SM_269b: Acute Myeloid Leukemias

Question 1

Describe clonal proliferation of immature myeloid precursors

Answer 1

Clonal proliferation of immature myeloid precursors

Question 2

AML has ___ blasts

Answer 2

AML has > 20% blasts

Question 3

AML usually occurs at age ___

Answer 3

AML usually occurs at age 65

• Slight male predominance
• Poor survival
• Rare in children but better survival

Question 4

Therapy-related AML occurs due to ___ and ___

Answer 4

Therapy-related AML occurs due to radiation / alkylating agents (cyclophosphamide, bendamustine) and topoisomerase-II inhibitors (etoposide, anthracyclines)

• Radiation / alkylating agents (cyclophosphamide, bendamustine): del 5 and del 7, 5-10 years latency
• Topoisomerase-II inhibitors (etoposide, anthracyclines): 11q23 translocation, 1-5 years after exposure

Question 5

Describe AML clinical presentation

Answer 5

AML clinical presentation

• General: fatigue, sweats, fever
• Bone marrow failure
  
  • Anemia (pallor, fatigue, SOB)
  • Thrombocytopenia (bruising, bleeding)
  • Neutropenia (infection)
• Extramedullary tissue infiltration: gingiva, skin, renal, lung, CNS, orbit

Question 6

Describe oncologic emergencies in AML clinical presentation

Answer 6

Oncologic emergencies in AML clinical presentation

• Hyperleukocytosis (leukostasis) -> tumor lysis syndrome
  
  • Hyperuricemia, hyperkalemia, hypocalcemia
  • Acute renal failure
  • Cardiac arrhythmia
  • Hypoxia, dyspnea
  • Altered mental status
• Coagulation abnormalities: disseminated intravascular coagulation

Question 7

___, ___, ___, ___, and ___ are prognostic factors of AML

Answer 7

Age, performance status, history of prior cytotoxic therapy or MDS, cytogenetics and gene mutations, and leukocyte count at presentation are prognostic factors of AML

Question 8

Describe use of bone marrow biopsy

Answer 8

Bone marrow biopsy

• Aspirate smear and core biopsy for morphology
• Flow cytometry
• Cytogenetics + FISH
• Molecular testing

Question 9

AML diagnosis requires ___ and ___

Answer 9

AML diagnosis requires ≥ 20% blasts in bone marrow or blood and evidence of myeloid differentiation

• Auer rods
• Cytochemistry: MPO+ or NSE+
• Expression of myeloid-associated markers by immunophenotyping (flow cytometry)

Question 10

Auer rods occur in ___

Answer 10

Auer rods occur in AML

Question 11

Describe AML blast morphology

Answer 11

AML blast morphology

• Myeloblasts w/ Auer rods
• Monoblasts
• Promonocytes
• Promyelocytes

Question 12

This is ___

Answer 12

AML

Question 13

AML cytochemistry involves ___ or ___

Answer 13

AML cytochemistry involves MPO+ myeloblasts or NSE+ monoblasts

Question 14

Describe antigens expressed by myeloid cells

Answer 14

Antigens expressed by myeloid cells

• Precursor markers: CD34, CD117
• Granulocytic markers: CD13, CD33, MPO
• Monocytic markers: CD14, CD64

Question 15

Morphological classification incorporates ___ and ___

Answer 15

Morphological classification incorporates type of cell and degree of maturity

Question 16

Describe chromosomal abnormalities in AML

Answer 16

Chromosomal abnormalities in AML

• In over half of adult AML
• Most important predictor of outcome
• Define diagnostic categories in WHO classification: AML with recurrent cytogenetic abnormalities, AML with myelodysplasia related changes

Question 17

Acute promyelocytic leukemia involves ___

Answer 17

Acute promyelocytic leukemia involves t(15;17) (q22;q12)

Question 18

Describe acute promyelocytic leukemia (APL) with t(15;17) (q22;12) / PML-RARA

Answer 18

Acute promyelocytic leukemia (APL) with t(15;17) (q22;12) / PML-RARA

• Young patient with low blood counts and bleeding / bruising
• Disseminated intravascular coagulopathy
• t(15;17) (q22;a12), PML-RARA
• Treated with all-trans-retinoic acid and arsenic trioxide
• High cure rate (most curable AML)

