MYELODYSPLASTIC SYNDROME

MEDICAL STUDENTS LECTURE

DR JATAU ED

INTRODUCTION

• Myelo = marrow in Greek

Dys = irregular in Greek

Plasia = proliferation in Greek

• Myelodysplastic syndrome is a group of malignant stem cell disorders characterized by ineffective blood cell production and variable risk of transformation to acute leukemia.

DEFINITION

• Clonal disorder of haemopoeitic stem cells which retain the ability to proliferate and differentiate into end stage cells, but do so in disordered and ineffective manner with asynchronous and delayed maturation of the different cell lines and early apoptosis ( cell death ) .
• Bone marrow is usually hypercellular with peripheral pancytopenia.

EPIDEMIOLOGY

• Usually idiopathic
• Annual incidence of 4.1 per 100,000
• Risk of Development increases with age
• Unusual <50yrs, unless viral infections, treatment or chemical induced
• Median age 65 or greater, with male predominance

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PREDISPOSING FACTORS

• Heritable – Genetic Disorders including Down’s, Congenital Neutropenias, Fanconi’s Anaemia, Ataxia Telangiectasia, NF-1….

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• Acquired – Mutagen Exposure (alkylators, Topo-isomerase II, Radioactive), Haemopoietic cell transplants, environmental exposures, Aplastic anaemia, PNH, Polycythemia Vera

PATHOGENESIS

• Stem cell is diseased with any or all of the erythroid, myeloid or megakaryocytic cell lines affected.
• An acquired somatic mutation of the stem cell CD 34 may cause one or several cytogenetic anomalies, influencing to a great extent the clinical evolution of the disease. e.g. Deletions of tumour suppressor genes on chromosomes 5 and 7, mutations of genes commonly involved in cancer (p53, ras)
• In addition to peripheral cytopenia, there is also shortened survival of the affected cells as well as qualitative deficiencies of these cells:

e.g. deficient chemotaxis of granulocytes., bleeding, etc.

CLASSIFICATION-FAB

• Refractory Anaemia(RA)-21%
• Refractory Anaemia with ringed sideroblasts (RARS)-17%
• RA with excess blasts(RAEB)-37%
• RA with excess blasts in transformation(RAEB-T)-12%
• Chronic myelomonocytic leukemia(CMML)-13%

CLASSIFICATION–WHO

CLINICAL AND LAB. FEATURES

• Asymptomatic and incidentally discovered as anaemia or multilineage cytopenia.
• Anaemia symptoms: fatigue, dyspnoea, palpitations, dizziness, angina, CHF, slowing of mental processes.
• Leuco-Neutropenia: also impaired chemotaxis, phagocytosis, bactericidal activity, often skin inf.
• Thrombocytopenias and impaired hemostasis.
• Paraneoplastic autoimmune manifestations: vasculitis, arthritis, edema, pulm. Infiltrates, pleural and peric. Effusions, iritis, myositis, skin ulcers , chloromas, neuropathies,
• Acquired Pure Red Cell Aplasia

PHYSICAL FINDINGS

• 60% Pale
• 26% Petechaie and/or Purpura
• Hepatosplenomegaly and lymphadenopathy are uncommon except in CMML
• Cutaenous Manifestations uncommon…but two recognized syndromes can occur in MDS

--> Sweet’s – acute febrile neutrophilic dermatosis

--> Myeloid Sarcoma – “chloroma”

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LABORATORY FINDINGS

• Bone Marrow and Blood changes variable, divided into FAB MDS subtypes.
• Chromosomal Abnormalities are associated as well.
• Anaemia almost always present with reticulocytopenia
• Pancytopenia in up to 50% of cases
• <5% have isolated neutropenia or thrombocytopenia without anaemia

RBCs

Peripheral blood

• Macrocytes
• Aniso-poikilocytosis
• Dimorphic picture
• Polychromasia
• Reticulocytopenia
• Basophilic stippling
• nrbc

Bone marrow

• Erythroid hyperplasia
• Multinuclearity
• Cell division disorders
• Megaloblast
• Cytoplasmic vacuoles
• Howell-Jolly bodies
• Ring sideroblast
• Internuclear bridging
• Erythroid hypoplasia

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WBCs

Peripheral blood

• Hypogranular neutrophils
• Unilobed or bilobed neutrophil (pelger-huet)
• Hypersegmented neutrophil
• Monocytosis
• Promonocytes
• Degranulated eosinophils

Bone marrow

• Hypogranularity of myeloid precursors
• Increased promonocytes
• Increased blast

PLATELETS

Peripheral blood

• Agranular platelets
• Giant platelets

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Bone marrow

• Micromegakaryocytes
• Large megakaryocytes with single or odd numbered round or oval nucleus
• Large megakaryocytes with multiple small, round nuclei
• Megakaryoblast

Ringed Sideroblasts

MDS-Bone Marrow

DYSPLASTIC MEGAKARYOCYTE

HYPOPLASTIC MDS in Fanconi’s�Pancytopenia

MDS – Laboratory characteristics

• Normo – or – macrocytic anemia, aniso-poikilocytosis.
• Normal B12, folate.
• Leuco-erythroblastosis may be present, when MDS advanced.
• Basophilic stippling, Howell-Jolly bodies, giant bands and hypogranular granuloc., Pelger-Huet anomaly, hypersegmentation.
• BM – hypercell., megaloblastoid = nucleo-cytoplasmic asynchrony, micro- and- very polyploid megakaryocytes.
• PNH – like defects in RBC-s ( CD55 and CD59 )-high complement sensitivity.

