The Myelodysplastic Syndromes

1
The Myelodysplastic Syndromes
Blood-Hematopoiesis-Lymphatics 2013

• Brad Gehrs, MD
• Department of Pathology

2
Downloading any of the photographs, images or
diagrams from this presentation for any purpose
other than studying for BHL is prohibited.
3
Myelodysplastic Syndromes

• Heterogeneous group of disorders characterized
  by
• Cytopenia of one or more lineages
• Dysplastic cellular appearance
• Abnormal or impaired cell function
• Variable predisposition to transform to acute
  myeloid leukemia

4
Myelodysplasia

• An insufficient number of funny looking cells
  that dont work well!

5
Myelodysplastic SyndromesPathogenesis

• Genetic damage to hematopoietic stem cells
• Ineffective hematopoiesis
• Marrow usually cellular, but many cells die in
  the marrow
• Proliferative rate often increased
• Increased apoptosis
• Impaired maturation differentiation

6
MDS Relationship with Other Diseases
CMPDs
MDS
AML
PNH
Aplastic Anemia
7
Myelodysplastic SyndromesHistorical Synonyms

• Preleukemia
• Refractory anemia
• Preleukemic anemia
• Smoldering acute leukemia
• Chronic erythremic myelosis
• Subacute myeloid leukemia
• Refractory normoblastic anemia
• Many others

8
Myelodysplastic SyndromesEpidemiology

• Approximately twice as common as AML
• Predominantly older population
• Median age gt65 years
• Risk increases with age
• Rare lt 50 years (except therapy-related)
• Men gt women in most series

9
Myelodysplastic SyndromesEtiology

• Familial Very rare
• Exposure to solvents (benzene), pesticides,
  petrochemicals
• Therapy-related (t-MDS)
• Alkylating drugs
• Radiation
• Majority of cases No known predisposing factors

10
Myelodysplastic SyndromesClinical Presentation

• Many asymptomatic Cytopenia detected on routine
  laboratory tests
• Common symptoms Fatigue, weakness, dizziness,
  exacerbation of angina
• Less common presentations
• Infections Primarily cutaneous
• Bleeding Petechiae, easy bruising

11
Myelodysplastic SyndromesLaboratory Values

• Highly heterogeneous
• Sine qua non Quantitative deficiencies in one or
  more cell types
• Anemia Most common
• Isolated cytopenia of another lineage in absence
  of anemia rare (lt5)
• Leukopenia 50 of cases
• Thrombocytopenia 25 of cases
• Pancytopenia Up to 50 at diagnosis

12
MDS Erythroid Abnormalities

• Anemia Almost universal
• Reticulocyte count inappropriately low
• Usually normocytic or mildly macrocytic
• Oval macrocytes common
• May have elliptocytes, teardrop cells or
  acanthocytes
• May have basophilic stippling, Howell-Jolly
  bodies, nucleated RBCs
• May have dimorphic RBC populations

13
Blood 100x
14
Myelodysplastic SyndromesLeukocyte Abnormalities

• Granulocytopenia 50 at diagnosis
• Nuclear changes
• Decreased segmentation (pseudo-Pelger-Huët
  anomaly)
• Abnormal chromatin condensation
• Nuclear sticks or ring-shaped nuclei
• Cytoplasm Decreased or absent cytoplasmic
  granules

15
Pseudo-Pelger-Huët Phenomenon
16
Myelodysplastic SyndromesPlatelet Abnormalities

• Thrombocytopenia 25 at diagnosis
• Isolated thrombocytopenia may be initial
  manifestation (rare)
• Giant platelets, absent or abnormal granules,
  megakaryocyte fragments may be present
• Thrombocytosis may be present in 5q- syndrome

17
MDS Bone Marrow Erythroid Abnormalities

• Erythroid hyperplasia common
• Nuclear-cytoplasmic asynchrony
• Megaloblastoid appearance
• Nuclear budding, multilobation, fragmentation or
  multinucleation
• Cytoplasmic vacuolization
• Ringed sideroblasts may be seen

18
Bone Marrow Aspirate (100x)
19
(No Transcript)
20
Bone Marrow Ringed Sideroblasts

• Ringed sideroblast gt5 large granules covering
  gt1/3rd the circumference of nucleus
• May be seen in any variant of MDS
• gt15 of erythroid precursors in Refractory Anemia
  with Ringed Sideroblasts (RARS)

21
Refractory Anemia with Ringed Sideroblasts
Bone marrow aspirate, iron stain (100x)
22
(No Transcript)
23
Bone marrow biopsy (H E 40x)
24
Myelodysplastic SyndromesFAB Classification

• Refractory Anemia (RA)
• Refractory Anemia with Ringed Sideroblasts (RARS)
• Refractory Anemia with Excess Blasts (RAEB)
• Refractory Anemia with Excess Blasts in
  Transformation (RAEB-t)
• Chronic Myelomonocytic Leukemia (CMML)

For reference only
25
MDS FAB Criteria
FAB Blasts Blasts TYPE
Blood Marrow Dyspoiesis Other RA
lt1 lt5 ? RARS
lt1 lt5 ?
gt15 Ringed Sideroblasts RAEB
lt5 5-20 RAEB-t
gt5 21-30 Auer
rods CMML lt5 lt20 ?
Monocytes

?1,000/mL
For reference only
26
Myelodysplastic Syndromes
I do not expect you to memorize this table.
27
World Health Organization (WHO) Classification of
Myelodysplasia

