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Myelodysplastic syndrome
overview
Razelle Kurzrock
Seminars in Haematology, Vol 39, No
3, Suppl 2 (July) 2002, pp 18-25
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 individual’s 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 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)
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 5azacytidine 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
patient’s 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.