BASOPHILIC STIPPLING

• MDS
• Lead, Arsenic, Mercury poisoning
• Thalassaemia
• Sideroblastic anaemia
• Unstable Hb

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HOWELL JOLLY BODIES

• MDS
• Severe Megaloblastic Anaemia
• Myelofibrosis
• Thallasaemia
• Myelopthisic Anaemia

Other RBC Inclusion bodies

MDS – Necessary diagnostic criteria

• 1. Persistent, unexplained cytopenia with the known morphologic anomalies.
• 2. Older adults with normo- or – macrocytic anaemia without B12, folate deficiency.
• 3. Hyper ( rarely hypo ) cellular BM with megaloblastoid and asynchronous maturation features. Ineffective hematopoiesis.
• 4. Cytogenetic anomalies in 40-60% of pts.: 5q & 7q deletions.
• 5. Blast count: Myeloblasts or monocytes over 1,000 / ul., CD34 is proof of blast, but not all blasts are CD 34 +.

Management

1. Observation
2. Supportive care
3. Intensive chemotherapy
4. Allogeneic or autologous transplant
5. Cytotoxic therapy
6. Immunosuppressive agents

THERAPY

• A. Supportive
• Early stage do not require treatment for some time if slowly evolving.
• RBC Transfusions according to symptoms:
• Haemoglobin concentration < 90 g/l in elderly will cause dyspnoea, angina, CHF.
• Erythropoietin and G-CSF have been used successfully in a some patients but has occasionally accelerated leukaemic transformation.

THERAPY ( cont. )

• Complications of transfusions:
• 1. Iron overload : each Unit of PRBC-s of ~ 250 ml contains 250 mg of Fe++.
• In addition – ineffective erythropoiesis with ring sideroblasts in the mitochondria, increase unutilized Fe²⁺ in the RES. – liver, spleen, BM, heart and pancreas – hemosiderosis .
• Canadian guide lines recommend Iron chelation therapy when Ferritin reaches 1,000.
• Alloimmunization due to repeat transfusions is bound to occur.
• T 4 lymphopenia occurs after repeat transfusions.

CHEMOTHERAPY

• Hypomethylating agents – DNA binding / competing: 5 Azacytidine and recently – Decytabine ( Dacogen )
• Anti-angiogenic agents – related to Thalidomide –

Lenalidomide ( Revlimid ) – very effective in 5q- syndrome.

• Allogeneic stem cell transplant with moderate conditioning regimen has been successful in 5q - , as well as in overlap MDS-MPD even in the elderly.
• Immune suppression in Hypoplastic MDS with anti-thymocyte globulin has been also successful.

DIFFERENTIAL DIAGNOSIS

• Megaloblastic Anaemia
• Aplastic Anaemia
• Myelofibrosis
• Atypical CML
• HIV
• Drugs (e.g. Ganciclovir)
• Etoposide

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Clinical Overlap / Associations:

• AML
• Aplastic anemia
• Myeloproliferative disease
• LGL leukaemia
• Autoimmune diseases

With Permission of J Maciejewski,M.D. Taussig Cancer Center/ Cleveland Clinic Foundation

With Permission of American College of Physicians from Young NS. Ann Intern Med. 2002 Apr 2;136(7):534-46

(ACP not responsible for accuracy of figure translation).

MDS – Differential diagnosis

• 1. Anemia of the “ Elderly “ – probably no such entity, since even at a cellularity of 30 % with adequate substrates of : Albumin, Fe ²⁺, B12, Folate, BM is capable of increasing its production up to 6-8 X basal, in the absence of
• 2. Chronic Inflammatory, neoplastic, renal hepatic or thyroid and other endocrine disease.
• 3. MDS often accompanies in elderly other co morbidities, which render diagnosis and therapy quite difficult.

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MDS – Differential diagnosis �continued

• 4. PNH clones may be found in both MDS and Aplastic Anemia (AA)

These type of MDS may respond to immunosuppression ( steroids and ATG )

AA treated may recover with clonal hematopoiesis, develop PNH, MDS and finally AML

• 5. MDS with Myelofibrosis (MDS-F )
• 6. Acute Megakaryocytic Leukemia (M7 by FAB) accomp. By fibrosis and branching reticulin.
• 7. Acute Panmyelosis with Fibrosis (APMF) – up to 20-25 % blasts in BM, dysplasia and pancytopenia.

PROGNOSIS

Poor:

1. Anaemia
2. Neutropenia
3. Thrombocytopenia
4. Trilineage dysplasia
5. Presence of blast
6. Raised lactic dehydrogenase

PROGNOSIS

• Poor ( Marrow Aspirate):
• Blast > 10%
• Trilineage dysplasia
• Trephine
• Abnormal localization of immature precursors ( Erythroid/ megakaryocytes)

PROGNOSIS

• Chromosome analysis:
• Monosomy 7
• Complex Karyotype
• Karyotypic evolution
• Molecular Studies:
• N- RAS mutation
• P53 mutation

CONCLUSIONS

• 1. MDS are quite frequent in aging populations, but are occasionally present in young persons and children.
• 2. Since MDS involves the pluripotent stem cell, any or all hematopoietic progenitors may be affected.
• 3. MDS in elderly is often accompanied by comorbidities, thus distracting our attention from symptoms and signs of MDS – cause of anaemia, bleeding tendency, recurrent infections.

CONCLUSIONS ( cont. )

• 4. The biology and evolution of MDS depends on a variety of factors:
• Subtype of MDS,
• Patient’s age and physical condition but mainly
• Co morbidities.
• 5. In patients with severe and irreversible co-morbidities supportive therapy is compelling.
• In healthier individuals, chemotherapy should be considered and even stem cell transplant with curative intent.

THANK YOU

FOR LISTENING

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