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Hematology RC Editable > AML > Flashcards

AML Flashcards

1
Q

Pathophysiology of APL

A

The retinoic acid alpha receptor gene (RARA) is encoded by the long arm of chromosome 17. It is mainly expressed in hematopoietic cells and has an important role in regulating gene expression. RAR alpha heterodimerizes with retinoid X receptor (RXR). In the absence of retinoid acid, RARA is bound by nuclear corepressor factor, and this causes transcriptional repression. In the presence of retinoic acid, RARA is activated and terminal differentiation of promyelocytes occurs.

In summary, PML/RARα acts through various mechanisms as a constitutive and potent transcriptional repressor of RARα-target genes

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2
Q

How does ATRA and arsenic work in APL?

A

ATRA and ATO dissociate the PML/RARa-RXR complex in ways that are dependent on caspases and proteasomes.

The degradation of PML-RARα may lead to release of transcription suppression and restoration of PML nuclear body structure. The blockade of other signaling pathways is also released, and the anti-apoptotic effect of PML-RARα is lost allowing induction of differentiation.

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3
Q

Pathophysiology of differentiation syndrome?

A

ATRA and ATO induce maturation of promyelocytes and promote tissue infiltration. There is also a systemic inflammatory response associated with increased cytokine expression, endothelial damage with capillary leak syndrome, and occlusion of the microcirculation.

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4
Q

Clinical features of differentiation syndrome?

A

Onset usually either within first week, or between weeks 3-4
Clinical manifestations:
Fever
hypotension
Weight gain (>5lbs)–> edema, effusions (pericardial, pleural), pulm edema
Dyspnea, hypoxia, CXR infiltrates
Rash (diffuse, erythematous)
Body pain
MOF (e.g., AKI)

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5
Q

Treatment of differentiation syndrome?

A

IV dexamethasone 10mg BID x minimum of 3 days, then taper
In most cases, continue ATRA, but consider holding if progressive or severe resp failure, renal failure, etc
Others: empiric Abx until r/o concomitant infection; consider diuresis if not hypotensive or in AKI; supplemental O2, mech vent PRN

~30% would die without treatment d/t resp failure or cerebral edema with treatment (steroids), most resolve within 24 hours; ~5% mortality

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6
Q

AML with normal cytogenetics, molecular tests to order prior to alloSCT?

A

FLT3-ITD
NMP1
Biallelic CEBPA

Others:
C-kit (if inv 16)
BCR-Abl (blast CML)

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7
Q

Morphology features of inv 3?

A

Abnormal megakaryocytes with increased platelet count

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8
Q

Morphology features of inv 16?

A

Dysplastic eosinophilia

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9
Q

Morphology features of APL?

A

Hypergranular vs hypo/microgranular (higher WBC)
Atypical promyelocytes (larger, bilobed/kidney-shaped nuclei, many violet granules, and multiple auer rods/cell)

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10
Q

Describe the WHO features of Acute monocytic leukemia?

A

Need >20% monoblasts, promonocytes
≥80% leukemic cells monocytic lineage (including monoblasts, promonocytes, monocytes)
Immunophenotyping: There is generally expression of at least two markers characteristic of monocytic differentiation such as CD14, CD4, CD11b, CD11c, CD64, CD68, CD36 and lysozyme. Variably express myeloid antigens CD13, CD33 (often very bright), C015 and C065.
CD34 is positive only in 30% of cases, while CD117 is more often expressed
Almost all HLA-DR+
Monoblasts are typically MPO negative; promonocytes may show some scattered MPO positivity
Auer rods are rare but possible

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11
Q

Describe the WHO features of Acute erythroid leukemia?

A

“Myeloid Neoplasms w/ Erythroid Predominance”

> 80% immature erythroid precursors w/ >/=30% proerythroblasts and <20% myeloblasts

The erythroblasts do not express markers of myeloid lineage and do not stain with MPO

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12
Q

Describe the WHO features of Acute megakaryocytic leukemia?

