8/13- MDS/AML Flashcards Preview

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Flashcards in 8/13- MDS/AML Deck (51):
1

What is MDS?

Myelodysplastic Syndrome

- Aka "refractory anemia", "preleukemia", or "smoldering leukemia"

Spectrum of clonal myeloid disorders characterized by:

- Ineffective hematopoiesis

- Cytopenias

- Qualitative disorders of blood cells

- Clonal chromosomal abnormalities

- Variable tendency to evolve into acute leukemia

2

Can divide/organize MDS how? (dkfjadj)

- "Clonal bicytopenia or tricytopenias"

- "Oligoblastic leukemia"

3

Epidemiology of MDS?

Most common clonal hematologic disorder

- 1-10/100,000 /year in Western countries

- 3,000-12,000 cases/year in US

Disease of the elderly – incidence increases logarithmically after the age of 20

Men affected more than women (1.5x)

4

Pathogenesis of MDS?

Clonal expansion of a multipotential hematopoietic cell

Chromosomal deletions or additions involving most frequently:

- Long arms (q) of chromsomes 5 and 7

- Del of 5 and 7

- Del of 11, 12, 13, 20

- Trisomy 8

Major mechanism is ineffective hematopoiesis: defective maturation and death of marrow precursor cells.

- Decreased production/sensitivity to hematopoietic growth factors

- Increased production of hematopoietic inhibitors (TNFa, Ifng) inducing apoptosis

- T-cell mediated immune dysregulation

5

Risk factors for MDS?

Radiation Drugs and toxins

- benzene and other solvents

- alkylating agents (-5, -7)

- topoisomerase II inhibitors (11q23)

- smoking

- hair dyes

- pesticides, herbicides, organic chemicals

Other hematologic disorders

- aplastic anemia, paroxysmal nocturnal hemoglobinuria, congenital neutropenia

Genetic disorders

- Down syndrome Fanconi’s anemia,

- Neurofibromatosis (von Recklinghausen’s disease)

6

Clinical Manifestations of MDS?

- Anemia: weakness, fatigue, palpitations, orthostasis

- Thrombocytopenia: bleeding, bruising

- Leukopenia: increased susceptibility to infection

- Other: Sweet disease, polyarthritis, neuropathy, acquired alpha thalassemia, splenomegaly

7

DDx of MDS?

- Drugs or toxic exposures

- Infections

- Rheumatic disorders

- Deficiencies of vitamins B12, B6, or folic acid

- Hypersplenism

- Metastatic cancer

- Acute leukemia

- Aplastic anemia

- Paroxysmal nocturnal hemoglobinuria

- Myelofibrosis

8

What are features of the PBS in MDS?

Red cells:

- Anisocytosis

- Normocytic or mildly macrocytic indices

- Low reticulocyte count

- Howell-Jolly bodies, Cabot rings, basophilic stippling

White cells:

- Small, poorly granulated neutrophils with hyper- or hypolobulated nuclei

- Increased monocytes

Platelets:

- Large, agranular

9

What is shown here?

Q image thumb

Pseudo Pelger-Huet cell

10

What is shown here?

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Stodtmeister cell

11

What is shown here?

Q image thumb

A: Basophilic stippling

B: Howell-Jolly bodies

C: Cabot's rings

12

Overview of bone marrow in MDS?

- Erythroid Dysplasia

- Myeloid Dysplasia

- Megakaryocytic Dysplasia 

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13

What is shown here?

Q image thumb

MDS

14

What is shown here? Condition/features? Prognosis? 

Q image thumb

Refractory Anemia

- Dimorphic population

- Less than 5% blasts in marrow

- AML in 10% at 2 yrs

- Median survival 3-6 yrs

15

What is shown here? Conditions/features? Prognosis?

Q image thumb

Refractory Anemia with Ringed Sideroblsats

- > 15% ringed sideroblasts

- Less than 5% blasts in marrow

- AML in 0% at 2 yrs

- Median survival: 3-6 yrs

16

MDS is associated with what genetically?

Isolated del(5q)

17

Epidemiology of MDS?

- Occurs primarily in middle-aged women

18

Characteristics of MDS?

- Characterized by macrocytic anemia and normal or increased platelet count

- Megakaryocytes with hypolobulated nuclei

- Favorable clinical course with absence of leukemic transformation

19

International Prognostic Index (IPI) for MDS?

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20

Standard treatment of MDS?

Supportive care:

- Erythropoietin, G-CSF, GM-CSF, IL-11

- Blood transfusion

- Deferoxamine or Exjade (iron chelator)

- Pyridoxine, folic acid

- Danazol Immunomodulation

- Antithymocyte globulin

- Cyclosporine

- Steroids

AML-style chemotherapy

Newer agents affecting DNA methylation

Bone marrow transplantation

21

What are 5-zacytidine (Vdiaza) and Decitabine (Dacogen)?

Response?

Side effects?

- Vidaza is prodrug for Decitabine, which reduces DNA methylation at cytosine residues and allows reactivation of silenced tumor-suppressor genes (demethylating agents)

- Overall response rate 16-17% (CR 7%, PR 16%, improvement in 37%)

- Significant side effects including cytopenias, GI disturbances, fever, fatigue and various aches and pains

22

Organization/Division of the Leukemias?

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23

Acute leukemias are a group of disorders characterized how?

