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Myelodysplastic Syndrome (PowerPoint)

VIEWS: 258 PAGES: 63

									    Ahmad Sh. Silmi
Msc Haematology, FIBMS
What Is Myelodysplastic Syndrome?
 The myelodysplastic syndromes are a group of disorders
  characterized by one or more peripheral blood cytopenias
  secondary to bone marrow dysfunction.
 In MDS the bone marrow cannot produce blood cells
  effectively, and many of the blood cells formed are
  defective.
 These abnormal blood cells are usually destroyed before
  they leave the bone marrow or shortly after entering the
  bloodstream.
 As a result, patients have shortages of blood cells, which are
  reflected in their low blood
Characteristics
 Varying degree of tri-lineage cytopenia ( red blood
  cells, white blood cells and platelets).
 Dysplasia
 Normocellular or hypercellular B.M.
 May progress to acute leukaemia
Signs and Symptoms
 Excessive tiredness, shortness of breath, and pale skin can
  be caused by anemia (shortage of red blood cells).

 Serious infections with high fevers can be caused by
  leukopenia (not having enough normal white blood cells)
  and, in particular, by having neutropenia or
  granulocytopenia (too few mature granulocytes).

 Excessive bruising and bleeding, for example, frequent or
  severe nosebleeds and/or bleeding from the gums, can be
  due to thrombocytopenia (not having enough of the blood
  platelets needed for plugging holes in damaged blood
  vessels).
 Incidence
1- Disease of elderly.
2- Median age is 65 years.
3- <10% are younger than 50 years.
4- Incidence rates 1/100,000 pop./ years.
5- Incidence rise to 1/1000 / years in > 60 years old.
6- Male slightly higher than female
MDS Etiology
 Two etiologic categories of MDS:
1.) De Novo:
      Associated with:
       -benzene exposure (gasoline)
       -cigarette smoking
       -viruses         -Fanconi’s anemia
2.) Therapy related:
      Associated with:
         -alkylating agent chemotherapy
         -radiation
Aetiology




This shows the tow arms of haemopoiesis
This shows how stem cell is affected
Aetiological Agents
 Tobacco smoke.
 Ionizing radiation.
 Organic chemicals (such as benzene, toluene, xylene, and
    chloramphenicol).
   Heavy metals.
   Herbicides.
   Pesticides.
   Fertilizers.
   Stone and cereal dusts.
   Exhaust gases.
   Nitro-organic explosives.
   Petroleum and diesel derivatives.
   Alkylating agents.
   Marrow-damaging agents used in cancer chemotherapy.
Chromosomal abnormalities and MDS

 Chromosomal abnormalities are present in up to
    50%of de novo cases of MDS and in virtually all
    cases of secondary MDS. The most common are:




   Abnormality    -7   +7   +8   5q-   7q-   11q-   12q-   13q-   20q- inv3   i(17q)   t(1;3)   t(1;7) t(3;3)

   Frequency(%)   15   5    19   27    4     7      5      2      5    1      5         1        2     1
Deletion of the long arm of chromosome 5
             (5q- syndrome )
 Strongly associated with RA.

 5q- accounts for up to 70% of cytogenetic abnormalities in
  this subtype.

 The q arm of chromosome 5 is particularly rich in genes,
  which encoded haemopoietic growth factors and their
  receptors. For example , IL-3 , IL-4 , IL-5 , GM-CSF and the
  M-CSF receptor are located in this region.

 The potential for the loss of any or all of these genes
  contribute to the disruption of ordered haemopoiesis.
            Monosmy 7 and 7q-
 Most strongly associated with secondary MDS.


 Associated with the loss of a major surface glycoprotein
 (gp 130) in neutrophile and susceptibility to bacterial
 infection secondary to impaired granulocyte monocyte
 chemotatic activity.
Deletion of the q arm of chromosome
              11 (11q-)
 Account for 20% of the chromosomal abnormalities in
 RAS.

 This abnormality is associated with raised iron stores
 and high ring sidroblast counts.

