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Oncology > 5 - Acute Myeloid Leukemia and Myelodysplastic Syndromes > Flashcards

5 - Acute Myeloid Leukemia and Myelodysplastic Syndromes Flashcards

1
Q

Hematopoietic Stem Cell Capabilities

A

Self-Renewal

Differentiation

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2
Q

Hematopoietic Stem Cells give rise to

A

Common Myeloid Progenitor

Common Lymphoid Progenitor

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3
Q

Common Myeloid Progenitors give rise to

A

Megakaryocyte–Erythroid Progenitor

Granulocyte-Monocyte Progenitor

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4
Q

Megakaryocyte-Erythroid Progenitors give rise to

A

Erythrocyte

Megakaryocyte

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5
Q

Megakaryocytes give rise to

A

Platelets

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6
Q

Granulocyte-Monocyte Progenitors give rise to

A

Neutrophils
Monocytes
Eosinophils

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7
Q

Common Lymphoid Progenitors give rise to

A

B Cell Progenitors

T Cell Progenitors

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8
Q

2 Hits of Leukemia

A

First hit: Lose the ability of the cells to differentiate
Second hit: Overproliferation of immature undifferentiated cells (Blasts) in the bone marrow

Complications:
No immune system
Anemic
Thrombocytopenic

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9
Q

Risk Factors for Acute Myeloid Leukemia

A

Ionizing Radiation
Organic Solvents
Chemotherapy (Alkylating agents, Topoisomerase II inhibitors)
Antecedent hematologic disorders
Inherited disorders (Down’s, Fanconi’s anemia, Li-Fraumeni)

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10
Q

Chemotherapy CAUSING Iatrogenic AML

A 
Alkylating agents (cause deletions of chromosomes 5 & 7, leukemia appears 5 - 7 years later) 0 - Poor prognosis
Topoisomerase II inhibitors (11q23 deletion - MLL) - Poor prognosis
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11
Q

Inherited disorders leading to AML

A

Down’s Syndrome (Trisomy 21)
Fanconi’s Anemia
Li-Fraumeni Syndrome (p53 mutations)

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12
Q

Polycythemia Vera

A

Myeloproliferative Neoplasm
Body making too many RBCs
Risk factor for developing AML later

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13
Q

Essential Thrombocytosis

A

Myeloproliferative Neoplasm
Body making too many platelets
Risk factor for developing AML later

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14
Q

Myelofibrosis

A

Myeloproliferative Neoplasm
Marrow being filled up with scar tissue
Risk factor for developing AML later

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15
Q

Fanconi’s Anemia

A

Abnormality of DNA repair

Risk factor for developing AML

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16
Q

Where is p53 located?

A

Chromosome 17

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17
Q

AML - Clinical Presentation - Symptoms

A 
Fatigue
Bruising/Bleeding
Dyspnea
Fever
Bone Pain
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18
Q

AML - Clinical Presentation - Signs

A 
Pallor
Hemorrhage
Ecchymoses
Petechiae
Infection
Hepatosplenomegaly
Skin or gum infiltration
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19
Q

Granulocytic Sarcoma / Myeloid Sarcoma

A

Tumor formed by leukemic cells

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20
Q

AML - Prognostic Factors

A

Age

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21
Q

AML - Less than age 50

A

Survival rate = 50%

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22
Q

AML - 50 - 54 years old

A

Survival rate = 40%

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23
Q

AML - 55 years or older

A

Worse prognosis

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24
Q

AML - 70 years old

A

Survival = 3 - 6 months at best

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25
Q

FAB Classification of AML - M0

A

Minimally differentiated

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26
Q

FAB Classification of AML - M1

A

Meyloblastic leukemia without differentiation

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27
Q

FAB Classification of AML - M2

A

Myeloblastic leukemia with differentiation

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28
Q

FAB Classification of AML - M3

A

Acute promyelocytic leukemia

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29
Q

FAB Classification of AML - M4

A

Myelomonocytic leukemia

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30
Q

FAB Classification of AML - M5

A

Monocytic leukemia

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31
Q

FAB Classification of AML - M6

A

Erythroleukemia

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32
Q

FAB Classification of AML - M7

A

Megakaryoblastic leukemia

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33
Q

AML M2

A

t(8;21) (q22;q22)

Younger patients
Extramedullary disease
Favorable prognosis
Fusion of RUNX1 & RUNX1T1 genes
See cells that contain both CD19 and CD33
~60% cure rate
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34
Q

AML M2 - Under the microscope

A 
Large blasts
Prominent nucleoli
Generous amount of cytoplasm
Some granules
Signs of differentiation (bands), some normal cell behavior
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35
Q

CD33

A

Marker seen on myeloid cells

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36
Q

What determines survival in AML?

