Myelodysplastic Syndromes

Norman Djamaludin

Division of Haematology and Medical Oncology

Department of Internal Medicine
Faculty of Medicine University of Sriwijaya

Definition of Myelodysplasia

Clonal disorder
Stable cytopenias for 2-6 weeks
Morphologic evidence of dysplastic changes
in at least 2 hematopoietic cell lines
Hypercellular or normocellular bone marrow
Propensity to transform into AML in 20%

Pathogenesis of Myelodysplasia

Ineffective erythropoiesis due to

increased apoptosis (programmed cell
death)
Impaired cellular maturation due to
intrinsic defects in cells of neoplastic
clone
Altered responses to regulatory
hormones

Presentation of Myelodysplasia

Most over age 60

Slight male predominance
Hx of acquired or congenital risk factors
radiation, chemotherapy (alkylating agents, topoisomerase
inhibitors)
Hodgkins disease, non-Hodgkins lymphoma, multiple myeloma
ovarian CA, breast CA

NH3, diesel, benzene

aplastic anemia, paroxysmal nocturnal hemoglobinuria
Fanconis anemia, Downs syndrome, Turners syndrome,
Blooms syndrome

Dyserythropoiesis

Macrocytosis
Low reticulocyte count
Ringed sideroblasts
Nuclear-cytoplasmic asynchrony
Bizarre nuclear configurations
Abnormal Fe metabolism

Macrocytosis, biphenotypic
population

Dysmorphic nucleated rbcs

Ringed sideroblast

Increased iron stores

Dysmyelopoiesis

Hypogranulation
Nuclear-cytoplasmic asynchrony
Pseudo-Pelger-Huet anomaly
Defective adhesion, phagocytosis, and
bacterial killing

Hypogranulation, nuclear-cytoplasmic asynchrony

Stodtmeister cell

Pseudo-Pelger-Huet anomaly

Aberrant granulation

Dysmegakaryocytopoiesis

Giant, agranular platelets

Micromegakaryocytes and mononuclear
megakaryocytes
Abnormal platelet function

Hypogranular platelets

Abnormal megakaryocyte

Circulating micromegakaryocyte

Mononuclear megakaryocyte

Other Manifestations of MDS

Rheumatologic - vasculitis, arthritis,

lupus-like syndromes
Neurologic - peripheral neuropathy
Metabolic - abnormal LFTs
Dermatologic - urticaria pigmentosa,
chloroma, Sweets syndrome

Chloroma

Granulocytic Sarcoma
1. Extramedullary aggregates of blast cells
2. Greenish color on sectioning due to
myeloperoxidase
3. AML (M2 with 8;21 translocation), MDS

Sweets Syndrome

Acute neutrophilic dermatosis

1. Tender red plaques and nodules
2. Benign infiltration of PMNs in
lower dermis
3. AML, MDS, NHL, idiopathic
4. Rx - systemic steroids

FAB Classification of MDS

Refractory
Anemia

RA with
Ringed
Sideroblast
< 5%
> 15% RS

RA with
Excess
Blasts
5-20%

RAEB in
Transformation
21-30%

CMML

% Blasts in < 1%
Blood

< 1%

< 5%

> 5%

Risk of
AML

1 yr - 5%
2 yr - 10%

0%

1 yr - 25%
2 yr - 35%

1 yr - 55%
2 yr - 65%

< 5%
> 1000
monos/l
14-33%

Median
Survival

3-6 years

3-6 years

5-12 mon

5-12 mon

% Blasts in < 5%
Marrow

< 20%

16-53 mon

Chronic Myelomonocytic
Leukemia

Features of
myeloproliferative
disorder (leukocytosis,
splenomegaly)
Trilineage dysplasia,
classical chromosomal
abnormalities
Risk of transformation
to AML correlated with
number of bone
marrow blasts

Cytogenetics of MDS

Abnormalities seen in 40-60% with primary

MDS
Abnormalities seen in > 80% with secondary
MDS
Valuable in prognostication
normal, Y-, 5q-> 2 years
+8
1-2 years
-7, -5, others
< 1 year

Deletion of Chromosome 7

Cytogenetic Analysis
1. Metaphase cells
2. Can screen for any
obvious cytogenetic
abnormality

Fluorescent In-situ Hybridization (FISH)

1. Interphase cells
2. Allows for computerized analysis
3. Restricted to well-established cytogenetic abnormality

Prognostic Factors of AML

Good Prognosis

Increased erythroid
activity
Younger age
Female sex
High percentage of
ringed sideroblasts

Bad Prognosis

High M:E ratio

Older age
Male sex
Trilineage dysplasia,
increased blasts

International Prognostic Scoring System

<5%
5-10%
11-20%
21-30%

0
0.5
1.5
2.0

Intermediate
1
Score 0.5-1.0
Median survival 3.5 yrs

Cytogenetic features

Score 0
Median survival 5.7 yrs

Percentage of blasts

Low

Normal, Y-, 5q-, 20qAll others

-7, 3 or more abnormalities

0
0.5
1.0

2
Score 1.5-2.0
Median survival 1.2 yrs

Number of cytopenias*

0-1
2-3

*Hgb < 10 g/dl, ANC < 1500, plt < 100K

0.5
1.0

High
Score > 2.5
Median survival 0.4 yrs

Treatment of Myelodysplasia

Supportive care
Hormonal and immunosuppressive
therapy
Hematopoietic growth factors
Differentiating agents
Chemotherapy
Bone marrow transplantation

Supportive care of MDS

RBC and platelet transfusions

Deferoxamine (Desferal)
Antibiotics
Avoidance of myelotoxic medications
Pyridoxine 200 mg QD

Growth Factors in MDS

GM-CSF
G-CSF
Erythropoietin
IL-3
IL-6
IL-11
Thrombopoietin

Differentiating Agents in MDS

Retinoids
Cholecalciferols
Hexamethylene bisacetamide
5-aza-2-deoxycytidine - inhibits DNA
methylation
Amifostine - cytoprotective agent

Immunotherapy in MDS

Antithymocyte globulin +/- cyclosporine

Complete remissions in hypoplastic MDS
Eliminated transfusion requirement in 44% with
normocellular and hypercellular MDS

Monoclonal antibody against CD33

Disproportionately expressed on blast cells
Effective in those with <10% blasts

Chemotherapy in MDS

Single agents

Low-dose cytarabine (LoDAC)

High-dose cytarabine (HiDAC)
Homoharringtonine
Topotecan

Combination therapy
Standard AML induction therapy
Fludarabine, cytarabine, idarubicin
Cyclophosphamide, cytarabine, topotecan

Bone Marrow Transplantation in

Myelodysplastic Syndrome

Allogeneic BMT
Best results with

young patients (DFS 75%)

marrow blasts counts < 5%
absence of marrow fibrosis
interval to BMT < 5 years
matched sibling donor

Treatment-related mortality
34-55%
Disease-free survival 2645%
Relapse 19-34%

Autologous BMT
Higher relapse rate

25%
42%
33%
TRM

DFS

Relapse