 The presence of the gene , which encoded the H-
 subunit of ferritin at chromosome 11 , may explain this
Abnormalities of chromosome 17 (i17q)
 It involves the loss or disruption of the Р53 tumor
 suppressor gene are seen in CML in association with
 transformation to the blastic phase and in up to 5% of
 cases of primary MDS.
 This predisposes to certain dysplastic features and
 neutrophil vaculation.
Abnormalities of chromosome 3
 Dysmegakaryopiesis and thombocytosis appear to be
 associated with Abnormalities of chromosome 3
The importance of indication of chromosomal
abnormalities
   To confirm diagnoses .
   To know the stage of disease.
   To know the direction of progression of disease.
   Multiple genetic abnormalities indicate late events in
    MDS.
Patterns of MDS evolution
 A stable group with no increase in B.M blasts and a
  normal karyotype .
 Rapid blast transformation with acquisition of new
  cytogenetic changes after an initial , stable phase .
 Gradually increasing blast count in the absence of new
  cytogenetic changes .
FAB classification scheme in 1985 for MDS
Refractory Anemia
 RA Definition:
 Dyplasia of the erythroid series only.
 Clinically, anemia is refractory to hematinic
  therapy
 Myeloblasts < 1% blood and < 5% marrow
 <15% ringed sideroblasts in marrow
 No Auer rods
 Other etiologies of erythroid abnormalities must
  be excluded. These include:
   drug/toxin exposure   -vitamin deficiency
   viral infection       -congenital disease
Refractory Anemia
 Epidemiology:
 5-10% of MDS cases.
 Older patients
 Morphology:
 Anisopoikilocytosis on peripheral smears
 Dyserythropoiesis with nuclear abnormalities
  (megaloblastoid change)
 < 15% ringed sideroblasts
Refractory Anemia
 Genetics:
 25% may have genetic abnormalities


 Prognosis:
 Median survival is 66 months
 6% rate of progression to acute leukemia
Peripheral Smear - Anisopoikilocytosis
Dyserythropoeisis on Bone Marrow Aspirate
Megaloblastoid Change on Bone Marrow
               Aspirate
Refractory Anemia with Ringed Sideroblasts
 RARS definition:
 Dyplasia of the erythroid series only.
 Clinically, anemia is refractory to hematinic
  therapy
 Myeloblasts < 5% in marrow, absent in blood
 >15% ringed sideroblasts in marrow
 No Auer rods
 Other etiologies of ringed sideroblasts must be
  excluded. These include:
   Anti- tuberculosis drugs
   Alcoholism
Refractory Anemia with Ringed Sideroblasts
 Epidemiology:
 10-12% of MDS cases.
 Older patients
 Males > females
 Morphology:
 Dimorphic pattern on peripheral smears
   Majority RBC’s normochromic, 2nd population
    hypochromic
 Dyserythropoiesis with nuclear abnormalities
 (megaloblastoid change)
Refractory Anemia with Ringed Sideroblasts

 Morphology (con’t.)
 < 15% ringed sideroblasts (RS)
    RS = Erythroid precursor with ≥ 10 siderotic granules
     encircling 1/3 or more of the nucleus.
    If excess blasts present, this dictates diagnosis, despite
     percentage of RS’s.
Refractory Anemia with Ringed Sideroblasts
 Genetics:
 Clonal chromosomal abnormalities in
 <10%; in fact, development of such an
  abnormality should prompt reassessment of
 diagnosis.

