AML Flashcards by Shaun Grobler

AML favourable molecular genetics

CBF Leuks - t(8;21) & inv 16
NPM1 WITHOUT FLT3
bZIP CEBPA

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AML Intermediate risk molecular genetics

NPM1 with FLT3
t(9;11)
Other cytogenetic abnormality

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AML Unfavourable molecular genetics (7)

Complex karyotype (>4 abnormality)
Inv(3)
t(6;9)
KMT2A
AML-MR
TP53
t(8;16)

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APL genetics

t(15;17) PML::RARA

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AML subtypes 2022 WHO classification

AML with defining genetic abN
AML MR
AML with other defined genetic alterations
AML defined by differentiation
Myeloid sarcoma

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Chemical exposure leading to AML or myelodysplasia

Benzene
Chlorambucil
Melphalan
(+RT)

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Transient abnormal myelopoiesis (TAM) of Downs Syndrome

Blasts:
Undifferentiated/small Megs with blebbing/large megakaryoblasts.

IMPT:
Positive CD117
Variable CD34, CD36, CD42 and CD61
Aberrant expression of CD56 and CD7.

Trisomy 21
GATA1

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What are the AML with defining genetic abN (6)(3)(2)

Translocations
2. PML::RARA t(15;17)
2. RUNX1::RUNX1T1 t(8;21)
3. CBFB::MYH11 inv16
4. DEK::NUP214 t(6;9)
5. RBM15::MRTFA t(1;22)
6. BCR::ABL1 t(9;22)

Rearrangements
1. KMT2A rearrangements (11q23)
2. MECOM “ (inv3)
3. NUP98 “ (11p15)

Mutations
1. NPM1 mutation
2. CEBPA mutation (biCEBPA and bZip)

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What are some key morphologic

features of AML with t(8;21) ?

Blasts:
* Large
* Deep basophilic cytoplasm
* Azurophilic granules (pseudo-Chediak Higashi)
* Perinuclear hofs
* Single, long tapered Auer rods

Neutrophils:
* Variable dysplasia
* Hyposegmentation
* Abnormal cytoplasmic granulation ( homogeneous pink)

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What is the immunophenotype of

AML with t(8;21) ?

Bright CD34, HLA-DR, MPO and CD13
Dim CD33
Maturation asynchrony (CD34 and CD15)
Other Key Markers positive:
- CD19, Pax-5 and CD79a
- TdT- weak expression
- CD56

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What are morphological features of AML with inv(16) or t(16;16) CBFB-MYH11 ?

Monocytic and granulocytic differentiation
Abnormal eosinophil component (M4 Eos)

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What is an unusual cytochemistry finding

in AML with inv(16) ?

Chloracetate esterase
- normally negative in normal eosinophils
- faintly positive in the abnormal eosinophils in this AML

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What is the immunophenotype of

AML with inv(16) ?

Complex immunophenotype with multiple blast populations
Immature blasts
- CD34 and CD117 high expression
Granulocytic lineage
- CD13, CD33, CD15, CD65 and MPO
Monocytic lineage
- CD14, CD4, CD11b, CD11c, CD64, CD36 and lysozyme
Other markers often positive
- CD2

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What are the morphological variants of AML with t(15;17) PML::RARA ?

I. Hypergranular
* Densely packed granules and auer rods (faggot cells)
* Lower WCC

II. Microgranular
* Paucity of granules/Auer rods
* Higer WCC
* CD2 positive (association with FLT3)

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What is the characteristic immunophenotype

of APL ?

Negative : CD34, HLA-DR
Positive: CD117, heterogenous CD13, bright CD33
Negative for granulocytic markers: CD15
Microgranular variant
- some CD34 positivity and CD2 positive
CD56 - positive in 20% of cases (worse outcome)

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Which variant APL translocations are
resistant to ATRA/ATO ?

ZBTB16-RARA (11q23)
STAT5B-RARA [t(17;17)]

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What are the prognostic and predictive factors of APL ?

very sensitive to ATRA and arsenic trioxide
- allows the cells to differentiate
best prognosis of all AML subtypes if treated appropriately
anthracycline is added for high risk patients

Key morphologic
features of AML with t(6;9) / DEK::NUP214 ?

Multilineage dysplasia

Key morphologic
features of AML with t(1;22) / RBM15::MRTFA ?

Similar to acute megakaryoblastic leukaemia (AML M7)

What is the immunophenotype of the

blasts in AML with t(1;22) ?

Express one or more of the platelet glycoproteins:
- CD41 (GP IIb)
- CD61 (GP IIIa)
- CD42b (GP Ib)
- cytoplasmic staining more specific and sensitive for megakaryocytic differentiation
Positive for CD13 and CD33
Negative for:
- CD45, CD34, and HLA-DR
- MPO, lymphoid markers and TdT

Key clincal and FBC
features of AML with t(1;22) / RBM15::MRTFA ?

