MYELODYSPLASTIC

SYNDROME
Candra Wibowo
Nephrology Division, Medical School of Trisakti University Jakarta

MYELODYSPLASTIC SYNDROME

Group of clonal disorders of hematopoietic stem

cells characterized by cellular dysplasia and
ineffective hematopoiesis
Results in cytopenias and dysmyelopoiesis
Variable risk of transformation to acute leukemia

PATHOPHYSIOLOGY

Primary MDS or Secondary MDS

A clonal mutation in hematopoietic stem cells
Bone marrow failure due to ineffective
hematopoiesis
Increased cytokines (TNF-a) inhibit hematopoiesis
Increased apoptosis
Results in futile cycling of blood cells with impaired
production of mature blood cells

PATHOPHYSIOLOGY

Multi-hit hypothesis
Initial hematopoietic stem cell injury due to
chromosomal abnormalities, cytotoxic
chemotherapy, radiation exposure, viral
infection, chemical exposure, or genetic
predisposition.
Sequential mutations possibly involving N-ras
oncogene, p53, IRF-1, antiapoptotic Bcl-2

PREVALENCE

Mainly a disorder of older patients, rarely

presents before age 50
Median age is 65 years
Male predominance

PREVALENCE

5 cases per 100,000 persons per year in US

Increases to 20-50 cases per 100,000 people per year
after age 60
13-15,000 new cases per year in US
At least as common as CLL

CLINICAL PRESENTATION
Non specific signs and symptoms of various
cytopenias
Fatigue, SOB, exercise intolerance, pallor,
tachycardia
Mucosal bleeding, petechiae, ecchymoses
Infection, fever
B-symptoms are uncommon
Splenomegaly and lymphadenopathy are rare

DIAGNOSIS

Anemia uniformly present with decreased

reticulocytosis
>50% present with pancytopenia
50% present with associated neutropenia
<5% isolated neutropenia or thrombocytopenia
Cytopenia with normal or hypercellular bone
marrow with single or multi-lineage dysplasia

MORPHOLOGY

Peripheral changes
include oval
macrocytic red
cells, hypogranular
granulocytes with
the pseudo-Pelger
Hut anomaly, and
giant platelets.

MORPHOLOGY

Megaloblastic red-cell
precursors with
multiple nuclei or
asynchronous
maturation of the
nucleus and the
cytoplasm

MORPHOLOGY

Ringed sideroblasts,
erythroid precursors
with iron-laden
mitochondria

CLASSIFICATION
Disease

Peripheral Blood

Bone Marrow

Refractory Anemia (RA)

Anemia
No or rare blasts

Erythroid dysplasia only

< 5% blasts
< 15% ringed sideroblasts

Refractory Anemia with

Ringed Sideroblasts
(RARS)

Anemia
No blasts

Erythroid dysplasia only

>15% ringed sideroblasts
< 5% blasts

Refractory cytopenia with

multilineage dysplasia
(RCMD)

Cytopenia
No or rare blasts
No Auer rods
< 1 109/L monocytes

Dysplasia in 10% of cells in

2 or more myeloid cell lines
< 5% blasts in marrow
< 15% ringed sideroblasts

Classification Cont.
Disease

Peripheral Blood

Refractory cytopenia with Cytopenia

multilineage dysplasia
No or rare blasts
and ringed sideroblasts
No Auer rods
(RCMD-RS)
<1109/L monocytes

Bone Marrow
Dysplasia in 10% of
cells in 2or more
myeloid cell lines <5%
blasts in marrow >15%
ringed sideroblasts

Refractory anemia
with excess blasts-1
(RAEB-1)

Cytopenias
<5% blasts
No Auer rods
<1109/L monocytes

Unilineage or
multilineage dysplasia
5% to 9% blasts
No Auer rods

Refractory anemia
with excess blasts-2
(RAEB-2)

Cytopenias
5% to 19% blasts
Auer rods
<1109/L monocytes

Unilineage or
multilineage dysplasia
10% to 19% blasts
Auer rods

Classification cont.
Disease

Peripheral Blood

Bone Marrow

Myelodysplastic
syndrome,
unclassified (MDS-U)

