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Myelodysplastic Syndromes:
Clonal Myeloid Diseases
Haskell (Gill) Kirkpatrick M.D.
8/24/05
Case Report
 74 y/o man with hx prostate cancer (XRT
2004) and ETOH intake presented with
dyspnea
 Exam pertinent for decreased pallor. No
lymphadenopathy or organomegaly.
 Labs: WBC 1.5, Hct 15, reticulocyte count
1%, platelets 44,000
CD34
CD117
MPO
MDS
 Arise from somatic mutations in
hematopoietic (myeloid) stem cell causing:
 Ineffective hematopoiesis
 Cytopenia(s)
 Qualitative disorders of blood cells and their
precursors
 Variable predilection to undergo evolution to
florid AML
 Stem cells have a defective capacity for
self-renewal and differentiation
History of Terminology
 “Odo-leukemia” coined in 1942
 Disorders on the threshold of leukemia
 “Pre-leukemic anemia” soon replaced
 Described cases of cytopenias that preceded the
onset of AML
 “Hemopoietic dysplasia” later shortened to
“Myelodysplasia”
 1975 conference on unclassifiable leukemias
Myelodysplasia: Misnomer
 Nomenclature coined at a time when
Dysmorphogenesis thought to be single
abnormality
 Dysplasia is a pathologic term that implies
a non-clonal, non-neoplastic process
 Encompasses heterogeneous spectrum:
 From acquired indolent idiopathic anemia…
 No discernable leukemic blasts
 To oligoblastic myelogenous leukemia
 Increased leukemic blast cells (>2%)
 “refractory anemia with excess blasts”
World Health Organization (WHO)
Classification
 FAB criteria introduced in 1982
 2001 WHO published new classification scheme
 Modifications made to improve prognostic value
 Major changes:
 Lower threshold for defining AML (Blasts count)
 Eliminated RA with excess blasts in transformation
(RAEBT)
 Divided categories into single or multi-lineage
dysplasia
 Divided RAEB into 2 categories
 Eliminated CMML from MDS category
 Categories not addressed: hypocellular MDS & MDS
with fibrosis
Incidence and Etiology
 15,000 new cases in U.S. annually
 5 per 100,000 persons per year
 Increases to 20 to 50 per 100,000 after the age
of 60
 As common as CLL (most common form
leukemia)
 Idiopathic
 Secondary (treatment related)
 Chemotherapy (particularly alkylating agents)
 Radiation
Clinical Features
 Asymptomatic
 Symptomatic anemia
 Recurrent infections due to
granulocytopenia
 Bleeding due to thrombocytopenia and/or
qualitative platelet defect
Laboratory features
 Blood
 Red cells: Anemia 85% patients at diagnosis
 MCV often increased
 Anisocytosis
 Poikilocytosis: oval, elliptical, teardrop, spherical,
fragmented
 Usually low reticulocyte count
 Granulocytes and Monocytes
 Monocytosis and neutropenia not uncommon
 Pseudo-Pelger-Hüet cells
 Hypogranular neutrophils
 Platelets
 Mild to moderate thrombocytopenia 25% cases
 Abnormal function assays can reflect qualitative defects
Blood
Laboratory features
 Marrow
 Normal or increased cellularity
 20% are hypoplastic
 Dysplasia in one or more cell line
 Erythroid hyperplasia and variation in
erythroblasts
 Ringed Sideroblasts: erythroblasts with
mitochondrial iron aggregates
 Hypogranulated neutrophils
 Unilobed/bilobed megakaryocytes
 Fibrosis
 Increase in reticulin and collagen fibers can be
seen in oligoblastic leukemia
Aspirate
Dysplastic RBCs binucleation, multinucleation,
nuclear budding, nuclear
bridging, karryorhexis,
vacuoles, PAS+
Megaloblastoid changes
Ringed sideroblasts
Macrophage storage
Megakaryocytes:
Small, hypolobulated
nuclei
Larger with widely
spaced nuclei
Morphology: Pitfalls and
Problems

Morphologic dysplasia not specific for MDS
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Small number of dysplastic cells can be seen in normal
individuals
Guidelines (WHO): 10% of cells must be dysplastic in a
single lineage
Quality of specimen can be an obstacle

Make sure adequate staining to call hypogranularity
(neutrophils)
Biopsies should be at least 1-2 cm extending into marrow
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Especially with low-grade MDS
Studies have shown this especially with dyserythropoiesis
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Other conditions: megaloblastic anemia, exposure to toxins
(i.e. arsenic), congenital dyserythropoietic anemia, growth
factors, HIV etc..
