ahmad sh. silmi msc haematology, fibms. what is myelodysplastic syndrome? the myelodysplastic...

Ahmad Sh. SilmiAhmad Sh. Silmi

Msc Haematology, FIBMSMsc 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

CharacteristicsVarying 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).

Incidence1- 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 EtiologyTwo 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 AgentsTobacco 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 AnemiaRA Definition:Dyplasia of the erythroid series only.Clinically, anemia is refractory to

hematinic therapyMyeloblasts < 1% blood and < 5% marrow<15% ringed sideroblasts in marrowNo Auer rodsOther etiologies of erythroid abnormalities

must be excluded. These include:drug/toxin exposure -vitamin deficiencyviral infection -congenital disease

Refractory AnemiaEpidemiology:5-10% of MDS cases. Older patientsMorphology:Anisopoikilocytosis on peripheral smearsDyserythropoiesis with nuclear abnormalities

(megaloblastoid change)< 15% ringed sideroblasts

Refractory AnemiaGenetics:25% may have genetic abnormalities

Prognosis:Median survival is 66 months6% 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 therapyMyeloblasts < 5% in marrow, absent in

blood>15% ringed sideroblasts in marrowNo Auer rodsOther etiologies of ringed sideroblasts

must be excluded. These include:Anti- tuberculosis drugsAlcoholism

Refractory Anemia with Ringed SideroblastsEpidemiology:10-12% of MDS cases. Older patientsMales > femalesMorphology: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 SideroblastsGenetics: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 BlastsRAEB 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 BlastsEpidemiology: 40% of MDS cases. Older patients (over 50 years) Morphology:Dysplasia of all three cell lines often

presentNeutrophil abnormalities may include:

Hypogranulation -hypersegmentation Pseudo-Pelger-huet (hyposegmentation/barbells)Pseudo Chediak-Higashi granules

Megkaryocyte abnormalities may includeHypolobation -Micromegakaryocytes

Refractory Anemia with Excess BlastsMorphology (con’t.)Erythroid precursor abnormalities may include:

Abnormal lobulation -megaloblastoid changeMultinucleation

0-19% myeloblasts in the blood5-19% in the marrowBone marrow:

Usually hypercellular (10-15% hypocellular)Abnormal localization of immature precursors (ALIP)

may be presentImmunophenotype:

Blasts express CD 13, CD33 or CD117The only MDS with a relevant phenotype

Refractory Anemia with Excess BlastsGenetics: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 monthsMedian survival, RAEB-2 = 10 monthsRAEB-1 = 25% rate of progression to acute leukemiaRAEB-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

WHORefractory anemiaRefractory anemia e ringed siderblastRefractory cytopenia e multilineage

dysplasiaRefractory cytopenia e multilineage

dysplasia & ringed sideroblastsRefractory anemia e excess blast-1Refractory anemia e excess blast-2Myelodysplastic syndrome unclassifiedMDS associated e isolated del (5q)

WHOSubtypeBloodBone Marrow

RAAnemiaErythroid dysplasia only

RARSAnemiaErythroid dys

>15% ringed

RCMDBi- pancytopenia >10%Dysp in 2 or more cell lineage

RCMD-RSBi-pancytopenia >10%Dys 2 or more cell lineage

>15% ringed

WHOsubtypeBloodBone Marrow

RAEB-1Cytopenia

<5% blast

Uni-multilineage dys, 5-9%blast

RAEB-2Cytopenia,

5-19%blast or Auer rods

Uni-multi dys

10-19%blast

Or Auer rods

MDS-UcytopeniaMyeloid or megakaryocte dys

MDS with 5qAnemia,nor or increased PLT

Mega e hypolobated nuclei, <5%blast

Relation FAB & WHOFABWHO

RARA(unilineage)

RCMD

5q-syndrome

RARSRARS(unilineage)

RCMD-RS

RAEBRAEB-1

RAEB-2

RAEBtAML e multilieage dys

AML & MDS-TR

CMMLMyelodysplastic/ myeloproliferative disease

Prognostic GroupsTwo groups based on survival and evolution to

acute leukemia

1.) “Good” groupRefractory anemia (RA)Refractory anemia with ringed sideroblasts (RARS)5q - syndrome

2.) “Bad” groupRefractory 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:

000.50.51.01.01.51.52.02.0

% Blasts% Blasts<5<55-105-10 ----11-2011-2020-3020-30

KaryotypKaryotypee

Normal, -Normal, -Y, del(5q), Y, del(5q), del(20q)del(20q)

Abnormal-Abnormal-ities ities

NOSNOS

≥ ≥ 3 3 abnormalitieabnormalities, chr 7 s, chr 7 abnormalitieabnormalitiess

CytopeniCytopeniaa

0-10-12-32-3

Differential DiagnosisSeveral common diagnostic considerations

given these findings including:

Causes of bone marrow failure(idiopathic or drug-induced aplasia)

HypersplenismVitamin B12 or folate deficiency(PNH)– can have similar BM findings and

MDS.

PathophysiologyThe 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 FindingPeripheral 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.

ErythrodysplasiaMajor 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 )

LeucodysplasiaNumber of WBC,s is Variable .Neutropenia .Monocytosis .Increased Promyelocyte .Hyposegmented Neutrophil .Hypogranular PMNs .Circulating metamylocytes .Decreased myeloperoxidase and alkaline

phosphatase activity

ThrombodysplasiaThrombocytopenia and Large ,

atypical platelets

Bone MarrowErythrodysplasia : - Ringed sideroblast, Hyponucleated RBC,s and condensed chromatin pattern .

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

Thrombodysplasia:o Increased number of bizarre megakaryocyteso Micromegakaryocyteso Mononucleas

Survival TimeRefractory 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

0

20

40

60

80

100

120

RAEB-2

RAEB-1

RCMD RCMD-RS

RA RARS 5q-

MDS Category

# M

on

ths

Treatmento Chemotherapy.

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

o B.M transplantation in young patients.