A

≥20% of blasts of which ≥50% are of MK lineage
Excludes cases of AML with: MDS changes
t (1;22), inv (3), t (3;3) – classified as AML w/ recurrent genetic abnormalities

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13
Q

Translocations classified as AML even without 20% blasts?

A

t(8;21), inv(16), t(16;16), and t(15;17).

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14
Q

Favourable Risk AML 2017 ELN
Updated 2022

A

t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD
bZIP domain mutated CEBPA

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15
Q

Intermediate Risk AML 2017 ELN
Updated 2022

A

Any FLT3-ITD
t(9;11)(p21.3;q23.3); MLLT3-KMT2A
Cytogenetic abnormalities not classified as favorable or adverse

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16
Q

Poor Risk AML 2017 ELN
Updated for 2022

A

t(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
(8;16) KAT6A::CREBBP
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
(3,v) other MECOM

−5 or del(5q); −7; −17/abn(17p)
Complex karyotype, monosomal karyotype

Mutated TP53
SARS BEZUS

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17
Q

Causes of Hip pain post induction

A

Recurrent/refractory AML / extramedullary (myeloid sarcoma - joint involvement)
Bone marrow necrosis / expansion
Infection (OM, muscle, septic arthritis, etc.)
G-CSF related
Avascular necrosis (more likely ALL due to steroids + asparaginase)
Hemartharosis/hematoma
Inflammatory/Gout
Referred pain (abdominal typhilitis)

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18
Q

Flow phenotype of APL

A

CD13+, CD33+, MPO+, CD34-, CD117-, HLADR- ; CD11b- (not monocytic)
CD56 = poor prognosis (extramedullary, CNS disease)
hypogranular variant of APL frequently co-expresses CD2, and can sometimes express CD34.

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19
Q

Indication for LP in AML?

A
  1. WBC > 40x10^9 some say 50,000/ul
  2. APL in relapse
  3. CD56+
  4. Inv (16) or chrms 11 abnormalities
  5. AMML (monocytic differentiation)
  6. Any signs and symptoms of CNS involvement (facial nerve palsy)

? Elevated LDH

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20
Q

What procoagulant and anticoagulants are affected in APL leading to increased risk of thrombosis and bleeding respectively?

A

Bleeding
1. elevated urokinase-type plasminogen activator
2. Decreased alpha2-antiplasmin
3. Decreased fibrinogen
4. Increased elastase to degrade antiplasmin

Thrombosis
1. Decreased tPA
2. Increased tissue factor
3. Increased PAI-1
4. Release of inflammatory cytokines (TNFalpha, other cytokines)
5. Decreased thrombomodulin

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21
Q

Reasons to stop ATRA or ATO?

A
  1. Arsenic acid toxicity (convulsions, muscle weakness, confusion and ECG abnormality
    -Consider chelation therapy (Dimercaprol 3mg/kg IM) + constant heart monitor
  2. APL differentiation syndrome (severe)- usually do not need to DC the drug
  3. Prolonged Qtc(withholding the drug for a QTc interval >450 msec in men and >460 msec in women)
  4. Hypersensitivity reaction/anaphylaxis
  5. Severe leukocytosis
  6. IIH (idiopathic intracranial HTN), usually will resolve after LP but consider holding if severe.
  7. Hepatotoxicity

DO not start in pregnancy/nursing mothers.

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22
Q

How does arsenic work in APL?

A

Binds to the PML moiety of the PML-RARa

At low dose (Synergism with ATRA):
-Induces differentiation
-Degrades PML/RARalpha fusion protein

At high dose:
-Increases apoptosis via caspase activation

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23
Q

Low-coco for APL induction, with doses.

A

ATRA: 45 mg/m2 per day in two divided doses until complete response.
Arsenic trioxide: 0.15 mg/kg per day until complete response.

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24
Q

Other translocation in APL (beside 15;17)?