Inter-observer reproducibility of dysplasia is poor
Cytogenetic Characterization of
MDS
 Role: confirmation of diagnosis & predicting outcome
 Contributed to understanding of pathogenesis
 Suspected multi-step process of insults to stem cell
genome
 Routine karyotyping
 De Novo MDS: Abnormal 40-70% cases
 Therapy-related (t-MDS): Abnormal 95% cases
 Predict survival and assess risk of transformation to
acute leukemia
 Often same abnormal chromosomes seen in AML
 No cytogenetic abnormality specific for MDS
 One unique case: 5q- syndrome
5Q- Syndrome
 Deletion of chromosome 5q is one of most
common abnormalities in MDS
 Common deleted region mapped to 5q31q32 (1.5 Mb)
 “5q- syndrome”
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Isolated 5q deletion
Severe anemia, normal or elevated platelets
Atypical megakaryocytes
No blasts
Typically indolent coarse
International Prognostic Scoring System
(IPSS)
 Derived from data from over 800 patients
managed with supportive care
 (Greenberg et al, Blood 1997)
 Compliments both classification schemes
 WHO and FAB
 Morphologic classification alone insufficient
Bone Marrow Transplant
 Allogeneic hematopoetic stem-cell
transplant
 Currently only treatment that can
significantly prolong survival
 Approximately 1/3 of transplanted patients
cured
 Significant morbidity and treatment related
mortality
 Only 8-10% of all MDS patients eligible and
have a donor (HLA-matched sibling)
 Young patients (45 or younger)
Therapeutic Goals When Transplant
Not an Option
 Consider natural history of the disease & patient
preference
 Low or Intermediate-1 patients (IPSS): longer
survival
 Principle goal: amelioration of hematologic deficits
 Need to be durable improvements
 Int-2/high risk patients:
 Extending survival becomes more “immediate
priority”
 Prolonging time to development of AML
Supportive Care
 Transfusions
 Erythropoietin
 G-CSF
 If no blasts
Targeting Angiogenesis in MDS
 Angiogenic molecules generated by the neoplastic
clone
 Vascular endothelial growth factor-A (VEGF-A)
 medullary neovascularity
 clonal expansion of receptor-competent myeloblasts
 Ineffective hematopoiesis in receptor naïve
progenitors
 Inflammatory cytokines potentiate ineffective
hematopoiesis
 Small molecule inhibitors of angiogenesis are a
potential class of therapeutics
 Thalidomide
 Lenalidomide (Revlamid)
Thalidomide and MDS
 Anti-angiogenic and TNFα inhibitory properties
 Phase II trials done
 Around 18% response rate (red cell transfusion
independence or >50% decrease in transfusion
requirement)
 Non-erythroid lineage improvement uncommon
 Prolonged treatment necessary for maximal benefit
 Median interval to response: 16 weeks
 Side effect profile becomes problematic (i.e.
neuropathy)
Lenalidomide (Revlimid)
 Derivative of thalidomide
 More potent and lacks neurologic toxicities
 Safety and efficacy trial (List et al NEJM
2/05)
 RBC transfusion independence with cytogenetic
response in 10/12 (83%) patients with del 5q31
 Transfusion independence in non-5q patients
39%
 Sustained > 2years
Lenalidomide (Revlimid)
 Phase II trial (List et al ASCO 5/05)
 148 patients
 Low or intermediate-1 risk (IPSS score)
 Del 5q isolated (as well as other
abnormalities)
 66% transfusion independence (median
duration > 47 weeks)
 Cytogenetic response 70% (complete
reponse 44%)
 Myelosuppression common
Other Novel Therapeutic Targets:
DNA methylation and Epigenetics
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Addition of a CH3 (methyl) group to a molecule (cytosine base)
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DNA methyltransferase
Epigenetics: Regulation of gene expression without altering DNA
sequence
Epigenetic silencing
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Gene promoter regions get methylated
Leads to histone modifications
Chromatin is remodeled and becomes “invisible” to transcription factors
Gene is “silenced”
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Important role in embryogenesis
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Thought to be exploited by cancers to help express their malignant
phenotype
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silence tumor-suppressor genes
DNA Methylation in MDS
 Multiple genes known to be hypermethylated/silenced
 P15 (cyclin dependent kinase inhibitor): frequent
target
 Inactivation associated with risk of progression to
AML
 Associated with disease progression
DNA Methylation Inhibitors
 5-Azacytidine (AZA) and 5-aza-2’-deoxycytidine
(DAC)
 Cytosine analogs: inhibit DNA methylation by
trapping DNA methyltransferases
 Irreversible bond, degredaded
 Cells then divide in absence of DNA methyltransferases
 Dosage key
 Hypomethylating at low doses, cytotoxic at high doses
 Maximally tolerated dose (MTD) determined in 70’s
 Recent low-dose studies show response (and
hypomethylation) at 10-30 times lower than MTD
 Current studies exploring optimal dosing schedules
ongoing
5-Azacytidine (Vidaza)
 Phase III randomized trial (Silverman et al JCO 2002)
 compared AZA to supportive care
 Treatment-naïve patients (various stages)
 60% response rate (hematologic) that was durable
 Improved quality of life
 Prolongation of median time to leukemic
transformation or death
 21 months vs. 13 months (statistically significant)
 Not powered for OS and cross-over permitted
 Sub-cutaneous injection daily X 7 days every 28 days
 FDA approval 2004 for treatment of MDS
Summary
 MDS represents a group of heterogeneous
neoplastic disorders
 Cytogenetics compliment morphology and
help determine prognosis and treatment
goals
 New novel therapies such as 5-Azacytidine
(Vidaza) and soon to be approved
Lenalidomide (Revlimid) have added
options for non-transplant candidates