SM_269b: Acute Myeloid Leukemias Flashcards
Describe clonal proliferation of immature myeloid precursors
Clonal proliferation of immature myeloid precursors
AML has ___ blasts
AML has > 20% blasts
AML usually occurs at age ___
AML usually occurs at age 65
- Slight male predominance
- Poor survival
- Rare in children but better survival
Therapy-related AML occurs due to ___ and ___
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
Describe AML clinical presentation
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
Describe oncologic emergencies in AML clinical presentation
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
___, ___, ___, ___, and ___ are prognostic factors of AML
Age, performance status, history of prior cytotoxic therapy or MDS, cytogenetics and gene mutations, and leukocyte count at presentation are prognostic factors of AML
Describe use of bone marrow biopsy
Bone marrow biopsy
- Aspirate smear and core biopsy for morphology
- Flow cytometry
- Cytogenetics + FISH
- Molecular testing
AML diagnosis requires ___ and ___
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)
Auer rods occur in ___
Auer rods occur in AML
Describe AML blast morphology
AML blast morphology
- Myeloblasts w/ Auer rods
- Monoblasts
- Promonocytes
- Promyelocytes
This is ___
AML
AML cytochemistry involves ___ or ___
AML cytochemistry involves MPO+ myeloblasts or NSE+ monoblasts
Describe antigens expressed by myeloid cells
Antigens expressed by myeloid cells
- Precursor markers: CD34, CD117
- Granulocytic markers: CD13, CD33, MPO
- Monocytic markers: CD14, CD64
Morphological classification incorporates ___ and ___
Morphological classification incorporates type of cell and degree of maturity
Describe chromosomal abnormalities in AML
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
Acute promyelocytic leukemia involves ___
Acute promyelocytic leukemia involves t(15;17) (q22;q12)
Describe acute promyelocytic leukemia (APL) with t(15;17) (q22;12) / PML-RARA
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)
This is ___
APL with t(15;17) (q22;12)
APL with t(15;17) (q22;a12) involves ___ that ___
APL with t(15;17) (q22;a12) involves PML-RARA fusion that blocks differentiation beyond promyelocyte stage
In APL, when ____ and ____ bind to PML-RARA, there is no differentiation beyond promyelocyte stage
In APL, when ATRA and ATO bind to PML-RARA, there is no differentiation beyond promyelocyte stage
Describe AML with t(18;21)
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
Describe AML with inv(16)
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
Describe gene mutations in AML
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
AML involves ___ pathogenesis
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)
AML diagnostic mutations are ____, ____, and ____
AML diagnostic mutations are NPM1, CEBPA, and RUNX1
AML prognostic mutations are ___ and ___
AML prognostic mutations are FLT3 and KIT
Describe nucleophosmin 1 (NPM1)
Nucleophosmin 1 (NPM1)
- Nucleolar phosphopotein
- Shuttles basic proteins between nuclear and cytoplasmic compartments
- Abnormal cytoplasmic localization of NPM1 protein led to discovery of mutations
Describe clinical implications of NPM1 mutations
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
Describe CCAAT / enhanced binding protein alpha-CEBPA mutations
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)
___ and NOT smCEBPA confer favorable outcomes in AML
dmCEBPA and NOT smCEBPA confer favorable outcomes in AML
Describe FLT3 mutation clinical implications in AML
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)
Labeling AML with a single mutation is ____
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
Describe AML treatment
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