A

Cytogenetics

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37
Q

2008 WHO Classifications of AML

A

AML with recurrent genetic abnormalities (classified by cytogenetic type)
AML with MDS-related changes
Therapy-related myeloid neoplasms

38
Q

inv(16) or t(16;16)
t(8;21)
t(15;17)

Normal Cytogenetics
NPM1 mutation in the absence of FLT3-ITD or isolated CEBPA mutation

A

Good prognosis

39
Q

+8 alone
t(9;11)
Other non-defined

Normal cytogenetics
t(8;21), inv(16), t(16;16) with c-KIT mutation

A

Intermediate prognosis

40
Q 
Complex (≥3 clonal abnormalities)
Monosomal karyotype
-5, 5q-, -7, 7q-
11q23 - non t(9;11)
inv(3), t(3;3)
t(6;9)
t(9;22)

Normal cytogenetics with FLT3-ITD mutation

A

Poor prognosis

41
Q

Phases of Leukemia Therapy

A

Induction

Postremission

42
Q

Leukemia Therapy - Induction

A

Cytarabine + Anthracycline
Inducing remission
Works 70% of the time in young patients (under 50) with no antecedent hematological disorders, no poor prognostic cytogenetics.
Over age 50, works about 50% of the time.
Antecedent hematological disorders, works about 30% of the time.

43
Q

Leukemia Therapy - Postremission

A

Consolidation - Doses similar to induction
Intensification - Higher doses of active agents
Maintenance - Lower doses over extended period of time

44
Q

Remission Definition

A

Restore normal blood cell production

Blast count down to 5% or less
Normal PMN count (over 1,000/μL)
Normal platelet count (over 100,000/μL)

Normal blood cells, no visible signs of leukemia in the bone marrow

45
Q

Cytarabine

A

Cytosine Arabinoside, Ara-C

Used for induction of leukemia treatment

46
Q

Cytarabine - Mechanism

A

Converted into active form (aracytidine triphosphate or ara-CTP)
Incorporated into DNA, causing strand termination
Inhibits DNA and RNA polymerase

47
Q

Cytarabine - Metabolism

A

Metabolized in the liver to inactive uracil arabinoside
Excreted in the urine
Often administered by continuous IV infusion (due to its short half life)

48
Q

Cytarabine - Side Effects

A

Gastrointestinal - Inflammation of mucous membranes, sometimes with ulceration and diarrhea
Bone marrow suppression - Leukopenia, thrombocytopenia and anemia

49
Q

Daunorubicin / Idarubicin - Mechanism

A

Intercalation into DNA, impairing transcription
Topoisomerase II inhibition
Generation of free oxygen radicals

50
Q

Daunorubicin / Idarubicin - Metabolism

A

Metabolized in the liver

Dose must be adjusted when patients have significant hepatic dysfunction

51
Q

Daunorubicin / Idarubicin - Side Effects

A

Gastrointestinal - Nausea & vomiting, inflammation of mucous membranes, diarrhea
Bone marrow suppression
Alopecia
Cardiac toxicity

52
Q

Chemotherapy broad timeline

A

Leukemia (Start)
Aplasia (2 weeks in)
Remission (4 weeks in)

53
Q

“Minimal” Residual Disease

A

You’ve eliminated 99.9% of the cancer.

That’s still 10^9 cancer cells left in the body. You gotta deal with them before they take over. Needs postremission therapy

54
Q

Leukemia - Postremission Therapy

A

High-dose Cytarabine
Autologous hematopoietic cell transplant
Allogeneic hematopoietic cell transplant (also the new immune system can help target the cancer cells too!!!!)

55
Q

AML Treatment - Patients with Favorable Prognosis Disease

A

3 - 4 cycles of high-dose cytarabine-based consolidation

56
Q

AML Treatment - Patients with Intermediate Prognosis Disease

A

If there is a sibling or matched related donor, use an allogeneic hematopoietic cell transplant

If there is no sibling or matched related donor, give 3 - 4 cycles of high-dose cytarabine-based consolidation

57
Q

AML Treatment - Patients with Poor Prognosis Disease

A

Allogeneic transplant using best available donor:

Sibling
Matched unrelated
Umbilical cord blood
Haploidentical donor

58
Q

If AML relapses

A

First try salvage chemotherapy

If that doesn’t lead to complete remission, try supportive care.

If it does, give supportive care, hematopoietic cell transplant and/or consolidation

59
Q

Adverse risk factors for survival after intensive induction

A

Age ≥ 80 years
ECOG ≥ 2 (poor functional status)
Complex karyotype
Creatinine >1.3 mg/dl

These factors indicate survival is in the 3 - 6 month ballpark

60
Q

Hypomethylating agents for older AML patients

A

Azacitidine
Decitabine

Reactivate certain tumor suppressor genes that are inactivated in AML

61
Q

Azacitidine

A

Hypomethylating agent for older AML patients
Prolongs survival, when compared to conventional care
Helps with MDS too, prolongs time before progression to AML

62
Q

Decitabine

A

Hypomethylating agent for older AML patients
Helps with MDS too
Higher Response rate than Azacitidine, but does not provide survival advantage in MDS.

