Reference:-Harrison’s Principles of Medicine

1. Myelodysplastic
syndromes

3. Myeloid Neoplasms
• Acute myeloid leukemia (AML)-- Immature
myeloid cells (blasts)
• Myeloproliferative neoplasms--increased or
dysregulated growth(one or more of the
formed elements)
• Myelodysplastic syndromes (MDS)--dysplastic
marrow precursors and peripheral blood
cytopenias.

4. Cont…
• Both MDS and myeloproliferative neoplasms
often transform to AML,
• AML and MDS often arise from an
asymptomatic precursor called CHIP
• Clonal hematopoieis of indeterminant
prognosis (CHIP)-- Normal blood counts
despite the presence of one of more clonal
acquired “driver” mutations in myeloid cells in
the blood and the marrow.

5. Myelodysplastic Syndromes
• A group of clonal stem cell disorders
characterized by maturation defects that are
associated with ineffective hematopoiesis
and a high risk of transformation to AML.
• The marrow usually is hypercellular or
normocellular, but the peripheral blood shows
one or more cytopenias.
• Most cases are idiopathic

6. ETIOLOGY AND PATHOPHYSIOLOGY
• Environmental exposures such as radiation
and benzene
• Secondary, therapy-related MDS—
-late toxicity of cancer treatment,
-radiation and
-the radiomimetic alkylating agents such as
busulfan, nitrosourea, or procarbazine (with a
latent period of 5–7 years), or the DNA
topoisomerase inhibitors (2-year latency)

7. Cont…
• Acquired aplastic anemia,Fanconi anemia, and
other constitutional marrow failure diseases
can evolve into MDS
• MDS is a disease of aging, suggesting random
cumulative intrinsic and environmental
damage to marrow cells.
• Cytogenetic abnormalities are found in one-
half of patients,

8. Cont…
• Recurrently mutated genes are:-
a) Epigenetic factors.
b) RNA splicing factors.(SF3B1)
c) Transcription factors.
• In addition, roughly 10% of MDS cases have loss-of
function mutations in the tumor suppressor gene TP53.
• Both primary MDS and therapy-related MDS are
associated with Chromosomal abnormalities:-
Monosomies 5 and 7,
deletions of 5q, 7q, and 20q,
and trisomy 8.

9. Cont…
• 5q– deletion leads to heterozygous loss of a
ribosomal protein gene (ribosomal protein
gene mutations cause Diamond-Blackfan
anemia,like much MDS characterized by
deficient erythropoiesis).

10. CLINICAL FEATURES
• Anemia dominates the early course--gradual
onset of fatigue and weakness, dyspnea, and
pallor,
• But at least one-half of patients are
asymptomatic, and their MDS is discovered
only incidentally on routine blood counts.
• Previous chemotherapy or radiation exposure
is an important historic fact.

11. Cont…
• Fever and weight loss should point to a
myeloproliferative rather than myelodysplastic
process.
• MDS in childhood is rare and, when
diagnosed, implicates an underlying genetic
disease.
• Children with Down syndrome are susceptible
to MDS as well as leukemia.

12. • The mean age at onset is older than 70 years.
• Secondary or therapy-related MDS is not age
related.
• Dysplastic changes can be observed in normal
individuals, and they can occur with vitamin
deficiencies and as drug effects.

13. Cont…
• A family history may indicate a hereditary
form of sideroblastic anemia, Fanconi anemia,
or a telomeropathy.
• Inherited GATA2 mutations, as in the
MonoMAC syndrome also can cause MDS in
young patients

14. Cont…
• The physical examination--signs of anemia;
approximately 20% of patients have
splenomegaly.
• Sweet’s syndrome (febrile neutrophilic
dermatosis)
• In the younger patient, stereotypical anomalies
point to a constitutional syndrome
-short stature,
-abnormal thumbs in Fanconi anemia;
-early graying in the telomeropathies;
-cutaneous warts in GATA2 deficiency.

15. Diagnostic Criteria

18. • WHO classification:
-Blast percentage
-Erythroid predominant leukemias are now
largely regarded as MDS;
• A single somatic mutation, in SF3B1, is now a
feature of sideroblastic anemias
• Identification of somatically mutated genes and
their correlation with clinical outcomes is
increasingly important in defining classification,
prognosis, and targeting therapy.

20. LABORATORY STUDIES
• Blood –
• Anemia is present in most cases, either alone or as part of
bi- or pancytopenia;
• Isolated neutropenia or thrombocytopenia is more unusual.
• Macrocytosis is common, as in most marrow failure
disease.
• Platelets also are large and lack granules.
Patients may have bleeding symptoms despite seemingly
adequate numbers due to functional platelet abnormality

21. • Neutrophils are hypogranulated; have
hyposegmented, ringed, or abnormally
segmented nuclei;
contain Döhle bodies;
and may be functionally deficient.
• Circulating myeloblasts usually correlate with
marrow blast numbers, and their quantity is
important for classification and prognosis.
• The total white blood cell count (WBC) is
usually normal or low, except in chronic
myelomonocytic leukemia.