 Prognosis:
 Median survival 6 years (72 months)
 1-2% rate of progression to acute leukemia
Dimorphic Red Cell Population
Ringed Sideroblasts
Ringed Sideroblasts
Megaloblastoid Change
Refractory Anemia with Excess Blasts
 RAEB definition:
 Refractory anemia with 5-19% myeloblasts in the bone
 marrow.
   RAEB-1:
       5-9% blasts in bone marrow and <5% blasts in blood.
   RAEB-2:
       10-19% blasts in the bone marrow
       Auer rods present
Refractory Anemia with Excess Blasts
 Epidemiology: 40% of MDS cases.
 Older patients (over 50 years)
  Morphology:
 Dysplasia of all three cell lines often present
 Neutrophil abnormalities may include:
   Hypogranulation     -hypersegmentation
   Pseudo-Pelger-huet (hyposegmentation/barbells)
   Pseudo Chediak-Higashi granules
 Megkaryocyte abnormalities may include
   Hypolobation    -Micromegakaryocytes
Refractory Anemia with Excess Blasts
 Morphology (con’t.)
 Erythroid precursor abnormalities may include:
   Abnormal lobulation -megaloblastoid change
   Multinucleation
 0-19% myeloblasts in the blood
 5-19% in the marrow
 Bone marrow:
   Usually hypercellular (10-15% hypocellular)
   Abnormal localization of immature precursors (ALIP) may be
    present
 Immunophenotype:
   Blasts express CD 13, CD33 or CD117
   The only MDS with a relevant phenotype
Refractory Anemia with Excess Blasts
 Genetics:
 Clonal chromosomal abnormalities found in 30% - 50% of
    RAEB cases. The abnormalities include:
     +8      – -5        – del(5q)
    – -7      – del(7q)    – Complex karyotypes

   Prognosis:
   Median survival, RAEB-1 = 18 months
   Median survival, RAEB-2 = 10 months
   RAEB-1 = 25% rate of progression to acute leukemia
   RAEB-2 = 33% rate of progression to acute leukemia
Hypercellular Bone Marrow
Blasts and Hypogranulation
Myeloblast with Auer Rod
        Chediak-Higashi-like Granules




Photograph courtesy of John Scariano, University of New Mexico, Dept. of Pathology 
Refractory Anemia with Excess Blasts in
       Transformation (RAEB-t)
     21-30 percent blasts in the marrow; more than
      5 percent in the bloodstream

     excessive numbers of monocytes (a type of
      white blood cell)

     normal or    hypercellular   (filled   with   cells)
      marrow

     accounts for about 25 percent of cases
Chronic Myelomonocytic Leukemia
           (CMMOL)
    5-20 percent blasts in the marrow; less than 5
     percent in the bloodstream

    cytopenia of at least two cell lines

    normal or hypercellular (filled with cells)
     marrow

    accounts for 15 to 20 percent of cases.
CMML
    Splenomegaly (10%)
    Maculopapular skin infiltration
    Monocytic pleural or pericardial effusion
    JMML (MPD/MDS)
1.   Pallor, bleeding, hepatosplenomegaly, skin
     involvement
WHO
 Refractory anemia
 Refractory anemia e ringed siderblast
 Refractory cytopenia e multilineage dysplasia
 Refractory cytopenia e multilineage dysplasia &
  ringed sideroblasts
 Refractory anemia e excess blast-1
 Refractory anemia e excess blast-2
 Myelodysplastic syndrome unclassified
 MDS associated e isolated del (5q)
WHO
Subtype   Blood             Bone Marrow
RA        Anemia           Erythroid
                           dysplasia only
RARS      Anemia           Erythroid dys
                           >15% ringed
RCMD      Bi- pancytopenia >10%Dysp in 2
                           or more cell
                           lineage
RCMD-RS   Bi-pancytopenia   >10%Dys 2 or
                            more cell lineage
                            >15% ringed
WHO
subtype       Blood                Bone Marrow

RAEB-1        Cytopenia            Uni-multilineage
              <5% blast            dys, 5-9%blast

RAEB-2        Cytopenia,           Uni-multi dys
              5-19%blast or Auer   10-19%blast
              rods                 Or Auer rods
MDS-U         cytopenia            Myeloid or
                                   megakaryocte dys

MDS with 5q   Anemia,nor or        Mega e hypolobated
              increased PLT        nuclei, <5%blast
Relation FAB & WHO
FAB          WHO
RA           RA(unilineage)
             RCMD
             5q-syndrome
RARS         RARS(unilineage)
             RCMD-RS
RAEB         RAEB-1
             RAEB-2
RAEBt        AML e multilieage dys
             AML & MDS-TR
CMML         Myelodysplastic/
             myeloproliferative disease
Prognostic Groups
 Two groups based on survival and evolution to acute
  leukemia

 1.) “Good” group
   Refractory anemia (RA)
   Refractory anemia with ringed sideroblasts (RARS)
   5q - syndrome
 2.) “Bad” group
   Refractory anemia with excess blasts (RAEB)
   Refractory anemia with excess blasts in transformation (RAEB-t)
   CMML


 MDS unclassified can be either
   International Prognostic Scoring
         System (IPSS) Factors
(1) the percentage of blasts in the bone
 marrow.