• Refractory cytopenia with unilineage dysplasia
  (RCUD)
• Refractory anemia with ringed sideroblasts (RARS)
• Refractory cytopenia with multilineage dysplasia
  (RCMD)
• Refractory anemia with excess blasts (RAEB)
• MDS associated with isolated del(5q) chromosome
  abnormality (5q- syndrome)
• MDS, Unclassifiable (MDS-U)

For reference only
28
WHO Classification of Myelodysplasia I
For reference only
29
WHO Classification of Myelodysplasia II
For reference only
30
Refractory Cytopenia with Unilineage Dysplasia

• Dysplastic changes in one lineage only
• Refractory anemia (RA)
• By far most common
• Refractory neutropenia (RN) Rare
• Refractory thrombocytopenia (RT) Rare

31
WHO Classification of MDSRefractory Anemia and
RARS

• By definition Dysplasia restricted to erythroid
  lineage
• Cases with multilineage dysplasia but low blast
  counts classified as RCMD
• Worse survival than cases with equivalent blast
  counts but pure erythroid dysplasia
• RARS Like RA, but 15 ringed sideroblasts

32
Refractory Cytopenia with Multilineage Dysplasia
(RCMD)

• Dysplastic changes in gt2 cell lines
• Usually erythroid plus granulocytic and/or
  megakaryocytic lineages
• Requires dysplastic changes in gt10 of cells in
  gt2 cell lines
• Blasts lt1 in blood, lt5 in marrow
• Shorter survival higher progression to AML than
  cases with dysplasia limited to erythroid series

33
Refractory Anemia with Excess Blasts (RAEB)

• Multilineage cytopenias dysplastic changes
  present
• More severe quantitative morphologic
  abnormalities than RA
• Subdivided into RAEB-1 RAEB-2 based on percent
  blasts in blood and marrow, Auer rods
• Shorter survival higher transformation to AML

34
WHO Classification of MDSRAEB-t vs. AML

• Category of RAEB-t eliminated
• Cases with gt20 blasts classified as AML

35
MDS with Isolated del(5q) Chromosome Abnormality
(5q- Syndrome)

• Predominantly occurs in older women
• Marked macrocytic anemia
• Platelet count normal to elevated
• Deletion in long arm of chromosome 5 as sole
  cytogenetic abnormality
• Deletion between q31-q33
• Long survival rare transformation to AML

36
Myelodysplastic SyndromesDiagnosis

• Myelodysplasia is a diagnosis of exclusion
• Must exclude
• Nutritional deficiency (folate, Vit B12, other)
• Alcohol abuse
• Myelosuppressive drugs (medical or recreational)
• Occupational exposure to toxic chemicals
• Human immunodeficiency virus (HIV) and other
  infections

37
No single feature is diagnostic of
myelodysplasia. The combination of morphologic
abnormalities in the blood and bone marrow must
be evaluated in the context of the clinical
history and cytogenetic results.
38
Myelodysplastic SyndromesCytogenetics

• Clonal cytogenetic abnormalities common in MDS
• 30-50 of de novo MDS
• gt80 of therapy-related MDS
• Wide variety of karyotypic abnormalities
• Usually numerical abnormalities or partial
  chromosome deletions
• Balanced translocations (as seen in AML) rare

39
Myelodysplastic SyndromesCommon Cytogenetic
Abnormalities

• Interstitial deletions
• del 5q 20
• del 7q 10-20
• Chromosome deletions
• del 7 10-50
• del Y 3-10
• del 17 3-17
• Chromosome duplications
• Trisomy 8 10-15

Not for memorization
40
Myelodysplastic SyndromesCytogenetics
Prognostic Importance

• Favorable cytogenetic results
• Normal -Y 5q- 20q-
• Unfavorable
• Complex chromosome 7 abnormalities
• Intermediate
• All others

Not for memorization
41
MDS Impact of Cytogenetics
Greenberg P et al Blood 1997 892079-2088
42
Myelodysplastic SyndromesClinical Course
Prognosis

• Clinical course heterogeneous
• Causes of death
• Infection Most common
• Bleeding
• Leukemic transformation 20-25

43
Myelodysplastic SyndromesTreatment

• Supportive
• Transfusions
• Antibiotics for infections
• Growth factors (EPO, G-CSF) helpful in some
  patients
• Cytotoxic chemotherapy Young patients with
  aggressive variants
• Allogeneic stem cell transplant considered for
  younger patients

44
Myelodysplastic SyndromesNovel Treatments

• Immunomodulatory/antiangiogenesis
• Thalidomide, lenalidomide (RevlimidTM)
• DNA methyltransferase inhibitors
• 5-Azacytidine, decitabine
• Arsenic trioxide
• Farnesyl transferase inhibitors
• Others

Not for memorization
45
Myelodysplastic SyndromesTake Home Messages

• Clonal disorder of early hematopoietic precursors
• Impaired proliferation, maturation
  differentiation
• Insufficient number of funny looking cells that
  dont work well!

46
Myelodysplastic SyndromesTake Home Messages

• Problems
• Infection
• Hemorrhage
• Transformation to AML (25)
• Older, more cytopenias, more blasts in blood
  bone marrow, abnormal chromosomes Bad
• Secondary MDS Bad

47
Myelodysplastic SyndromesTake Home Messages

• Treatment is largely supportive
• Transfusions for anemia
• Antibiotics for infection
• Platelets for hemorrhage
• G-CSF or EPO may help (some)
• Think about allogeneic stem cell transplant in
  younger person