269. AML

Question 1

AML

• define
• epi
• RF
• CP
• 5 prognostic factors

Answer 1

AML: clonal proliferation of immature myeloid precursors
Epi: older males (65yo median), poor survival (5% 5 year survival), rare in children but better survival
RF: prior hx of chemo, radiation (therapy related has WORSE PRoGNosis), heme malignancy (MDS, MPN); benzenee exposure, cigarette smoking; down syndrome, fanconi anemia
CP: General sx: fever, fatigue, night sweats; bone marrow failure: anemia, thrombocytopenia, neutropenia; extramedullary tissue infiltration (Gingiva, skin, renal, lung, CNS, orbit)
- Tumor Lysis Syndrome (hyperuricemia, hyperK, hypoCa, renal failure, arrythmia, hypoxia, dyspnea, AMS)
- Coag Abnormalities (DIC)

1. Age
2. Performance Status
3. Hx of prior cytotoxic therapy or MDS
4. Cytogenetics and gene mutations
5. Leukocyte count at presentation

Question 2

AML Dx

• morphology
• immunophenotype
• cytogenetics

Answer 2

Dx: >20% blasts in BM or PB
Morph: evidence of myeloid differentiation
- Auer Rods
- Cytochem: MPO+ or NSE+
BM: hypercellular sheets of blasts
IHC: CD34+, CD117+

Cytogenetics: >50% AML have abnormality, MOST IMPORTANT PREDICTOR OF OUTCOME

1. Low Risk: Acute Promyelocytic Leukemia with t(15;17)/PML-RARA (blocks differentiation of immature cells): good prognosis, highest cure rate (All Trans Retinoic Acid, Arsenic Trioxide (ATO)), CP: DIC
   - in young pt
   - many auer rods, bilobed nuclei
2. Cord Binding Factor AML
   - either t(8;21) or inv(16)
   - in young adults, GOOD prognosis
   - Kit mutation = higher risk of relapse
   - t(8;21) = large blasts with Auer rods
   - inv(16) = atypical eosinophils (blue cytoplasmic granules)

Question 3

AML: Molecular Alterations and Tx

• what is the “two hit” pathogenesis paradigm
• what are three gene mutations that are diagnostic in AML and two gene mutations that are prognostic?
• tx

Answer 3

First hit: promotes proliferation (RTK genes)
Second hit: impairs differentiation (driver mutation)

Diagnostic:

1. NPM1 - causes abnormal localization of NPM1 protein to cytoplasm, IMPROVES OUTCOMES
2. CEBPA - favorable outcomes if double mutation
3. RUNX1

Prognostic:

1. FLT3 - WORSE outcomes (target tx with TKIs)
2. KIT

Tx: induction chemotx with post-remission chemotx or HSC transplant (consider new targeted therapies)