferoxamine (Desferal®)
Route: SQ
t ½: 0.5 hours
Dosing: Infused over 8-12 hrs
5-7 nights/week
Deferasirox (Exjade®)
Route: PO
t ½: 12-16 hours
Dosing: Dissolved in solution, taken daily

68. Pharmacotherapy In MDS
Azacitidine
Decitabine
Lenalidomide
Anti-thymocyte Globulin (ATG)

69. IPSS

70. Median Survival in MDS

71. Large pronormoblast in pervovirus
.infection

72. Differential Diagnosis
Non-neoplastic simulators
Other myelodysplastic disorders
eoplastic disorders may simulate myelodysplasia
Vitamin/micronutrient deficiencies
B12/folate
Copper
Ring sideroblasts present
Cytoplasmic vacuoles
May be due to
Zinc excess
Gastrectomy
Total parenteral nutrition
Infections
HIV
Parvovirus
HHV-6 in children
Toxins
Ethanol
Heavy metals
Growth factors
-macrophage colony-stimulating factor (GMCSF
Erythropoietin
)Drugs (numerous