- Neoplastic transformation of hematopoietic stem cell (Clonality)

- Malignant cells either do not differentiate or differentiate abnormally

- Abnormal cells accumulate in blood, marrow and tissues

- Normal hematopoiesis is inhibited

- Fatal if untreated

24

Relative frequency of leukemias?

CLL: 32%

AML: 30%

ALL: 13%

Other: 13%

CML: 125

25

TEST TEST TEST

What is shown here?

Q image thumb

AML! Acute Myelogenous Leukemia

BE ABLE TO RECOGNIZE THIS

- Can see Auer rods!

26

Epidemiology of AML?

Percentage of acute leukemias in adults/children?

- 15-20% of acute leukemia in children

- 80% of acute leukemia in adults

- 12,000 new cases/yr in the US

- 8,000 deaths/yr in US

- Median age is 63 (Disease of the elderly!)

27

Risk factors for AML?

Genetics:

- Chromsomal abnormalities: Down's, Klinefelters

- Chromsomal instability: Fanconi's anemia, Bloom's

Prior chemotherapy:

- Alkylating agents: Cyclophosphamide, Mechlorethamine

- Topoisomerase II inhibitors: Etoposide, Anthacyclines

Radiation exposure: Hiroshema survivors, Radiologists (before modern shielding)

Environmental exposure: benzene

Prior hematologic abnormalities: Myelodysplasia, MPNs

28

What is shown here? 

Q image thumb

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29

WHO/FAB Classification of AML?

AML with genetic abnormalities

- t(8;21) or inv (16)

- 11q23 abnormalities

- APL with t(15;17) AML with multilineage dysplasia

- Evolution from MDS

- No MDS, but dysplasia in 2 or more cell lines AML secondary to therapy

- Radiation/alkylating agent

- Topoisomerase II inhibitor AML NOS (FAB classification)

30

FAB Classification of AML?

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31

M2 (AML with maturation) is associated with what translocation?

t(8:21)

32

M3 (Acute promyelocytic leukemia) is associated with what translocation?

t(15:17)

33

M4 (Acute myelomonocytic leukemia) is associated with what translocation?

inv 16

34

Clinical Presentation of AML?

Cytopenias:

- Anemia (fatigue)

- Leukopenia (infection/fever)

- Thrombocytopenia (bleeding)

Hyperleukocytosis: increased risk of CNS involvement

- Leukostasis (blast count > 50-100K, limited flexibility of blasts, lungs/brain most affected)

Extramedullary disease:

- Gums with M4/M5

- Chloromas with M2

- CNS Coagulopathy

- DIC, especially with M3 (also M4 and M5)

35

Petechiae are usually indicative of what abnormality?

Low platelet count

36

What is shown here?

Q image thumb

Hyperleukocytosis in pt with M4

- HUGE buffy coat!

37

Which form of AML is associated with gum infiltration?

M5

38

Which form of AML is associated with M3?

DIC Ex)

- Platelets 5,000

- Fibrinogen 25 

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39

CNS hemorrhage may occur in pt with what form of AML?

M3 (from DIC)

- Most feared complication (bleed before you can treat the leukemia)

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40

CNS leukemia may cause what nerve complications?

CN VII palsy (Bell's palsy)

41

Diagnosis of AML?

Bone marrow exam

- Wright-Giemsa stain

- Sudan/special stains

- Flow cytometry (aspirate)

- Cytogenetics (aspirate)

- Molecular rearrangements

42

Cytogenetics and prognosis in AML?

Good prognosis:

- t(8:21)

- inv(16)

- t(15:17)

Intermediate:

- Normal

Poor:

- del 5/5q or 7/7q

- Abnormalities of 11q23

- Multiple abnormalities

43

What is the most common subtype of AML?

- Genetics?

- Prognosis?

M2 AML (AML with maturation)

- 50% have t(8:21)

- Better prognosis than average 

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44

What demographic groups are most commonly affected by M3 AML?

- Genetics?

- Prognosis?

- Treatment?

M3 AML (Acute Promyelocytic Leukemia/APL)

- Seen in younger Hispanic pts

- May see Auer rods or big chunky granules in PBS (emergency!) 80-100% have t(15:17)

Risk of DIC: bleeding, thrombosis

Unique treatment: all-trans-retinoic acid

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45

What is this?

Q image thumb

M2 AML, t(8:21)

46

What is this? 

Q image thumb

M3 AML

- May see Auer rods or big chunky granules (emergency!)

47

What is shown here?

Q image thumb

Abnormal cell with t(15:17) on FISH

- Indicative of M3 AML

48

Treatment of AML? Complications? Maintenance therapy?

Induction chemotherapy:

- Anthracycline plus

- Cytarabine

Complications:

- Prolonged neutropenia

- infection

- Prolonged thrombocytopenia

Consolidation chemotherapy

No maintenance except M3

Bone marrow transplantation

49

Treatment of APL (M3 AML)?

ATRA (all transretinoic acid) + Chemotherapy

or

ATRA + Arsenic

(ATRA can put pts into remission, but doesn't keep them there; not enough)

 

50

Prognosis of AML for children? Adults?

Children:

- 90% complete remission

- 40% long-term cure rate

Adults:

- 65-70% complete remission

- 30% long-term cure

51

Adverse prognostic factors in AML?

- Age > 60 yo

- Poor risk cytogenetics

- Antecedent hematologic disorder

- WBC > 100K

- Presence of multidrug resistance gene 1 (MDR)

- Failure to achieve complete remission with first cycle