A

1.NPM/RARA and t(5;17)
-responsive to ATRA therapy
2. NuMA/RARA and t(11;17)
-responsive to ATRA therapy
3. PLZF/RARA and t(11;17)
-resistant to ATRA therapy
4. STAT5B/RARA and t(17,17)(q21;q21)
-resistant to ATRA therapy
5.BCOR/RARA and t(X;17)(q11;q21.1)
-resistant to ATRA therapy
6. ZBTB16- RARa
-resistant to ATRA therapy

Please F off Stat bcuz ZBTB
Plzf stat5 bcor zbtb
11, 17, X

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25
Q

2 benefits and 2 issues/side effects with ATRA for APL

A

Benefits: induces complete remission; shortens duration of coagulopathy

Problems: diferentiation syndrome, has to be PO, other S/E: transaminitis, IIH, hypertriglyceridemia, dry skin/mucous membranes, bone pain.

26
Q

What poor heme outcomes are associated with differentiation syndrome?

A

Increased incidence of relapse, esp. extramedullary relapse
lower PFS (EFS), OS

27
Q

How do you document molecular response after induction and consolidation in APL?

A

*The median time to hematological CR in the APML4 protocol was 53 days
1.Induction
-BMBx after induction to look for CR
-If only in PR can continue induction therapy until CR achieved

2.Consolidation
-Repeat BMBx after consolidation to look CRm (molecular CR) w/ PML-RARA fusion transcript testing w/ RT-PCR
-If no CR, repeat in 4 weeks; if still no: treat as refractory
-If CRm achieved, proceed to maintenance

Recommend q3 month Bone Marrow monitoring for MRD until 2 years (if WBC <10 at initial presentation) and 3 years (if initial WBC >10 at initial presentation) after consolidation.

28
Q

Side effects of ATRA?

A

Long QTc
Shingles
Hepatotoxicity
Hyper trigs
IIH/Pseudotumor cerebri
Leukocytosis
Differentiation syndrome

Typical retinoid toxicity (symptoms that are similar to those found in patients taking high doses of vitamin A): Headache, fever, dry skin, dry mucous membranes (mouth, nose), bone pain, nausea and vomiting, rash, mouth sores, itching, sweating, eyesight changes

29
Q

Good and bad molecular in AML?

A

GOOD
-NPM1 + (FLT3-ITD – or low allelic ratio <0.5)
-Biallelic CEBPA

BAD
-NPM1 –/+ with FLT3-ITD + (adverse if high allelic ratio)
-Inv(16) with c-kit mutation
-Mutated RUNX1
-Mutated ASXL1
-Mutated TP53

30
Q

Common toxicities of high dose araC

A

Myelosuppression
Cerebellar dysfunction
Ocular dysfunction (hemorrhagic conjunctivitis)
Liver toxicity
Fevers
Cytarabine Syndrome: fever, myalgia, bone pain, CP, rash, conjunctivitis, malaise
Rash
Thrombophlebitis

31
Q

Agent for IDH2 mutated AML

A

Enasidenib

32
Q

Agent for FLT3 mutated AML

A

Gilteritinib
Quizartinib
Sorafenib
Midostaurin (dirty drug, considered a mulitikinase as has off target effects)

33
Q

Agent for CD33 mutated r/r AML

A

Gemtuzumab (anti-CD33 antibody-drug conjugate)

Pulled from the market in 2010 for hepatotoxicty and VOD. Re-approved in 2017 at 3mg/m2. Given on days 1,4,7

Also can be used as single agent in R/R setting.

34
Q

Agent for IDH1 mutated r/r AML

A

Ivosidenib

35
Q

Agents for older, unfit r/r AML

A

AZA + VTX
lDAC + VTX
Glasdegib + low dose (Ara-C or 7+3)
If good risk cyto (low dose cytarabine)
PO AZA

36
Q

What precursor CD markers are missing in APL

A

CD34, CD117 and HLA-DR

(MPO+ and CD33+)

37
Q

MOA of Rasburicase, why is it CI in G6PD?

