Myelodysplasia :from marrow failure

to malignant transformation

Ahmed Elshebiny, MDAhmed Elshebiny, MDUniversity of MenoufyiaUniversity of Menoufyia

Blood is continuously renewed

The Bone Marrow is the blood Factory

May be exposed to damage or failure

Bone Marrow Failure Syndromes

Bone Marrow Failure Syndromes

AA PNH MDS

Acquired Constitutional

Autoimmune Fanconi

DC

Diamond-Blackfan

others

Toxic, Irradiation, Infection

Pure Red Cell Aplasia

Agranulocytosis

Bone Marrow Failure May involve one or more cell lines Lymphocytes are usually spared

Venn Diagram

APLASTIC ANEMIA

MDSPNH

AML

Bone Marrow Failure Syndromes

Hematology lectures

Myelodysplastic syndrome (MDS) It is a term for a heterogeneous collection of

haemopoietic stem cell disorders usually affecting older adults.

There is underlying ineffectiveness of haemopoiesis that results in dysplasia of bone marrow precursors and peripheral cytopenias.

Dysplastic erythroid maturation (dyserythropoiesis)

NormalDyserythropoiesis

Pathology The cardinal features of MDS are

Increased marrow proliferation Failure of stem cells to differentiate And increased marrow apoptosis.

The disease is of clonal origin Chromosomal abnormalities are detectable in 30-

70% of patients. The no. of chromosomal abn. may correlate with the risk of progression to AML.

Epidemiology MDS is primarily a disease of the elderly,

with a median age at diagnosis of between 60-80 years.

The incidence is approximately double that of AML.

The recent increase in MDS incidence may be related to growing awareness, better diagnosis, and an aging population.

Etiology Primary Secondary

MDS (clinical) Moderate anaemia is the most common

clinical problem in MDS patients, but complete myeloid bone marrow failure also occurs leading to death from bleeding or infection.

Approximately half of the patients transform to AML.

MDS (clinical) May be preceded by a few years by an

unexplained macrocytic anemia with no evidence of megaloblastic anemia and a mild thrombocytopenia or neutropenia.

Thrombocytopenia as the presenting symptom may be mistaken for immune thrombocytopenia.

Cytogenetic abnormalities in MDS

FAB classification of MDS In 1982 The FAB group classified MDS according

to Morphology and the % of myeloblasts in the BM and PB.

These included Refractory anaemia (RA) Refractory anaemia with ringed sideroblasts (RARS) Refractory anaemia with excess blast in marrow (RAEB) CMML Refractory anaemia with excess blast in transformation (RAEB-t)

FAB classification of MDS

Newer classifications WHO IPSS

Treatment Stem cell transplant DNA methyl transferase inhibitors

Azacytidine Immunomodulation

Thalidomide and lenalidomide Immunosupression Histone deacetylase inhibitors Chemotherapy

Fate of MDS Transformation to acute leukaemia occurs in

up to 40% of patients. Although progression to frank AML is a

primary concern, 20-40 % or more of patients die of infections and/or haemorrhagic complications.

Sideroblastic anemias Inherited (X-linked) Acquired

Myelodysplasis Myeloproliferative disorders Myeloid leukemia Lead toxcicity Drugs e.g INH Alcohol others

Ring sideroblasts

Aplastic Anemias

Aplastic Anemias

Acquired Conistituitional

Single line

Agranulocytosis

Pure Red Cell Aplasia

Multilineage

Aplastic Anemia Named so in 1904 The theoretical basis for marrow failure

includes primary defects in or damage to the stem cell or the marrow microenvironment

Distinction between congenital or acquired may be difficult

80 % of patients have acquired cause which is an autoimmune disease

Aplastic Anemia

Drugs associated with AA NSAIDs(Butazones, Indomethacin,Piroxicam,

Diclofenac) Antibiotics( e.g sulfonamides) Furosemide Phenothiazines Corticosteroids Penicillamine Gold Allopurinol

Pancytopenia

Pancytopenia has many causes of which AA is not the most

common

1-Pancytopenia with hypocellular bone marrow

1. Acquired Aplastic Anemia

2. Inherited Aplastic Anemia

3. Some MDS

4. Rare aleukemic leukemia

5. Some acute lymphoblastic leukemia

6. Some lymphomas of bone marrow

2-Pancytopenia with cellular bone marrow

Primary bone marrow disease1. MDS2. PNH3. Myelofibrosis4. Mylophthisis5. Hairy cell leukemia6. Aleukemic leukemia

Secondary to systemic disease1. SLE2. alcoholism3. B12 or folate difficiency4. Hypersplenism5. Overwhelming infection6. Brucellosis7. Sarcoidosis8. T.B.

3 -Hypocellular marrow with or without cytopenia

1. Q fever

2. Ligionaires

3. Toxoplasmosis

4. Anorexia Nervosa

5. T.B.

6. Hypothyroidism

Investigations of MDS CBC, film, retics….. Bone marrow examination Cytogenitics

Iron Studies SI TIBC Transferrin Saturation Ferritin

Bone marrow aspiration and biopsy

PNH Hemolysis Venous thrombosis Aplastic anemia

P.N.H

PNH and Aplastic Anemia PNH is caused by an acquired genetic defect limited

to the stem-cell compartment affecting the PIGA gene.

Mutations in the PIGA gene render cells of hematopoietic origin sensitive to increased complement lysis.

Approximately 20% of patients with aplastic anemia have evidence of PNH at presentation, as detected by means of flow cytometry.

Furthermore, patients whose disease responds after immunosuppressive therapy frequently recover with clonal hematopiesis and PNH.

Approaches to treatment of Bone Marrow Failure Syndromes

1. Transfusions

2. Growth Factors

3. Immunosuppression

4. SCT

5. Others drugs

References Bethesda Handbook of Clinical hematology

2010 Hamilton et al : Hematology in Clinical

practice 2005 E-medicine online textbook, Hematology Other web resources