HSM and cytopenias
EM disease
Liver fibrosis (Budd Chiari)

Risk stratification of APL

SANZ Risk (WCC and Plt)

High: WCC > 10
Int: WCC < 10 & Plts < 40
Low: WCC < 10 & Plts > 40

Treatment approach to APL

Induction:
* Low/Int Risk = ATRA+ATO / ATRA+Chemo (Dauno)
* High Risk = ATRA+ATO+Gemtuzumab / ATRA+Chemo (7+3)
* Week 4 BM = Cont until blasts < 5%

Consolidation

RQPCR:
Low Risk MRD Negative = FBC q3mo for 2-3yrs
High Risk MRD Negative = Maint Tx if ATRA+Chemo

MRD Positive = Try other induction strategy/HSCT

APL Coagulopathy (Bleeding and Thrombosis)

Bleeding:
* > Fibrinolysis
* Annexin 2 (Receptor for Plasminogen and tPA)
* Granule content degrades vWF and fbg

Thrombosis:
* Endothelial disruption and Blast surface = > TF
* Cytokine release = > TF
* Cancer procoagulant (Activates F10)
* Death of blasts expose Phosphat. Serine

Symptoms of Differentiation Syndrome

* Fever * < BP * Wt gain * Pulmonary: * Dyspnoea * CXR opacities * Pleural/Pericardial effusion * AKI

Treatment of Differentiation Syndrome

* **Dexa** 10mg BD * If Severe - **Stop** ATRA/ATO & **Dauno±Cytarabine** or **HU** (< WCC)

Molecular and IMPT of AML with t(9;22) BCR::ABL1

* p210 * Positive for CD7, CD19 and TdT

DDx for AML with Dysplasia

1. AML t(6;9) 2. MECOM 3. AML-MR

DDx for AML with Monocytoid appearance (M4/M5)

1. NPM1 2. KMT2A (adults) 3. APL (microgranular) 4. NUP98

DDx for AML with M7 fts

1. t(1;22) 2. NUP98 3. MECOM 4. KMT2A (kids) 5. CBFa1::GLIS (RAM IMPT)

DDx for Basophilia

1. Acute basophilic leukaemia 2. t(6;9) 3. AML t(9;22) 4. CML-BP 5. Mast cell leukaemia

WHO 2022 AML defined by morphology types

**M0** (Min differentiation) * 2+ Myeloid markers (CD13, 33 and 117) * *MPO Negative* **M1** (Without Maturation) * *MPO Positive* * < 10% of BM cells are granulocytes **M2** (With Maturation) * < 10% of BM cells are granulocytes * *< 20% Monos* **Acute Basophilic Leukaemia** * Basophils and precursors *20-80%* * Metachromatic blasts on Tolidine Blue * t (x;6) MYB::GATA1 (in male infants) * IMPT: Positive for CD11b, 13, 33, 34, 38, *123 and 203* **M4** (MyeloMonocytic) * Granulocytes > 20% of BM cells * *Monos > 20% but < 80% of BM cells* **M5** (Monocytic/Monoblastic) * *80% + of leukaemic cells are monocytoid* **M6** (Acute erythroblastic leukaemia) * *Blebs and vacuoles* * CD36, CD71 and CD117 (subset) Positive * CD34 and HLA-DR Negative **M7** (Acute Megakaryoblastic Leukaemia) * Adults (TP53, RB1, ASXL1 and DMT3A) * Kids * With DS (RUNX1 and GATA1) * Without DS (CBFa2::GLIS2, RBM15::MRTFA, NUP::KDM5A, KMT2A) * IMPT: * Positive: CD36, CD41, CD42b, CD61, CD33, CD34 (half of cases) and CD4, CD7, CD56 * Negative: MPO * *RAM IMPT: Bright CD56, mod CD34 and variable CD117* - CFBa2::GLIS

Diagnostic criteria for AML-MR

I. **>20% Blasts** II. **No previous:** * Cytotoxic chemo * MPN * AML with defining gentic abnormality * MNGP III. **Hx of MDS**/Overlap or IV. **Defining cytogenetic/molecular** abnormalities

What are the defining cytogenetic abnormalities for AML-MR

1. del5q 2. del7q/mono7 3. del11q 4. del12p 5. del13q/mono13 6. del17p/iso17

What are the defining molecular abnormalities for AML-MR

1. ASXL1, BCOr, EZH2 2. SF3B1, SRSF2 3. STAG2

What are dysplastic features in the BM

I. **Granulocytes**: * Hypogranular * Hypo/hypersegmented * Pseudo Pelger-Huet II. **Megs** * MicroMegs * Monolobated/hypolobated * Loose nuclear fragments III. **Erythroid** * Megaloblastic changes * Karyorrhexis * Nuclear irregularity * Multiple nuclei * Cytoplasmic vacuoles * Ring sideroblasts * NOTE: AML M6 trumps AML-MR

What are the AML with other defined genertic alterations?

I. RUNX1T3(CBFa2)::GLIS2 / **inv16** * M7 - RAM IMPT II. KAT6A::CREBBP / **t(8;16)** * Erythrophagocytosis, Leukaemia cutis and DIC * Monocytoid (Positive CD4, CD14) * Positive for CD13, CD33, CD56, HLA-DR * Negative for CD34 and CD117 III. FUS::ERG / **t(16;21)** * Bad prognosis IV. MNX1::ETV6 / **t(7;12)** V. NPM1::MLF1 / **t(3;5)**

AML with Mixed/Ambiguous Lineage classification WHO 2022

I. **ALAL with defining genetic abN** * MPAL with BCR::ABL1 * MPAL with KMT2A * Other: * MPAL with ZNF384 * ALAL with BCL11B II. **ALAL IMPT defined** * MPAL, B/M * MPAL, T/M * MPAL, Rare * ALAL, NOS * Acute undifferentiated leukaemia

What is Acute Undifferentiated Leuakemia

* **No lineage specific markers** * **Not > 1 maker** for a lineage * **1 Myeloid marker** (CD13, 33, 117) * **Positive for CD34, HLA-DR and TdT** * Variable expression of CD7 or CD56

Lineage specific markers

I. **B**: * Bright CD19 with 1+ (CD10, CD22, CD79a) * Dim CD19 with 2+ II. **T**: * c/sCD3 III. **Myeloid**: * MPO or * Mono 2+ (NSE, CD11c, CD14, CD64, lysozyme)