22. Bone Marrow
• The bone marrow is usually normal or
hypercellular,
but in about 20% of cases it is sufficiently
hypocellular to lead to confusion with
aplastic anemia.
• No single characteristic feature of marrow
morphology distinguishes MDS,
• Dyserythropoietic changes (especially
nuclear abnormalities) and
Ringed sideroblasts in the erythroid lineage;

23. J. Marrow films. Prussian blue
stain. Ring sideroblasts. Wright stain. Erythroid hyperplasia with macroerythroblasts.
K. Marrow film. Prussian blue
stain. Ring sideroblasts.

24. • Hypogranulation and hyposegmentation in
granulocytic precursors, with an increase in
myeloblasts; and megakaryocytes showing reduced
numbers of or disorganized nuclei.
• Megaloblastic nuclei and defective hemoglobinization
in the erythroid lineage are common.
• Prognosis strongly correlates with the proportion of
marrow blasts.
• Cytogenetic analysis and fluorescent in situ
hybridization can identify chromosomal abnormalities.

26. DIFFERENTIAL DIAGNOSIS
• Deficiencies of vitamin B12 or folate should be
excluded
• Copper deficiency can lead to cytopenias and
dysplastic marrows of varying cellularity
• Marrow dysplasia can be observed in acute viral
infections, drug reactions, or chemical toxicity but
should be transient.
• More difficult are the distinctions between
hypocellular MDS and aplasia or between RA with
excess blasts and early acute leukemia.
• The WHO considers 20% blasts in the marrow as the
criterion that separates AML from MDS.

27. PROGNOSIS
• The median survival varies
5q– or sideroblastic anemia--Years
RA with excess blasts or severe pancytopenia
associated with monosomy 7--Months
• The International Prognostic Scoring System, revised in
2012 assists in making predictions.
• Most patients die as a result of complications of
pancytopenia and not due to leukemic transformation;
one-third succumb to diseases unrelated to their MDS.

28. Cont…
• Poor prognostic indicators
-Precipitous worsening of pancytopenia,
-Acquisition of new chromosomal abnormalities
on serial cytogenetic determination,
-Increase in the number of blasts, and
-Marrow fibrosis
• Prognosis of therapy-related MDS, regardless of
type, is extremely poor, and most patients will
progress within a few months to refractory AML.

29. TREATMENT
• Only hematopoietic stem cell transplantation
offers cure of MDS.
• MDS has been regarded as particularly
refractory to cytotoxic chemotherapy
regimens
• Like AML in the older adult, drug toxicity is
frequent and often fatal, and remissions if
achieved are brief.

30. Cont…
• Epigenetic modulators--
• The hypomethylating agents Azacitidine and
Decitabine
• Azacitidine improves blood counts and
survival in MDS, compared to best supportive
care.
• Used in high-risk patient who is not a
candidate for stem cell transplant

31. Cont…
• Lenalidomide-- Effective in reversing anemia in
MDS patients with 5q– syndrome;
• Toxicities -- Myelosuppression and
Deep vein thrombosis &
pulmonary embolism

32. Cont…
• ATG, cyclosporine, and the anti-CD52
monoclonal antibody alemtuzumab are
especially effective in younger MDS patients
(<60 years old) with more favorable IPSS
scores and who bear the histocompatibility
antigen HLA-DR15.

33. Cont…
• EPO alone or in combination with G-CSF can
improve hemoglobin levels,. particularly in
those with low serum EPO levels who have no
or a modest need for transfusion

34. SUPPORTIVE CARE
• Infection in the presence of severe neutropenia--
parenteral, broad-spectrum antibiotics.
• When indwelling plastic catheters become
contaminated, vancomycin should be added .
• Menstruation should be suppressed either by
oral estrogens or nasal follicle-stimulating
hormone/luteinizing hormone antagonists.
• Aspirin and other NSAIDS-- avoided in the
presence of thrombocytopenia

35. Cont…
• RBCs should be transfused -- usually at a
hemoglobin value of 70 g/L (90 g/L if there is
underlying cardiac or pulmonary disease);
• A regimen of 2 units PCV every 2 weeks will
replace normal losses in a patient without a
functioning bone marrow.
• In chronic anemia, the iron chelators,
deferoxamine and deferasirox,
-should be added at approximately the 50th
transfusion

36. Thank You