A

Rasburicase ( which is exogenous urate oxidase) converts uric acid to allantoin → makes it more easily renally cleared

In pts with G6PD, hydrogen peroxide is formed as a breakdown product which leads to oxidate hemolysis.

38
Q

HA, pancytopenia-? APL

Name 3 urgent investigations
Name 2 treatments that need to be initiated on a Sunday

A

3 Urgent Investigations:
CT Head
Fibrinogen
FISH for t(15;17)

2 Treatments that need to be initiated:
ATRA 45 mg/m2 in 2 divided doses, first dose STAT
Supportive transfusions (plt > 50, fibrinogen >1.5)

39
Q

2 classes of therapy induced AML: name implicated drugs, latency period and characteristic cytogenetic abnormalities of each

A

Alkylating agents (cyclophosphamide,melpalan,chlorambucil,busulfan,dacarbazine,cisplatin)
Preceding MDS phase, evolution to AML after 5‐7 years, complex cytogenetics often involving chromosome 5 and/or 7.

Topoisomerase‐II inhibitors (danorubicin/etoposide/doxorubicin/mitoxantrone)
May have short MDS phase, shorter (1‐3 year) latency, frequent 11q23 (MLL), 21q22 (RUNX1), abnormalities with MLL/KMT2A rearrangements

40
Q

What are 2 serious toxicities seen with ATO/ATRA regimen that is not seen with other ATRA containing regimens for APL?

A

Hepatotoxicity (63% vs. 6% grade 3-4)
QT prolongation (16% vs. 0%)

Data from Lo-Coco Trial
Population: newly diagnosed APL
Interventions: ATRA-ATO vs. ATRA-chemotherapy (idarubcin)
Outcome: event free survival after 2 years
Results: 97% vs 85%

41
Q

Risk factors for invasive aspergillosis?

A
  1. Severe/prolonged neutropenia
  2. allogenic transplant
  3. GVHD
  4. CMV
  5. Glucosteroids (in ALL)
  6. History of previous IA
  7. Intensive chemotherapy (FLAG, NOVE >AZA)
  8. Prior immunodeficiency (GATA-2)
  9. Prior exposure (construction worker, farmer)
  10. Prior lung pathology (CF, COPD)
  11. Prior significant exposure to antibiotics
  12. ICU admission
  13. Immunosuppression post HSCT
42
Q

How does Allopurinol work in TLS?

A

Inhibitor of xanthine oxidase, which is responsible for successive oxidation of hypoxanthine and xanthine, resulting in production of uric acid.

43
Q

4 reasons to stop ATO therapy

A
  • QTc prolongation > 500 msec (black box warning)
  • Differentiation syndrome (black box warning)
  • Encephalopathy (black box warning)
  • Hepatoxicity (AST/ALT/bilirubin>5xULN)
44
Q

Epigenetics
What are 2 characteristics you must have?
What are 4 therapies that use epigenetics?

A

2 characteristics you must have
1. DNA methylation
2. Histone deacetylation

4 therapies:
1. Azacitadine
2. Decitabine
3. Rombidepsin
4. Vorinostat
5. Pabinonstat

45
Q

What are the lineage requirements for Myeloid, B-cell and T-cell

A

Myeloid
1. MPO
2. Monocytic differentiation with at least 1 of: NSE, CD11c, CD14, CD64, lysoyme

B-cell
1. Strong CD19 with at least 1 of: CD79a, cytoplasmic CD22 or CD 10
2. Weak CD19 with at least 2 of: CD79a, cytoplasmic CD22 or CD 10

T cell
1. Cytoplasmic CD3
2. Surface CD3

46
Q

Pt with APL on maintenance ATRA with signs of increased ICP. What is the diagnosis and treatment?

A

Pseudotumor cerebri (PTC).

TX
1. Decrease dose or hold ATRA until stable
2. Acetazolamide
3. Topiramate (Anti-seizure)
4. Therapeutic LP

47
Q

Presence of what CD markers confers increased risk of extramedullary risk at presentation.