Cytopenias
No or rare blasts
No Auer rods

Unilineage dysplasia in
granulocytes or
megakaryocytes
<5% blasts
No Auer rods

MDS associated with

isolated del(5q)

Anemia
<5% blasts
Platelets normal or
increased

Normal to increased
megakaryocytes with
hypolobated nuclei
<5% blasts
No Auer rods
Isolated del(5q)

Differential Diagnosis

AML, CML, CMML

Aplastic anemia, fanconi anemia
Myelofibrosis
B12, folate deficiency
HIV, parvovirus B19
Hepatitis viruses (non A,B,C)
PNH
Heavy metal poisoning
Medications: valproate, mycophenolate, ganciclovir,
chloramphenicol
Industrial chemical, insecticide exposures (benzene)

Cytogenetics

Chromosomal abnormality 40-70%

Increased severity of disease, risk for
leukemic progression, and poorer
prognosis with more complex
karyotypes
Favorable: normal, del (5q), del (20q)
Intermediate: other single gene defects
Poor: Complex karyotype or ch7

Prognosis

Overall risk of progression to acute

leukemia 22-35%
International Prognostic Scoring
System
Advanced age
Performance status

International Prognostic
Scoring System

IPPS

Treatment

Control symptoms
Improve quality of life
Decrease progression to AML
Low Intensity: Low and Int-1 IPPS
High Intensity: Int-2 and High risk
IPPS

Supportive Therapy

Antibiotics
Minimize transfusions
Growth factors
Epoetin-alpha, darbepoetin alpha
G-CSF, GM-CSF
EPO/G-CSF combination

Low Intensity

Lenalidomide
Immunomodulatory derivative of thalidomide
Multi-center study 43 pts MDS: 49% response
Hg or transfusion independence. 83%
response del (5q). 9 of 12 del (5q) normal
karyotype.
Dose related myelosuppression
FDA approved for low- or INT-1-risk MDS
associated with a del (5q)

Low Intensity

Azacitidine
Pyrimidine nucleoside analog,
antineoplastic hypomethylation DNA
Randomized trial 191 pts MDS 5-Aza vs
supportive care
32% pts complete or partial remission
Time to AML progression 21mo. vs 13 mo.
Supportive care
Approved for RA, RARS, RAEB 1-2

Low Intensity

Decitabine
Pyrimidine nucleoside analog of cytidine
Inhibits DNA methylation
66 pt study, response 25% Int-I, 48% Int
-2, 64% High risk. Survival High risk 1.2
years. 31% cytogenetic response
FDA approved for all MDS subtypes, INT1, INT-2 and high risk IPSS groups.

Immunosuppressants

Hypocellular MDS or MDS w/

immunologic component (vasculitis or
HLA-DR15) Immune-mediated
suppression
Treat with Antithymocyte globulin
(ATG) plus/minus cyclosporine A
ATG 40 mg/kg per day intravenously
for four days

High Intensity

AML induction chemotherapy for MDS w/

>10% bone marrow blasts if age <60, good
PS
Allogeneic hematopoietic cell
transplantation (HCT), potentially curative.
MDS <60 with HLA matched sibling donor.
-30-40% disease free survival HCT. 40%
transplant mortality.
-60-70% disease free survival HCT young
pts, full HLA matched donor.

Back to the case

Refractory cytopenia with multilineage dysplasia

Darbepoetin and G-CSF

HSCT protocol conditioning w/ campath,
fludarabine, and busulfan
S/p HLA matched, ABO mismatched sibling
peripheral blood stem cell transplant w/ good
engraftment and full donor chimera

References

Komrokji RS, Bennett JM. Evolving classifications of

the myelodysplastic syndromes. Curr Opin Hematol.
2007 Mar;14(2):98-105.
Ma X, Does M, Raza A, Mayne ST. Myelodysplastic
syndromes: incidence and survival in the United
States.Cancer. 2007 Mar 7;109(8):1536-1542
Cazzola M, Malcovati L. Myelodysplastic syndromes-coping with ineffective hematopoiesis. N Engl J Med.
2005 Feb 10;352(6):536-8
Heaney ML, Golde DW. Myelodysplasia. N Engl J Med.
1999 May 27;340(21):1649-60