5-day regimen
Remission rates 25% - 50% (slide says 24%, mouth said 1/4 to 1/2)
Median survival 7 - 8 months
Mediam time to response 3 cycles

10 day regimen
47% complete remission rate
Median survival 12 - 13 months

63
Q

Acute Promyelocytic Leukemia (APL)

A

Subtype of AML (10% of AML cases)
Presents with DIC, bleeding diathesis
Characterized by t(15;17) resulting in PML/RAR-α fusion
Responds to retinoic acid and arsenic trioxide (common in Chinese folk remedies)

64
Q

PML

A

Pro-Myelocytic Leukemia

Chromosome 15

65
Q

RAR-α

A

Retinoic Acid Receptor α

Chromosome 17

66
Q

Pathogenesis of APL

A

RAR partners with PML
NCoR (Nuclear Co-Repressors) & HD (Histone Deacetylases) are recruited
Transcription is halted at an immature promyelocytic phase
Differentiation is prevented
Leukemia ensues

67
Q

When you treat APL with pharmacologic doses of All-Trans Retinoic Acid (ATRA)

A

Retinoic Acid is no longer functionally partnered with PML
NCoR and HD are released
Differentiation is allowed!

This is the standard of care for APL!

68
Q

Differentiation-Induced Leukocytosis in APL

A

After treatment, the cells differentiate and proliferate over the first 4 weeks, then they die off, dropping your white count.

Staying on the drug beyond that allows your white count to steadily creep back up again.

69
Q

APL Differentiation Syndrome - Course

A

Early:
Fever
Dyspnea
Weight Gain

Late:
Pulmonary Infiltrates
Pleural & Pericardial Effusions

70
Q

APL Differentiation Syndrome

A 
~30% of patients during induction
Often associated with leukocytosis
Requires prompt intervention
Begin dexamethasone 10mg IV twice daily, continuing for 3 days at least
Can be fatal if treatment is delayed
71
Q

APL Therapy other than ATRA

A

Arsenic Trioxide

72
Q

APL Therapy

A

ATRA-Arsenic Trioxide

This has better outcomes than ATRA-Idarubicin

73
Q

Myelodysplastic Syndrome (MDS)

A

Heterogeneous clonal neoplastic bone marrow disorder
Ineffective hematopoiesis → Bone Marrow Failure
Increased risk of progression to AML

74
Q

MDS Markers

A

Increased proliferation
Increased apoptosis

Low white count
Low platelets
Low hemoglobin

75
Q

MDS - Aberrant Epigenetic Programs

A

Gains and losses of DNA methylation genome-wide AND at specific loci
Mutations in genes that regulate epigenetic programs:

DNA Methylation Control:
TET2
DNMT3a

Histone Methylation Control:
EZH2
ASXL1

76
Q

MDS Classification - Refractory Anemia

A
77
Q

MDS Classification - Refractory Anemia with Ringed Sideoblasts

A
78
Q

MDS Classification - MDS with del(5q)

A
79
Q

MDS Classification - Refractory Cytopenias with Multilineage Dysplasia

A
80
Q

MDS Classification - Refractory Anemia with Excess Blasts - 1 (RAEB-1)

A

5 - 9% Blasts

Cytopenias

81
Q

MDS Classification - Refractory Anemia with Excess Blasts - 2 (RAEB-2)

A

10 - 19% Blasts
Cytopenias
Peripheral Blasts Present

On the spectrum moving towards leukemia

82
Q

MDS Classified - Unclassified

A
83
Q

5q- Syndrome

A 
Isolated deletion of Chromosome 5q
Female predominance
Characterized mainly by anemia
Thrombocytosis is common
Neutropenia is mild
Low rate of progression to AML
84
Q

MDS Treatment - Hematopoietic Growth Factors

A

Erythropoietin (when given alone, improves HgB in 25% of patients)
Erythropoietin + G-CSF (improves HgB in 38 - 48% of patients)
Darbepoetin (improves HgB in 64% of patients)

85
Q

Darbepoetin

A

Long-acting erythropoietin

86
Q

5q- Syndrome Treatment

A

Lenalidomide
Derivative of Thalidomide

2/3 patients become transfusion-independent
We see cytogenetic responses, getting rid of their detectable genetic lesions in 45% of patients (complete) or 28% of patients (partial)

Myelosuppression is common, though, leading to significant neutropenia in 55% or thrombocytopenia in 44%

87
Q

MDS Treatment - Young patient with an HLA-matched donor

A

Allogeneic Transplant

88
Q

MDS Treatment - No HLA match, stable disease

A

Supportive care

Investigational therapy with low toxicity

89
Q

MDS Treatment - No HLA match, young or progressive disease

A

Low or intermediate-1: Lenalidomide

Intermediate-2 or High: Azacitidine, decitabine, or AML induction

90
Q

MDS Treatment - 5q- Syndrome

A

Lenalidomide

Oncology (23 decks)

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