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path 310 > acute myeloid leukemia > Flashcards

acute myeloid leukemia Flashcards

1
Q

describe the clinical presentation of patients with AML (4)

A

(1) fatigue - decreased rbcs - decreased o2 reaching tissues
(2) increased/unexplained bleeding - decreased platelets
(3) more prone to infections - decreased wbcs (immune cells)
(4) leukostasis - increased blasts - increased blood viscocity and poor circulation

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2
Q

are most cases of AML idiopathic? what are some causes?

A
  • most are idiopathic

- other causes = genetotxic stress, family history, genetic predisposition, previous blood cancer

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3
Q

what are the 5 testing parameters for AML? (what is needed for a diagnosis?)

A

(1) clinical presentation
(2) morphology
(3) immunophenotyping
(4) cytogenetics
(5) molecular studies

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4
Q

describe the morphology of an AML blood smear (2)

A
  • less than 20% blasts in the peripheral blood/bone marrow is diagnostic of AML and ALL
  • AML patients blast cells have auer rods where ALL pateitns don’t
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5
Q

what is often the first indication of AML?

A

morphology observed in a blood smear

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6
Q

what is typically done to test for AML and cell phenotype? (to confirm AML)

A

bone marrow studies

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7
Q

describe a bone marrow aspirate done to confirm AML

A
  • use syringe to remove liquid from the bone marrow cavity
  • fluid is then used to make slides for review under a microscope
  • these can then be used for further ancillary tests
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8
Q

describe a bone marrow biopsy done to confirm AML

A
  • large bore needle is used to remove a core of bone marrow
  • sample is then examined under a microscope in thin sections to reveal bone architechture
  • sample is usually taken from the iliac crest
  • this tissue can then be used for further morphological and immunohistochemistry analysis
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9
Q

why is a sample from the iliac crest ideal?

A

because as you age the areas with active bone marrow decrease and are replaced with fat, but most of the axial skeleton bone marrow remains active

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10
Q

what is a disadvantage to bone marrow procedures?

A

invasive

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11
Q

describe immunophenotyping using flow cytometry

A
  • cells are incubated with fluorescently tagged antibodies
  • they are then passed under a laser and fluoresce if they have the antigen of interest
  • this is useful for determining the proteins expressed on the leukemic cells and their lineage (to guide treatment
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12
Q

describe immunophenotyping using immunohistochemistry

A
  • done on the bone marrow biopsy tissue sections
  • similar to flow cytometry - cells are incubated with antibodies attached to a colorimetric endpoint detection system
  • a positive result = brown on a histology slide
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13
Q

describe cytogenic analysis of AML tissue

A
  • its routine to preform a karyotype on all suspected acute luekemia cases, but FISH analysis may also be done on bone marrow sample
  • this type of testing provides information on the presence of translocations which are necessary for proper classification
  • recall that AML has progenitor cells that are preferentially commited to the myeloid lineage but are unable to differentiate
  • translocation is the likely cause of this improper pathway
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14
Q

what is the two-hit model?

A

describes the two types of mutations required to cause leukemia:

  • HIT 1 = differenetiation block - requires a mutation that will block differentiation to prevent immature progenitor cells from differentiating any further
  • this often involves loss of function mutations in transcription factors needed for differentiation and often stems from chromosomal translocation events
  • HIT 2 = enhanced proliferations - a mutation that enhances proliferation occurs
  • typically a gain of function mutation in enzymes involved in signalling pathways (that transmit signals to the nucelus telling the cell to divide)
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15
Q

what are the reccuring translocations associated with AML? (3)

A
  • t(8;21)(q22;q22) - portion of chromosome 8 was translocated onto chromosome 21
  • aka core binding factor rearrangement
  • q = long arm of chromosome and that portion indicates the neighbourhood involved in the translocation
  • inv(16) - material on chromosome 16 in inverted
  • requires skilled cytogeneticist to identify
  • t(15;17) - a portion of chromosome 17 was translocated onto chromosome 15
  • forming the derivative chromosome 15
  • aka PML-RARA rearrangement bc contains fusion sequence derrived from PML and RARA genes
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16
Q

in general, how do the mutations associated with AML result in AML?

A

impair cellular differentiation by affecting the cellular machinery that controls cell maturation

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17
Q

what are the common core binding factors affected by t(8;21) and inv(16) translocations?

A

CBFa (aka RUNX1) and CBFβ

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18
Q

what is the role of core binding factors in a healthy individual

A

when stem cells are called upon to produce more mature cells the core binding facors lead to transcription of target genes and the activation of maturation programs

19
Q

describe specifically how t(8;21) leads to AML

A
  • after the translocation event, CFBa is fused with another protein ETO (RUNX1T1) which impairs the function of both CFB proteins
  • thus, the cellular machinery can no longer activate the target gene transcription and the cells remain locked in the immature phase
20
Q

describe specifically how inv(16) leads to AML

A

after the inversion event CFBβ is fused with another protein AMMHC (MYH11) which impairs the function of cellular machinery and results in maturation arrest

21
Q

describe specifically how t(15;17) leads to AML

A

similar manner as other mutations - results in impaired function of cellular machinery causing maturation arrest

22
Q

what do the 3 mutations leading to AML represent?

A

a convergence point in evolution leading to the same functional outcome

23
Q

the 3 mutations leading to AML arrest leukemogenesis at which phase of the two-hit model?

A

HIT 1 (differentiation block)

24
Q

AML is stratified into 3 risk categories based on the cytogenic abnormality, what are they?

what is the 5 year survival rate and relapse rate for each?

