5 - Acute Myeloid Leukemia and Myelodysplastic Syndromes Flashcards
(90 cards)
1
Q
Hematopoietic Stem Cell Capabilities
A
Self-Renewal
Differentiation
2
Q
Hematopoietic Stem Cells give rise to
A
Common Myeloid Progenitor
Common Lymphoid Progenitor
3
Q
Common Myeloid Progenitors give rise to
A
Megakaryocyte–Erythroid Progenitor
Granulocyte-Monocyte Progenitor
4
Q
Megakaryocyte-Erythroid Progenitors give rise to
A
Erythrocyte
Megakaryocyte
5
Q
Megakaryocytes give rise to
A
Platelets
6
Q
Granulocyte-Monocyte Progenitors give rise to
A
Neutrophils
Monocytes
Eosinophils
7
Q
Common Lymphoid Progenitors give rise to
A
B Cell Progenitors
T Cell Progenitors
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
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)
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
11
Q
Inherited disorders leading to AML
A
Down’s Syndrome (Trisomy 21)
Fanconi’s Anemia
Li-Fraumeni Syndrome (p53 mutations)
12
Q
Polycythemia Vera
A
Myeloproliferative Neoplasm
Body making too many RBCs
Risk factor for developing AML later
13
Q
Essential Thrombocytosis
A
Myeloproliferative Neoplasm
Body making too many platelets
Risk factor for developing AML later
14
Q
Myelofibrosis
A
Myeloproliferative Neoplasm
Marrow being filled up with scar tissue
Risk factor for developing AML later
15
Q
Fanconi’s Anemia
A
Abnormality of DNA repair
Risk factor for developing AML
16
Q
Where is p53 located?
A
Chromosome 17
17
Q
AML - Clinical Presentation - Symptoms
A
Fatigue Bruising/Bleeding Dyspnea Fever Bone Pain
18
Q
AML - Clinical Presentation - Signs
A
Pallor Hemorrhage Ecchymoses Petechiae Infection Hepatosplenomegaly Skin or gum infiltration
19
Q
Granulocytic Sarcoma / Myeloid Sarcoma
A
Tumor formed by leukemic cells
20
Q
AML - Prognostic Factors
A
Age
21
Q
AML - Less than age 50
A
Survival rate = 50%
22
Q
AML - 50 - 54 years old
A
Survival rate = 40%
23
Q
AML - 55 years or older
A
Worse prognosis
24
Q
AML - 70 years old
A
Survival = 3 - 6 months at best
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FAB Classification of AML - M0
Minimally differentiated
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FAB Classification of AML - M1
Meyloblastic leukemia without differentiation
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FAB Classification of AML - M2
Myeloblastic leukemia with differentiation
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FAB Classification of AML - M3
Acute promyelocytic leukemia
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FAB Classification of AML - M4
Myelomonocytic leukemia
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FAB Classification of AML - M5
Monocytic leukemia
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FAB Classification of AML - M6
Erythroleukemia
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FAB Classification of AML - M7
Megakaryoblastic leukemia
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AML M2
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
```
34
AML M2 - Under the microscope
```
Large blasts
Prominent nucleoli
Generous amount of cytoplasm
Some granules
Signs of differentiation (bands), some normal cell behavior
```
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CD33
Marker seen on myeloid cells
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What determines survival in AML?
Cytogenetics
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2008 WHO Classifications of AML
AML with recurrent genetic abnormalities (classified by cytogenetic type)
AML with MDS-related changes
Therapy-related myeloid neoplasms
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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
Good prognosis
39
+8 alone
t(9;11)
Other non-defined
Normal cytogenetics
t(8;21), inv(16), t(16;16) with c-KIT mutation
Intermediate prognosis
40
```
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
Poor prognosis
41
Phases of Leukemia Therapy
Induction
| Postremission
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Leukemia Therapy - Induction
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
Leukemia Therapy - Postremission
Consolidation - Doses similar to induction
Intensification - Higher doses of active agents
Maintenance - Lower doses over extended period of time
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Remission Definition
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
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Cytarabine
Cytosine Arabinoside, Ara-C
| Used for induction of leukemia treatment
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Cytarabine - Mechanism
Converted into active form (aracytidine triphosphate or ara-CTP)
Incorporated into DNA, causing strand termination
Inhibits DNA and RNA polymerase
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Cytarabine - Metabolism
Metabolized in the liver to inactive uracil arabinoside
Excreted in the urine
Often administered by continuous IV infusion (due to its short half life)
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Cytarabine - Side Effects
Gastrointestinal - Inflammation of mucous membranes, sometimes with ulceration and diarrhea
Bone marrow suppression - Leukopenia, thrombocytopenia and anemia
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Daunorubicin / Idarubicin - Mechanism
Intercalation into DNA, impairing transcription
Topoisomerase II inhibition
Generation of free oxygen radicals
50
Daunorubicin / Idarubicin - Metabolism
Metabolized in the liver
| Dose must be adjusted when patients have significant hepatic dysfunction
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Daunorubicin / Idarubicin - Side Effects
Gastrointestinal - Nausea & vomiting, inflammation of mucous membranes, diarrhea
Bone marrow suppression
Alopecia
Cardiac toxicity
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Chemotherapy broad timeline
Leukemia (Start)
Aplasia (2 weeks in)
Remission (4 weeks in)
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"Minimal" Residual Disease
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
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Leukemia - Postremission Therapy
High-dose Cytarabine
Autologous hematopoietic cell transplant
Allogeneic hematopoietic cell transplant (also the new immune system can help target the cancer cells too!!!!)
