This document provides an overview of myelodysplastic syndrome (MDS). Key points include: - MDS is a group of bone marrow disorders characterized by low blood cell counts, dysplastic changes in the bone marrow, and a risk of developing acute myeloid leukemia. - It primarily affects older adults but can occur in younger patients as well. Risk factors include prior chemotherapy/radiation exposure, smoking, and certain genetic conditions. - The disease involves malignant transformation of myeloid stem cells. Common genetic mutations impact DNA methylation and gene expression regulation. - Patients present with anemia and related symptoms. Diagnosis involves blood and bone marrow tests showing dysplastic features. Prognosis depends on factors like blast percentage

1. MYELODYSPLASTIC
SYNDROME
Presentedby–Dr. Pritika Nehra
SMSMEDICALCOLLEGE,
JAIPUR

2. Introduction
• complex group of myeloid disorders characterized by
 peripheral blood cytopenias
 dysplasia in bone marrow hematopoietic cellular elements
 Increased risk of development of AML
• Diagnosis is often supported by the presence of cytogenetic
alterations and, more recently, genetic mutations

3. EpidemiologyAnd Etiology
• Disease of aging ( median age - 70 yrs ). India –45yrs
• The incidence in U.S.- 4.1 per 1,00,000.
• Cause is not known
i) Therapy-related(t)-MDS , secondary to exposure to prior
chemo or radiation therapy
 complex karyotypes
 occur in younger patients
 different patterns of disease evolution and cytogenetic
abnormalities
 very poor prognosis

4. ii) Environmentalfactors
 High benzene exposure (>3 ppm)
 family history of hematopoietic cancer
 Smoking
 exposure to agricultural chemicals or solvents
Drinking wine reduced risk for all FABtypes by almost
50%

5. iii) Geneticsyndromes ass. with BM failure
 Ribosomopathies - Diamond-Blackfan anemia
- Schwachman-Diamond syndrome
- Dyskeratosis congenita
- Cartilage hair hypoplasia
- Treacher Collins syndrome
 Patients with Fanconi anemia are also at increased risk of
developing MDS (Runx1 mutation)

6.  Rarefamilial syndromes
• Younger patients with thrombocytopenia or MDS should
be screened for Runx1 mutations
• Germline mutations in GATA-2 have also been involved in
a familial syndrome of MDS/AML,MonoMAC, and
lymphedema
• MonoMAC is an autosomal dominant syndrome associated
with monocytopenia; Band NKcell lymphopenia; and
mycobacterial, fungal, and viral infections, also associated
with pulmonary alveolar proteinosis

7. PATHOGENESIS

8.  MDS:astemcell disorder
• malignant transformation of myeloid stem cell
• clones derived from an abnormal stem cell
 Apoptosisin MDS
• increased apoptosis of haemopoietic precursors
• Presenceof cytopenias despite a typically hypercellular
bone marrow.
• For those patients undergoing leukaemic transformation,
the cytopenias arise due to maturation block of the
malignant cells
• more prominent in early MDS, such asRAand RARS,than
in advanced MDS with excess myeloblasts

9. IneffectiveHematopoiesis
• Colony forming capacities of pleuripotent stem cells and
their progeny are low or absent
• Lower level of GM-CSF, M-CSF,IL6 .IL 3
• CFU- GM less responsive to both G-CSF &GM-CSF
• More dramatic in pts with RAEBor RAEB–t
Angiogenesis
• Autocrine production of angiogenic molecules promotes
expansion of leukemic clone
• Vascular endothelial growth factor(VEGF) and its receptor
VEGFR-1And VEGFR-2is overexpressed

10. Immunologicalabnormalitiesin MDS
• Commonly encountered in MDS
• T-cell expansion
• B- cell alteration
• Particularly in cases of hypoplastic MDS
• • Acquired mutations in the PIG-A gene characteristic
of paroxysmal nocturnal haemoglobinuria (PNH) are
also encountered

11. Molecular Pathogenesis
The most frequent events are genes involved in control of
gene splicing and epigenetic regulators such as TET2or
ASXL1or EZH2.
• TET2
 located on chromosome 4q24
 DNAhydroxymethylation
 mutations in TET2-abnormal DNAmethylation patterns
that could broadly impact gene expression patterns in
MDS
 role in the homeostasis of hematopoietic stem cells
 associated with response to azacitidine

12. • EZH2
 located on chromosome 7 , Polycomb group family
 control of epigenetic gene repression
 EZH2 mutations in MDS inactivate the gene
 poor prognosis
• specific molecular pathways may separate different subsets
of patients
• Bejar et al. separated pts into 2 major subgroups: those
with p53 mutations and complex cytogenetics, and those
without p53 mutations
Aberrant DNAMethylation Of PromoterCpg Islands-
 common both in AMLand MDS
 use of hypomethylating agents in MDS
 patients with higher methylation scores had worse survival

13. Clinical Presentation& Complications
• not specific.
• Mostly diagnosed after peripheral blood examination
• suspected based on presence of one or more cytopenias
• symptoms of anemia, thrombocytopenia, fever, other
constitutional symptoms, or unexplained infections
• thorough evaluation to rule out other conditions that may
exclude MDS diagnosis
• diagnostic test always includes evaluation of the
morphology of a bone marrow specimen
• Cause of death - MDS-related with the most common
events being infection (38%), transformation to AML
(15%), and haemorrhage (13%

14. Diagnostic Evaluation
• Based on presence of dysplastic features on BMaspirate
Recommended -500 BMcells and 200 PBFcells
Dysplasia >10% of cells for each specific lineage
 Erythroid dysplasia -sideroblasts,cellular vacuolization
 Dysgranulopoiesis -alterations in size, nuclear
hypolobation, or hypersegmentation
 Dysmegakaryopoiesis -micromegakaryocytes, hypolobation
or multinucleation
• Examination of a BM biopsy helps in evaluating cellularity
and the presence of significant fibrosis, making a diagnosis
of hypoplastic MDS versus aplastic anemia