A

CD56

48
Q

Patient with acute leukemia and severe hypokalemia, what is the probable subtype?

A

AMML

49
Q

4 clinical poor prognostic factors in AML (ie. not cyto, molecular).

A
  1. Older age (>60 and especially >75)
  2. t-AML
  3. Extra medullary disease
  4. Progression from MDS or MPN
50
Q

What molecular markers should you send at diagnosis for AML for prognostic significance or because there are specific drug targets which the pt may benefit from or they will change mangement (ie. risk stratify to favourable or poor)? (hint, there are 8).

A
  1. FLT3
  2. NPM1
  3. IDH1
  4. IDH2
  5. CEBPA
  6. ASXL1
  7. RUNX1
  8. Tp53
51
Q

What patient populations should be considered for CPX351 (Vyxeos)?

A

Age 60-75 with:
1. t-AML
2. Secondary AML
3. AML with myelodysplasia- related changes

52
Q

3 mutations that are consider founder mutations and may be present on MRD testing after CR and thus cannot be used to measure MRD status.

A
  1. RUNX1
  2. DMT3A
  3. ASXL1

The detection of these mutations may not represent the presence of AML MRD and thus may not be of prognostic significance for relapse.

53
Q

Most common type of myeloid leukemia to develop in children with Down Syndrome?

A

Acute megakaryoblastic leukemia
Usually with acquired GATA1 mutations.
May be preceded by transient myeloproliferative disorder (TMD), a condition unique to these children.

54
Q

What where the inclusion and exclusion criteria for the VIALE-A Study?

A

Inclusion:
1. New AML diagnosis
2. Not previously treated
3. Ineligible for induction therapy as defined by:
1. Age >75
2. Age 18-74 with 1 of:
-CHF requiring Tx
-LVEF <50%
-Chronic stable angina
-ECOG 2 or 3
-DLCO or FEV1 <65%

Exclusion:
1. Prior HM or VTX or chemo for MDS
2. Favourable risk cyto

55
Q

What where the treatment arms for the VIALE-A Study including doses? What was the primary end point?

A
  1. Venetoclax 400mg daily D1-28 + AZA 75mg/m2 D1-7 q28days
  2. Placebo +AZA 75mg/m2 D1-7 q28days

VTX Ramp up:
D1:100mg
D2:200mg
D3-28:400mg (cycle 2 and beyond, keep on 400mg)

Primary endpoint: OS
14.7 months with venetoclax/azacitidine and 9.6 months with azacitidine alone

56
Q

VIALE-A Study, what proportion of pts required dose interruption secondary to cytopenias?

A

75%

57
Q

What are 5 treatments for AML (including APL) that can cause differentiation syndrome?

A
  1. ATRA +/- ATO
  2. Gilteritinib
  3. Quizartinib (FLT3 inhibitor)
  4. enasidenib (IDH2)
  5. ivosidenib (IDH1)
58
Q

In pt with MPAL, what 2 molecular tests must be sent which may affect mangement?

A
  1. BCR-ABL (add a TKI)
  2. KMT2A (poor prognosis)
59
Q

2 molecular mutations in myeloid neoplasms with germline predisposition without thrombocytopenia or organ dysfunction?

A
  1. DDX41
  2. CEBPA

low plts- RUNX1, ETV6 and ANKRD26
with BM failure- GATA 2, or a/w noonan’s or down syndrome.

60
Q

AML on IDAC, gait ataxia. What is the diagnosis and what are 2 RFs for developing this condition?

A
  1. Cytarabine related cerebellar toxicity

RFs
1. Older age
2. Renal dyfxn as cleared by kidneys

61
Q

What is Glasdegib (MOA) and what pt population does it show benefit in?

A
  1. once daily inhibitor of Hh signaling pathway- increases sensitivity to chemotherapy and reduces leukemic stem cell growth.
  2. Used in unfit, elderly pts with AML in combination of LDAC

Significant improvement in CR and OS.

Hematology RC Editable (28 decks)

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