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AML Treatment - Patients with Favorable Prognosis Disease
3 - 4 cycles of high-dose cytarabine-based consolidation
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AML Treatment - Patients with Intermediate Prognosis Disease
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
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AML Treatment - Patients with Poor Prognosis Disease
Allogeneic transplant using best available donor:
Sibling
Matched unrelated
Umbilical cord blood
Haploidentical donor
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If AML relapses
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
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Adverse risk factors for survival after intensive induction
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
Hypomethylating agents for older AML patients
Azacitidine
Decitabine
Reactivate certain tumor suppressor genes that are inactivated in AML
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Azacitidine
Hypomethylating agent for older AML patients
Prolongs survival, when compared to conventional care
Helps with MDS too, prolongs time before progression to AML
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Decitabine
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
Acute Promyelocytic Leukemia (APL)
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
PML
Pro-Myelocytic Leukemia
| Chromosome 15
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RAR-α
Retinoic Acid Receptor α
| Chromosome 17
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Pathogenesis of APL
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
When you treat APL with pharmacologic doses of All-Trans Retinoic Acid (ATRA)
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
Differentiation-Induced Leukocytosis in APL
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
APL Differentiation Syndrome - Course
Early:
Fever
Dyspnea
Weight Gain
Late:
Pulmonary Infiltrates
Pleural & Pericardial Effusions
70
APL Differentiation Syndrome
```
~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
APL Therapy other than ATRA
Arsenic Trioxide
72
APL Therapy
ATRA-Arsenic Trioxide
This has better outcomes than ATRA-Idarubicin
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Myelodysplastic Syndrome (MDS)
Heterogeneous clonal neoplastic bone marrow disorder
Ineffective hematopoiesis → Bone Marrow Failure
Increased risk of progression to AML
74
MDS Markers
Increased proliferation
Increased apoptosis
Low white count
Low platelets
Low hemoglobin
75
MDS - Aberrant Epigenetic Programs
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
MDS Classification - Refractory Anemia
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MDS Classification - Refractory Anemia with Ringed Sideoblasts
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MDS Classification - MDS with del(5q)
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MDS Classification - Refractory Cytopenias with Multilineage Dysplasia
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MDS Classification - Refractory Anemia with Excess Blasts - 1 (RAEB-1)
5 - 9% Blasts
| Cytopenias
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MDS Classification - Refractory Anemia with Excess Blasts - 2 (RAEB-2)
10 - 19% Blasts
Cytopenias
Peripheral Blasts Present
On the spectrum moving towards leukemia
82
MDS Classified - Unclassified
83
5q- Syndrome
```
Isolated deletion of Chromosome 5q
Female predominance
Characterized mainly by anemia
Thrombocytosis is common
Neutropenia is mild
Low rate of progression to AML
```
84
MDS Treatment - Hematopoietic Growth Factors
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
Darbepoetin
Long-acting erythropoietin
86
5q- Syndrome Treatment
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
MDS Treatment - Young patient with an HLA-matched donor
Allogeneic Transplant
88
MDS Treatment - No HLA match, stable disease
Supportive care
| Investigational therapy with low toxicity
89
MDS Treatment - No HLA match, young or progressive disease
Low or intermediate-1: Lenalidomide
Intermediate-2 or High: Azacitidine, decitabine, or AML induction
90
MDS Treatment - 5q- Syndrome
Lenalidomide
