AML Flashcards
FLT3:
- Present in nearly 1/3 of AML patients
- Results in constitutive activation and downstream signaling thru RAS/RAF/MEK pathway and PI3K pathway
- More frequent in younger adults
- Associated with higher WBC count and blast %; also with increased risk of relapse and decreased OS
- FLT3 variant allele frequency (VAF) should also be checked as VAF <0.5 translates to relatively improved outcomes
Multikinase inhibitors: sunitinib, sorafenib, midostaurin, taurtinib
- Dirty inhibitors” due to multipathways affected
- Sorafenib-Some studies suggest using with 7+3 in young AML patients regardless of mutational status; one study showed 5 year EFS 40 vs 22% respectively regardless of mutational status
- Midostaurin- RATIFY trial: Pts aged 18-60 with FLT3 mutated AML treated with 7 + 3 + midostaurin vs placebo showed 5 year OS 50.8 vs 43.1
- Has anti-cKIT, PDGF-R, VEGF, protein kinase C activity as well
RAS:
- Present in 10-15% of cases
- Includes NRAS, KRAS, PTPN11, NF1 leading to aberrant signaling thru RAS/RAF/MEK pathway
- Acquisition of RAS mutations can be seen in MDS to AML progression and portends to poor diagnosis in this scenario
- NRAS mutations are FAVORABLE with comutations in DNMT3A and NPM1
- Development of MEK, PI3K inhibitors are used for these mutations however development of resistance to single agent therapy is common due to activation of bypass pathways
KIT:
Found in core-binding factor mutations; associated with poor prognosis
Epigentic Modifier Mutations
identified in >50% of AML; likely that these mutations promote clonal outgrowth but are insufficient to initiate leukemic transformation without other mutational events
DNMT3A:
R882 missense mutation is most common mutation
- Mutated in 20% of de novo AML; one of the most common mutations overall in AML
- R882 missense mutation causes impaired HSC differentiation, increased self-renewal, and a differentiation block
- Frequently occurs with advanced age
- Coexists with NPM1, FLT3-ITD, or IDH1 mutations
- Prognostic significance is unclear of DNMT3A mutation
TET2: (Ten-eleven transolocation-2)
- Occurs in 10-20% of MDS and AML; more common in CML
- Impedes breakdown of 5-methylcytosine leading to increased HSC self-renewal, impaired myeloid differentiation, and hypermethylated epigenetic signature
- Prognosis is variable with these mutations
ASXL1: (Additional sex comb-like 1)
- Loss of function mutation occurs in 10-20% of AML
- Associated with advanced age, antecedent malignancy, concurrent RUNX1 mutation
- Associated with poor outcomes
IDH1/IDH2 (Isocitrate dehydrogenase):
- Catalyzes oxidative decarboxylation
- Catalyzes oxidative decarboxylation of isocitrate to a-ketoglutarate in the Kreb’s cycle
- Occurs in 20% of AML; more frequent in older age, intermediate-risk, and seen with NPM1 mutations
- Mutations cause decreased a-ketoglutarate which is needed for DNA hydroxymethylation, histone demethylase activity, and B-cell lymphoma 2 (Bcl-2) dependent mitochondrial respiration
- IDH-R172 has unique gene expression profile with fewer co-mutations and has favorable prognosis with intensive chemotherapy
Nucleophosmin mutations (NPM1):
chaperone protein that is one of the most common mutations seen in AML (50%); if without FLT3-ITD - favorable response to chemotherapy even in older patients; if with FTL3-ITd - markedly poor prognosis
CEBPA:
- Unique entity associated with favorable prognosis
- Occurs in 10% of AML in predominantly younger patients and N
RUNX1:
- Transcription factor essential during embryogenesis in HSC generation
- Associated with POOR prognosis:
- Associated with antecedent hematologic disorders or secondary AML
- Advanced age
- Worse cytopenias at diagnosis
- Shorter OS
- Chemoresistance to therapy
GATA2:
- Encodes a zinc-finger transcription factor with major role in hematopoesis
- 5% of all AML patients have this
- Does not impact overall favorability of outcome
Markers that identify secondary AML
ASXL1, SRSF2, SF3B1, U2AF1, ZRSR2, EZH2, BCOR, STAG2