A

(1) good - if have t(8;21), t(15;17) or inv(16)
- 5 year survival rate = 70%
- relapse rate = 33%
(2) intermediate - if have normal karyotype (50% of patients)
- 5 year survival rate = 48%
- relapse rate = 50%
(3) poor - complex cytogenetics
- 5 year survival rate = 15%
- relapse rate = 78%

25
Q

which risk category requires further genetic testing? what test is preformed?

A

intermediate - next generation sequencing or PCR-based assays

26
Q

describe next generation sequencing, what is it used for?

A
  • used to ditect gene fusions or mutations in AML patients
  • allows for millions of individual dna strands to be sequenced in parallel while incorporating dna bases
  • these bases terminate the sequencing rxn and fluoresce which can be captured by a camera after each PCR cycle
  • bioinformatics programs align the short sequences to a reference human genome and any mismatch btwn the two sequences shows the presence of a mutation
27
Q

mutations can be classified into different tiers, what are they?

A

tier 1 = mutations in aa coding regions
tier 2 = mutations in regulatory regions of the gene
tier 3 = mutations in repetitive regions
tier 4 = mutations in other unique regions

28
Q

AML is considered one of the simpler cancers, why?

A

only comes about due to tier 1 mutations

29
Q

what are PCR-based assays used for?

A

used to ditect gene fusions or mutations in AML patients

30
Q

compare the use of NGS and PCR-based assays

A
  • PCR-based assays are more cost effective and faster

- NGS offers a higher throughput

31
Q

what is often done after full diagnostic panel for confirmation of AML?

A

analysis of bone marrow biopsy histology

32
Q

describe how the analysis of bone marrow biopsy histology can be used to diagnose AML

(what are the key histological differences btwn healthy tissue and AML tissue)

A
  • have bone marrow cells, hepatocytes and fat cells within the bone marrow of healthy tissue
  • fat is inversly proportional to age (age 40 = ~40% fat in bone marrow)
  • AML bone marrow has almost no fat cells bc blast cells proliferate and take over the bone marrow - destroying fat cells
  • I.e. the majoirty of cells in the bone marrow look the same, and there is a reduction in all other normal maturing blood elements
33
Q

what is the main consideration for AML treatment?

A
  • curative or palliative treatment?
  • can’t live long with AML so generally go for curative if patient isn’t elderly
  • if elderly go for palliative
34
Q

what are the two forms of curative care?

A
  • induction chemotherapy to acheive remission

- consolidation therapy - to prevent relapse

35
Q

what are examples of supplementary care given to AML patients?

A
  • antibiotics - cant inject wbcs and these patients are subject to infections
  • nutrition supplements - often get mouth and esophageal sores and can’t eat
36
Q

how do we treat AML with t(8;21)?

A

standard 3+7 treatment regimen:

  • daunorubicin is first administered intravenously for 3 days
  • this drug interacts with dna by intercalation and inhibition of macromolecle biosynthesis
  • also inhibits the progression of topoisomerase II which relaxes dna supercoils for transcription
  • cytarabine is then administered for 7 days following daunorubicin
  • this molecule is similar enough to human cytosine deoxyribose to be incorporated into human DNA but its different enough to kill the cell
37
Q

what are disadvantages to the standard 3+7 regimen?

A
  • kills all rapidly dividing cells but is not particularily targeted
  • leads to potenital toxic effects
  • hair, gut lining, etc also rapidly dividing so these are effected
38
Q

how do we treat AML with t(15;17)?

A
  • all-trans retinoic acid (ATRA)
  • targeted treatment thanks to the presence of PML-RARA mutation
  • is leukemia cells are provided with a form of vit. A (retinoic acid) it induces t(15;17) blast differentiation
  • ATRA overcomes the differentiation block imposed by t(15;17), allowing cells to mature normally
  • aresenic acid is also added to enhance the differentiation and kill leukemic cells (basis of this is not understood but it works)
39
Q

is ATRA toxic or non-toxic?

A

essentially non toxic because bc it specifically targets blast cells causing them to mature into normally functioning granulocytes

40
Q

describe bone marrow transplantation as treatment for AML

A
  • if there is relapse after standard treatment this is the final option for currative treatment
  • main goal is to acheive graft-vs-leukemia effect (where donor immune cells eliminate host leukemia cells after chemo)
41
Q

what factors must be considered before a bone marrow transplant? why? (3)

A
  • age: better for younger patients (<60) who have relapsed or have high risk
  • transplant donor: requires transplantation of HSCs from matched sibling or unrelated donor
  • toxicities: this requires toxic therapy after but can be currative
42
Q

describe mutant IDH inhibitors as a potential peronalized AML treatment

A
  • isocitrate dehydrogenase (IDH) 1 and 2 are enzymes involved in the citric acid cycle
  • its been discovered that patients with mutated IDH enzymes produce the onco-metabolite 2HG which accumulates within the body
  • 2HG blocks HSCs differentiation, contributing to AML
  • mutant IDH inhibitors have been developped and show promise for reversal of this blockade
43
Q

what is the Darwinian “Pre-Leukemia” model

A
  • new genetic model of AML
  • recent studies have shown that acute leukemia doesnt actually have an acute onset
  • “pre-leukemia” suggests hidden mutations that we couldnt identify before (thanks to NGS)
  • we now know that 25% of people have identifiable mutations in their cells only some of them will go on to develop blood cancer
  • i.e. we are now looking to shift towards blood surveilance to look for clones at earlier stages
  • this has a lot of ethical considerations tho
  • overall idea is that there’s more going on than suggested in the 2 hit model

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