Myelodysplastic syndrome

Dr. Tjatur Winarsanto SpPD

RS Ciremai
Cirebon

Myelodysplastic syndrome
(MDS)
It is a term for a heterogeneous collection of
haemopoietic stem cell disorders affecting
older adults.
There is underlying ineffectiveness of
haemopoiesis that results in dysplasia of
bone marrow precursors and peripheral
cytopenias.

 Moderate anaemia is the most common

clinical problem in MDS patients, but
complete myeloid bone marrow failure also
occurs leading to death from bleeding or
infection.
Approximately half of the patients
transform to AML.

 Prognosis depends on the individuals risk factors,

with median survival ranging from 5.7 years in
lower-risk group to 1.2 years or less in those with
higher-risk MDS.
MDS is extremely difficult to treat. Most cases are
resistant to current therapies, and the most potent
anti-MDS treatments (transplantation and dose
intensive chemotherapy) are often too toxic for the
majority of patients.

MDS: Epidemiology
Older adults (median age: 70 years)
Primary vs. Secondary MDS (S/P chemotherapy)
Incidence: 3/100,000 non-age corrected
20/100,000 over age 70

MDS: Etiology
Primary
No known history of toxic exposure
Possible etiologies: Virus, Benzene, cigarette (2
fold risk).

Therapy-related
Chemotherapy (alkylating agents)
Radiation Therapy

MDS: Clinical
Symptoms of Cytopenia
Anemia > Neutropenia +/- Thrombocytopenia
Organomegaly (infrequent)

MDS background
Pathobiology
The cardinal features of MDS are
Increased marrow proliferation
Failure of stem cells to differentiate
And increased marrow apoptosis.

The disease is of clonal origin

Chromosomal abnormalities are detectable in 30-70%
of patients. The no. of chromosomal abn. may correlate
with the risk of progression to AML.

FAB classification
In 1982 The FAB group classified MDS according
to Morphology and the % of myeloblasts in the BM
and PB.
These included

Refractory anaemia (RA)

Refractory anaemia with ringed sideroblasts (RARS)
Refractory anaemia with excess blast in marrow (RAEB)
CMML
Refractory anaemia with excess blast in transformation
(RAEB-t)

Morphological
characteristics of MDS

WHO classification
The WHO proposed changes including
reclassification of RAEB-t to AML and
adding a subgroup called refractory
cytopenias with dysplasia (RCD)

Myelodysplastic Syndromes
FAB Classification

RA
RARS
RAEB
RAEB-T

CMML

WHO classification
Myelodysplastic Syndromes
RA
RARS
RCMD & RCMD-RS
RAEB-1 & RAEB-2
MDS Unclassified
MDS del(5q)
Myelodysplastic/Myeloproliferative
Diseases
CMML
Atypical CML
Juvenile CMML
MDS/MPD, unclassified

International Prognostic Scoring

System (IPSS)
The most practical and validated MDS
classification system currently available to
clinicians is the IPSS which predicts both
survival and risk of transformation to AML
based on:
Marrow blast %
Cytogenetics
And number of cytopenias.

The scope of MDS

MDS is primarily a disease of the elderly,
with a median age at diagnosis of between
60-80 years.
The incidence is approximately double that
of AML.
The recent increase in MDS incidence may
be related to growing awareness, better
diagnosis, and an aging population.

 Prognosis for most patients is poor.

If not cured by BMT, the disease is invariably
fatal.
The common symptoms at presentation, fatigue or
weakness, are attributable to cytopenia.
Easy bruising, ecchymosis, epistaxis, gingival
bleeding, and bacterial infections may also be
encountered.

 Transformation to acute leukaemia occurs

in up to 40% of patients.
Although progression to frank AML is a
primary concern, 20-40 % or more of
patients die of infections and/or
haemorrhagic complications.

Conventional therapies
Supportive care including blood products
with deferoxamine, haemopoietic growth
factors and antibiotics. EPO increases red
blood cells in some patients, GM-CSF may
limit infections.
Hormone suppressive therapy with danazol
has been used to help resolve anaemia and
reduce transfusion requirements.

 Most attempts to induce haemopoietic cell

differentiation have failed. For example, interferon
alfa-2 transiently improves platelet counts in some
MDS patients. However progression is also possible.
Clinical studies with differentiation promoters such
as retinoids, Vit D3, butyrates have been
disappointing.
In contrast, the hypomethylating agent 5-azacytidine
has produced significant clinical benefit in patients
with MDS

 Low intensity chemotherapy with cytarabine

induces response in approximately 30% of MDS
patients. However , the relapse rate is high, and
there is no improvement in overall survival.
Recent studies show that using low dose
cytarabine in conjunction with M-CSF, GM-CSF,
or ATRA may improve overall response and
survival.

 Bone marrow transplantation is currently the only

potentially curative therapy for MDS patients.
Overall disease-free survival at 3 years with
allogenic procedures ranges approximately from
35-60% depending on IPSS score and other
patients risk factor especially age.
However, the procedure related mortality among
these pt is significant, with patients older than 50
years having an approximately 50% chance of
dying from the transplant itself.

Anti-MDS agents in development

ATRA
Amifostine cytoprotective agent
Melphalan
Azacytidine- blocks DNA methylation and may
initiate transcription and differentiation.
Thalidomide-antiangiogenic, anti-TNF alpha and
immunosuppressive.
Immunosuppressive therapy-ATG, cyclosporine A

 Farnesyltransferase inhibitors- modulate

multiple proteins and /or cell signaling
pathways that have been implicated in MDS
pathophysiology or progression, including
Ras, p53..
Antiproliferative, antiangiogeneic and
proapoptotic activity

Conclusion
In the majority of patients with MDS who
are not eligible for allogenic
transplantation, the disease is fatal.
Approximately 2/3 of patients die within 34 years of diagnosis.
Patients with high risk MDS generally
survive approximately one year.

 Except for a recent trial of azacytidine, none of the

other currently available drugs for MDS extends
survival, and many are highly toxic.
The FTIs are an example of targeted therapy with
potential clinical applicability in MDS-modulating
an array of tumour signaling cascades via
inhibition of farnesyitransferase.

Current treatment options for

MDS
No MDS-specific therapies are available .
Clinicians typically choose the therapy on the basis
of risk factors, such as patient age, MDS subtype,
IPSS score, and performance status.
For example, lower risk patients generally receive
supportive care and perhaps low intensity
chemotherapy or differentiating agents.
While those with higher risk may be candidates for
dose intensive chemotherapy or in younger patients,
bone marrow transplantation.