Question 19

This is ___

Answer 19

APL with t(15;17) (q22;12)

Question 20

APL with t(15;17) (q22;a12) involves ___ that ___

Answer 20

APL with t(15;17) (q22;a12) involves PML-RARA fusion that blocks differentiation beyond promyelocyte stage

Question 21

In APL, when ____ and ____ bind to PML-RARA, there is no differentiation beyond promyelocyte stage

Answer 21

In APL, when ATRA and ATO bind to PML-RARA, there is no differentiation beyond promyelocyte stage

Question 22

Describe AML with t(18;21)

Answer 22

AML with t(18;21)

• Molecular: RUNX1-RUNX1T1
• Young adults
• May present with myeloid sarcoma
• Good prognosis
• Kit mutation: 20-30% of cases (higher risk with relapse)
• Morphology: large blasts with long sharp Auer rods

Question 23

Describe AML with inv(16)

Answer 23

AML with inv(16)

• Molecular: CBFB-MYH11
• Young adults
• May present with myeloid sarcoma
• Good prognosis
• Kit mutation: 30-40% of cases (higher risk of relapse)
• Morphology: atypical eosinophils

Question 24

Describe gene mutations in AML

Answer 24

Gene mutations in AML

• 50% of AML have no defining chromosomal abnormality
• Clinical utility of detecting mutations in AML: diagnosis (disease defining mutations), prognosis, targeted therapy, and disease monitoring

Question 25

AML involves ___ pathogenesis

Answer 25

AML involves two-hit pathogenesis * Class 1 (promote proliferation): RTK genes (FLT3, KIT, RAS) * Class 2 (impair differentiation): chromosomal abnormalities such as t(8;21) or inv (16), gene mutations (CZEBPA, RUNX1, MLL, NPM1)

Question 26

AML diagnostic mutations are \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 26

AML diagnostic mutations are NPM1, CEBPA, and RUNX1

Question 27

AML prognostic mutations are ___ and \_\_\_

Answer 27

AML prognostic mutations are FLT3 and KIT

Question 28

Describe nucleophosmin 1 (NPM1)

Answer 28

Nucleophosmin 1 (NPM1) * Nucleolar phosphopotein * Shuttles basic proteins between nuclear and cytoplasmic compartments * Abnormal cytoplasmic localization of NPM1 protein led to discovery of mutations

Question 29

Describe clinical implications of NPM1 mutations

Answer 29

NPM1 mutations * Most common genetic aberration in AML * Often seen in AML with monocytic differentiation * More often in adults * Prognosis: favorable outcomes in absence of cytogenetic abnormalities and FLT3-ITD * Mutations stable over the course of disease: useful in monitoring disease and detection of MRD

Question 30

Describe CCAAT / enhanced binding protein alpha-CEBPA mutations

Answer 30

CCAAT / enhanced binding protein alpha-CEBPA mutations * 5-10% of AML * Confer favorable outcomes in cytogenetic negative AML * Two types of mutations: biallelic (dmCEBPA), monoallelic (smCEBPA)

Question 31

\_\_\_ and NOT smCEBPA confer favorable outcomes in AML

Answer 31

dmCEBPA and NOT smCEBPA confer favorable outcomes in AML

Question 32

Describe FLT3 mutation clinical implications in AML

Answer 32

FLT3 mutation clinical implications in AML * Prognosis: FLT3-ITD confers worse outcomes, impact of FLT3-KD mutations remains controversial * Therapy: stem cell transplantation, tyrosine kinase inhibitors (midostaurin)

Question 33

Labeling AML with a single mutation is \_\_\_\_

Answer 33

Labeling AML with a single mutation is inadequate * Mutations do not occur in isolation: genetic complexity, integrated genomic profiling * AMLs are spatially and temporally heterogeneous: genetic heterogeneity and clonal evolution

Question 34

Describe AML treatment

Answer 34

AML treatment depends on type of leukemia, risk factors, and targetable mutations * General: induction chemo followed by post-remission chemo (consolidation) or hematopoietic stem cell transplantation * FLT3: midostaurin * IDH1: ivosidenib * IDH2: enasidenib