15. EvolutionofMDS Classification

16. F
ABclassificationin 1983
Five entities were defined:
• Refractory anemia (RA)
• RAwith ringed sideroblasts(RARS)
• RAwith excessblasts(RAEB)
• RAwith excessblasts in transformation (RAEB-t)
• Chronic myelomonocytic leukemia (CMML)

17. DIFFERENCESBETWEENWHO ANDFAB
• The WHO uses cytogenetic findings.
• RAEB-twas eliminated as it got included within
AML(>20%blasts).
• criteria proposed by the WHO replaced the prior FAB30%
blasts criteria,decreased to 20% by WHO
• CMMLwas removed and put in a new category of
myelodysplastic/myeloproliferative diseases.
• Adds the subtypes 5q syndrome and unclassifiable MDS.
• Recognizes the prognostic importance of %of bone
marrow blasts

20. • The most important assay,mandatory , is cytogenetic
analysis.There is no specific cytogenetic pattern diagnostic
of MDS
• both a diagnostic and a prognostic value
• In patients with profound marrow hypocellularity, the
presence of a cytogenetic alteration will differentiate
hypoplastic MDS from aplastic anemia
• Recent 5-subgroup classification , forms basis of IPSS-R

21.  Flowcytometrycan help in the confirmation of MDS, and
specific phenotypes may have prognostic value.
• Presently , no panel diagnostic of MDS, can’t replace
morphologic examination
• may try to quantitate the percentage of blasts by
annotating the number of CD34+ cells.
• not an appropriate tool to estimate % of blasts, only
complementary
 Newer genomic technologies are currently being
developed that allow the analysis of multiple genetic events
in MDS and other cancers.
• These include next-generation gene sequencing and
analysis of single nucleotide polymorphisms, not currently
integrated into clinical practice

22. MDS-RelatedSyndromes:CMMLand
OverlapMyelodysplasticMyeloproliferative Syndromes
• Chronic myelomonocytic leukemia - distinct WHOentity
• also includes BCR/ABLnegative CML,MDS/MPN
unclassified, juvenile myelomonocytic leukemia, and
potentially refractory anemia with ring sideroblasts and
thrombocytosis (RARS-T).
• Traditionally, CMML- subtype of MDS. IPSS- patients
with CMMLif the white cell count was less than 12 ×
103/L
• The natural history of patients with CMMLis distinct from
that of patients with classic MDS. Patients tend to have
higher frequency of Bsymptoms and extramedullary
manifestations of the disease. Tissue infiltration causing
hepatic or renal dysfunction is not uncommon.

23. • Diagnosis –
 Persistent monocytosis (>1 ×109/L) without evidence of
BCR/ABLfusion genes or PDGFRalterations.
 Blasts(promonocytes) < 20%and
 dysplasia is routine, less pronounced than MDScategories
• CMML-1 andCMML-2 , based on the percentage of bone
marrow and peripheral blood blasts (CMML-1 < 10% bone
marrow blasts or < 5% in peripheral blood; CMML-2 with
more blasts)
• markers of myelomonocytic differentiation - CD33 and CD13
• Cytogenetic alterations occur as in other cases ofMDS
• presence of RASmutations - 40% of patients.
MDS/MPN unclassified (MDS/MPN-U) disorders - advent of
agents that inhibit JAK2,a common molecular alteration in
MPN that may explain the proliferative feature of the disease

24. Approach to MDS

25. HISTORY–
• Family history
• Exposure to Radiotherapy , Chemotherapy
• Recurrent Infections , Bleeding Gums
PHYSICALEXAMINATION
• Anemia
• 20% of pts have splenomegaly
• Unusual skin lesions –
Sweet syndrome, Granulocytic Sarcoma
• Autoimmune abnormalities (uncommon) - Seen in 14%of
the patients. Most common is cutaneous vasculitis.

26. • Stereotypical anomalies point to a constitutional syndrome
 Short stature, abnormal thumbs - Fanconi anemia
 Early graying - Telomeropathies
 Cutaneous warts -GATA2 deficiency
LABORA
TORYSTUDY
CBC
• Threshold for cytopenia (IPSS)
 Hb < 10 g/dl
 Absolute neutrophil count< 1.8x 109 /L
 Platelets < 100 x 109/L
• Anemia (MC),alone or as part of bi/pancytopenia
• Isolated neutropenia or thrombocytopenia is more unusual.

27. PBF
• RBCs- macrocytic
• Platelets - large and lackgranules.
• Neutrophils - hypo granulated; hypo segmented, ringed,or
abnormally segmented nuclei; contain Döhle bodies; and
may be functionally deficient
• Circulating myeloblasts usually correlate with marrow blast
 BONEMARROW
• Usually normal or hypercellular
• 20% of cases:hypocellular to be confused with AA.
• No single characteristic feature of marrow morphology
distinguishes MDS, but the following are commonly
observed:

34. DIFFERENTIALDIAGNOSIS
• Vitamin B12 or folate deficiency
• Vitamin B6deficiency - Can be assessed by a
therapeutic trial of pyridoxine if the bone marrow
shows ringed sideroblast
• AML - WHO considers the presence of 20% blasts inthe
marrow as the criterion that separates AMLfromMDS
• Reactive Causes of Dysplasia –
HIV, recent cytotoxic therapy, alcoholism , recurrent
infections
• Congenital Sideroblastic Anaemia
• Paroxysmal Nocturnal Haemoglobinuria
• Toxins (lead &benzene) and Drugs ( Isoniazid )

36. RiskStratification