Update Myelodysplastic syndrome MDS - 台中榮民總醫院

5 Sep 2013
Myelodysplastic syndrome
MDS
Update
楊 陽 生
台 中 榮 民 總 醫 院
血 液 腫 瘤 科
(summary slide sets)

MDS: a stem cell disorder

What is MDS
“clonal disorder affecting hematopoietic maturation,
characterized by ineffective hematopoiesis and bone
marrow failure with resultant cytopenias, often
culminating in florid acute leukemia”
Huh

MDS: History - long ago
• Reports of cytopenic disorders began appearing in
the early 20th century
• 1942: “odo-leukemia”
odo = threshold
• 1949: “preleukemic anemia”
(Chevalier et al)
(Hamilton-Paterson)
• 1953: expanded definition to include all blood lines
“clonal myeloid hemopathy”
(Block et al)

Variety of Term in history
other terms used over the last 50 years:
•Herald state of leukemia
•Refractory anemia
•Sideroachrestic anemia
•Idiopathic refractory sideroblastic anemia
•Pancytopenia with hyperplastic marrow
•Oligoblastic leukemia

Confusion
• No surprise that there is confusion and ignorance
about this disorder:
Historical coupling of MDS to acute myeloid leukemia
• There is a relationship
• Has hindered consideration of MDS as a distinct
entity
– biased investigational and therapeutic efforts towards
the leukemia

MDS: History - more recent
• Paris,1975: hemopoietic dysplasia
– subsequently shortened to myelodysplasia
• 1982: French-American
American-British classification scheme
(FAB)
• 1999-2002: World Health Organization classification
scheme
• 2000~: Approaching a molecular classification !

What is myelodysplasia
• Disordered production of one or more cell lines
“dysplasia”
• Abnormal growth and differentiation of hematopoietic
precursors
• Abnormal appearance under the microscope

Causes of MDS
• May follow exposures to bone marrow toxins
– chemotherapy
– radiation
– organic compounds
• Some follow inherited tendencies
– Fanconi anemia, disorders of DNA repair
• > 80% have no identifiable exposure or cause

Cytogenetic abnormalities and epigenetic
changes are key drivers of MDS
pathogenesis
Stromal/
angiogenic
factors 2
Direct
environmental
toxicity 1
Epigenetic changes
e.g. DNA
hypermethylation 3
Immune
dysfunction 1,2
Stem cell
dysfunction
MDS
Cytogenetic
abnormalities/
DNA damage 1
Impaired
apoptosis 1
1. List AF, Doll DC. in: Lee RG, et al. eds. Wintrobe’s Clinical Hematology. 10th ed. 1999:2320–41
2. Greenberg PL, et al. Hematology Am Soc Educ Program 2002;136–61
3. Leone G, et al. Haematologica 2002;87:1324–41

• Affect people of any age
– including children
MDS: Epidemiology
• Overall incidence: approx. 4/per 100,000 in general
population
• More common in advancing age
– North America: mid-late 60’s
• Peak incidence occurs at 60-90 years of age
> 20 per 100,000 at age of 70-85 years
> 30 per 100,000 at age 85+ years

MDS: Epidemiology
• 10000-15000 15000 new diagnosis per year in USA
• About 8200 patients with MDS in Germany
• MDS Foundation estimates that in people older than
70 there are 15 - 50 new diagnoses/100,000 persons
per year
– extrapolating USA estimates, perhaps 3000-6000
Canadians have an MDS diagnosis at any given time

Diagnosis of MDS

• Requires suspicion
Diagnosis
• Typically 2 settings where MDS should be suspected:
1. Signs or symptoms of a blood disorder
– fatigue, exercise intolerance, pale
– serious or recurrent infections
– inappropriate bleeding and bruising
2. Unexpected finding in blood suggesting MDS:
– low blood count of any kind
• > 80% have anemia ± others
• 30 - 45% have low platelets
– macrocytosis (large red cells)
– high monocyte count
– abnormal appearing blood cells

Diagnostic evaluation (required)
• complete history and examination
• complete blood counts and differentials
• iron, B12 and folate levels
• bone marrow aspirate & biopsy
– chromosome analysis: “cytogenetics”
• serum erythropoietin levels
– prior to transfusions

Diagnostic tests as needed
Tests that are useful in some clinical circumstances
•Flow cytometric study
•HLA tissue typing (if stem cell transplant(BMT) a
consideration)
•HIV testing
•Specific disease related gene identification (molecular
diagnosis)
•other specific tests
– PNH
– other HLA determinations

MDS diagnosis
• No perfect diagnostic test
• No absolute diagnostic criteria
• Combination of findings:
– Appearance of dysplasia in blood and marrow
– Abnormal cytogenetic testing
– Abnormal flow cytometry findings
– Abnormal molecular study

Classification
and
Risk stratification

IPSS calculation

Molecular Changes in MDS

Genetic alterations of epigenetic pathways
in MDS

Frequency and clinical consequences of
recurrent gene mutations in patients with
MDS

Epigenetic changes
• There are 3 known mechanisms of epigenetic
changes
– DNA methylation
– Histone modification
– RNA-associated silencing
• Changes are potentially reversible
• Changes are a target for therapy
Egger G, et al. Nature. 2004;429:457-463.
Jones PA, et al. Nat Rev Genet. 2002;3:415-428.

Epigenetics
DNA methylation and gene expression
• CpG islands
– Hypermethylation is the most well-recognized
epigenetic change
– Located near the promoter regions
– Most CpG islands are nonmethylated
CpG=cytosine-phosphodiester-guanine.
Jones PA, et al. Nat Rev Genet. 2002;3:415-428.
Esteller M, et al. EMBO Rep. 2006;6:624-628.

DNA methylation
N
NH 2
DNA
methyltransferase
N
NH 2
CH 3
O
N
O
N
Cytosine
Cytosine + methyl group
• DNA methylation maintained by DNA methyltransferases
(DNMTs)
• Methylation occurs at CpG dinucleotides in DNA (CpG rich
islands, located in promoter region)
Esteller M. N Engl J Med 2008;358:1148–59

DNA methylation silences genes in cancer
including tumour-suppressor genes
Normal tissue
Transcription factor
Gene ON (gene transcription → protein expression)
Promoter region
Many hundreds of CpG Islands become
aberrantly methylated in all types of cancer cells
Tumour
Gene OFF
Esteller M. N Engl J Med 2008;358:1148–59

MDS: Therapy Overview

Conventional MDS treatment
• Many potential therapies available to
and tried in MDS patients
• Most show some benefit
• Most benefits are
– small
– only in a minority subset of patients
• Hard to know who should receive
them and what to expect

Therapy Options
• Blood transfusions
• Management of Iron Overload
• Infection control
• Growth factors: EPO, rG-CSF;
Danazol
• Chemotherapy
• Epigenetic Therapy (Vidaza, Dacogen)
• IMiD

The Role of the Specialty Clinic
1. Provide guidance for primary
caregivers
2. Maximize supportive care
3. Optimize individualized management
4. Clinical trials and data collection
5. Dissemination of current state of
knowledge