(2)whether chromosome abnormalities are
 present and, if so, which ones.

(3)how low the patient's blood counts are. These
 are given a score; the lowest scores have the
 best outlook for survival.
                  Prognostic Scoring
 The International Myelodysplastic Syndrome Working
  Group developed a scoring system based on 3 variables:

            0           0.5         1.0              1.5     2.0
% Blasts
            <5          5-10               --        11-20   20-30
Karyotype Normal, -Y,   Abnormal-   ≥3
                                    abnormalities,
          del(5q),      ities       chr 7
          del(20q)      NOS         abnormalities



Cytopenia
            0-1         2-3
Differential Diagnosis
 Several common diagnostic considerations given these
 findings including:

 Causes of bone marrow failure(idiopathic or drug-
  induced aplasia)
 Hypersplenism
 Vitamin B12 or folate deficiency
 (PNH)– can have similar BM findings and MDS.
Pathophysiology
 The initial hematopoietic stem cell injury
  can be from cytotoxic chemotherapy,
  radiation, virus, chemical exposure, or
  genetic predisposition.

 A clonal mutation predominates over bone
  marrow, suppressing healthy stem cells.
Laboratory Finding
 Peripheral blood :
   Red blood cells : ovalmacrocytosis , hypochromia.
   WBCs: promyelocyte and hyposegmentation.
   Platelet: large , dysplastic forms.
 Bone Marrow:
   RBCs : erythroid hyperplasia , megaloblastic appearance
  and dyserythropoiesis with excess sidroblasts.
  WBCs: abnormal monocyte maturation and granulocyte
  maturation bulge.
  Platelet: megakaryocytosis and dysthrombopoiesis.
Erythrodysplasia
 Major changes are found in the peripheral blood counts
    and morphology, and bone marrow abnormalities also
    are present.

 The peripheral blood counts, (CBC) and blood film :

-   Premature red cell death .
-   Anemia will vary in degree from mild to severe
-   Macro - ovalocytosis
-   Basophilic stippling .
-   Decreased reticulocyte count .
-   Nucleated RBC,s .
-    blood indices:
     (Increased MCV, decreased MCHC, decreased MCH )
Leucodysplasia
 Number of WBC,s is Variable .
 Neutropenia .
 Monocytosis .
 Increased Promyelocyte .
 Hyposegmented Neutrophil .
 Hypogranular PMNs .
 Circulating metamylocytes .
 Decreased myeloperoxidase and alkaline phosphatase
 activity
Thrombodysplasia
 Thrombocytopenia and Large , atypical
 platelets
Bone Marrow
 Erythrodysplasia :
  - Ringed sideroblast, Hyponucleated RBC,s and
    condensed chromatin pattern .


 Leucodysplasia:
- Myeloid hyperplasia .
- Partial maturation arrest at myelocyte stage .


 Thrombodysplasia:
  o Increased number of bizarre megakaryocytes
  o Micromegakaryocytes
  o   Mononucleas
Survival Time
 Refractory anemia : Survival time varies from 2 to 5
  years in most series
 Refractory anemia with ringed sideroblasts : The
  same like RA.
 Refractory anemia with excess blasts : Median survival
  for RAEB-2 is approximately 10 months.
 Refractory anemia with excess blasts in
  transformation: median survival time is 6 months or
  less.
Median Survival – Myelodysplastic Syndromes

                 120
                 100
      # Months




                 80
                 60
                 40
                 20
                  0
                        RA     RA RCMD RC    RA   RARS   5q-
                       EB-2   EB-1     MD-
                                       RS
                                   MDS Category
 Treatment
o Chemotherapy.

o Supportive therapy, such as WBCs, RBCs, Platelets
 transfusions.

o B.M transplantation in young patients.

								
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