Myelodysplastic Syndromes

Question 1

What are myelodysplastic syndromes (MDS)? What can it progress to?

Answer 1

Heterogeneous disorders of myeloid stem cells with ineffective hematopoiesis (RBC production)

Can progress to AML

Question 2

What must be seen in bone marrow for diagnosis of MDS?

Answer 2

Hypercellular, abnormal maturation of cells, increased blasts (<20%, or would be leukemia)

Evidence of dysplasia in one or more cell lineages, affecting >10% of cells

Question 3

What is seen on peripheral blood smear of MDS in general?

Answer 3

Cytopenias - with variable reduction RBCs, platelets, and granulocytes, some with functional defects.

RBCs = normocytic or **macrocytic**
WBCs = abnormal nuclear lobation and granules with impaired killing activity

Question 4

What is one commonly tested WBC anomaly seen in peripheral smear in MDS?

Answer 4

Pseudo-Pelger-Huet anomaly

• neutrophils with bilobed nuclei, and hypogranularity
• will have impaired killing activity

Question 5

What is general the underlying cause of MDS?

Answer 5

Usually due to environmental factors such as past exposure to radiation or chemotherapy.

• Alkylating agents worst for chemotherapy
• Benzene and tobacco smoke also predipose

Question 6

What genetic abnormalities and benign hematologic disease can predispose to MDS?

Answer 6

Genetic - Down syndrome (also predisposes to AML), Fanconi anemia, Bloom syndrome, Ataxia-Telangectasia

Hematologic - Paroxysmal nocturnal hemoglobinuria, congenital neutropenia

Question 7

How do patients with MDS diagnosis present?

Answer 7

Usually older adults with nonspecific symptoms due to cytopenias.

Anemia symptoms most common - macrocytic

Neutropenia causes infections

Thrombocytopenia causes bleeding

Question 8

How do the RBCs appear in MDS?

Answer 8

Macrocytic and dysplastic

• multinucleated
• dyssynchrony between cytoplasm and nucleus
• ring sideroblasts could be present

Question 9

How can you track how quickly MDS is progressing to AML?

Answer 9

WHO classifications of refractory anemia with excess blasts

5-10% blasts - not very close
10-20% blasts - getting very close

Question 10

What is the only MDS genetic variant you need to know how to treat and what is the treatment?

Answer 10

Isolated 5q deletion causing MDS

Treatment is lenalidomide
-> derivative of thalidomide

Note: 7q is also a common MDS variant

Question 11

What other conditions can present similar to MDS (cytopenias, macrocytic anemias, etc)

Answer 11

Vitamin B12 / Folic acid deficiency

Heavy metal toxicity

Viral infections

Copper deficiency / Zinc excess

Question 12

How are low, medium, and high risk patients with MDS treated?

Answer 12

Low - tranfusions and iron chelation

Medium - hypomethylating agents to stop methylation of tumor suppressors (slows progression)

High - bone marrow transplant

Question 13

What is the definition of aplastic anemia and why is this name a misnomer?

Answer 13

Diminished or absent hematopoeitic precursors in bone marrow - usually pluripotent ones.

Misnomer because it affects all cell lines = pancytopenia

Question 14

What two conditions cause congenital aplastic anemia?

Answer 14

1. Fanconi anemia

2. Dyskeratosis Congenita - X-linked telomerase defect

Question 15

What is Fanconi anemia caused by? Symptoms?

Answer 15

Autosomal recessive mutation in DNA repair enzymes causing chromosomal breakages and bone marrow failure

Short stature, increased cancer incidence, cafe au lait spots, thumb /radial defects

Question 16

What is the most common cause of aplastic anemia / what does it usually follow?

Answer 16

Usually idiopathic, following acute hepatitis

Question 17

What are the other causes of acquired aplastic anemia other than idiopathic?

Answer 17

Drug-induced

• radiation
• drugs: benzene, chloramphenicol, sulfa drugs, alkylating agents, antimetabolites

Viral - Parvovirus, HIV, EBV

Question 18

What is the mechanism of action of aplastic anemia?

Answer 18

Damage induced by whatever cause causes lymphocyte activation

Unregulated lymphocyte activation of cytotoxic T cells directed against stem cells

Question 19

What does the bone marrow and peripheral smear look like in aplastic anemia?

Answer 19

Everything looks normal, with cytopenias

• > otherwise would just be hypoplastic MDS
• > bone marrow looks hypocellular but otherwise normal

Question 20

What gene is lost in paroxysmal nocturnal hemoglobinuria and what proteins does this prevent from being expressed on surface of cells?

Answer 20

PIG-A

Loss of GPI leads to loss of:

1. Decay accelerating factor (DAF / CD55)
2. Membrane Inhibitor of Reactive Lysis (MIRL / CD59)

These both inhibit complement. Loss leads to intravascular hemolysis

Question 21

When is PNH the worst and why?

Answer 21

Worst at the night time

• > mild respiratory acidosis during sleep
• > Acid triggers complement
• > hemoglobinemia / hemoglobinuria can be seen in morningtime

Question 22

Why is PNH included in this lecture?

Answer 22

It is associated with aplastic anemia, and PNH can be a component of the autoimmune reaction

Question 23

What are the treatments for aplastic anemia, especially when autoimmune?

Answer 23

Immunosuppressive regimens: cyclosporine (blocks T cells), antithymocyte globulin

Bone marrow transplant

Transfusions and bone marrow stimulation via GM-CSF can also be tried

Question 24

What cytogenetic abnormalities are present in aplastic anemia?

Answer 24

There should be none

-> this is what differentiates it from hypoplastic MDS