Myelodysplastic Syndrome 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: -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) 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 Bone Marrow Blood Subtype Anemia RA RARS RCMD RCMD-RS Erythroid dysplasia only Anemia RA Erythroid dys >15% ringed RARS >10%Dysp in 2 or more cell lineage Bi- pancytopenia RCMD >10%Dys 2 or more cell lineage Bi-pancytopenia RCMD-RS

WHO Bone Marrow Blood subtype RAEB-1 RAEB-2 MDS-U MDS with 5q Uni-multilineage dys, 5-9%blast Cytopenia <5% blast RAEB-1 Uni-multi dys 10-19%blast Or Auer rods Cytopenia, 5-19%blast or Auer rods RAEB-2 Myeloid or megakaryocte dys cytopenia MDS-U Mega e hypolobated nuclei, <5%blast Anemia,nor or increased PLT MDS with 5q

Relation FAB & WHO WHO FAB RA RARS RAEB RAEBt CMML RA(unilineage) RCMD 5q-syndrome RA RARS(unilineage) RCMD-RS RARS RAEB-1 RAEB-2 RAEB AML e multilieage dys AML & MDS-TR RAEBt Myelodysplastic/ myeloproliferative disease CMML

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 the percentage of blasts in the bone marrow. whether chromosome abnormalities are present and, if so, which ones. how low the patient's blood counts are. These are given a score; the lowest scores have the best outlook for survival.

Prognostic Scoring 0.5 1.0 1.5 2.0 <5 5-10 -- 11-20 20-30 0-1 2-3 The International Myelodysplastic Syndrome Working Group developed a scoring system based on 3 variables: 0.5 1.0 1.5 2.0 % Blasts <5 5-10 -- 11-20 20-30 Karyotype Normal, -Y, del(5q), del(20q) Abnormal-ities NOS ≥ 3 abnormalities, chr 7 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 : Bone Marrow: 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 : Leucodysplasia: Thrombodysplasia: - Ringed sideroblast, Hyponucleated RBC,s and condensed chromatin pattern . Leucodysplasia: Myeloid hyperplasia . Partial maturation arrest at myelocyte stage . Thrombodysplasia: Increased number of bizarre megakaryocytes Micromegakaryocytes 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

Treatment Chemotherapy. Supportive therapy, such as WBCs, RBCs, Platelets transfusions. B.M transplantation in young patients.