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Donna B. Adams ANP-BC, ONCDivision of Cellular Therapy
April 21, 2017
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FAB Classification
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Risk Stratification and Prognosis
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Risk Stratification and Prognosis
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http://www.cancernetwork.com/cancer-management/acute-leukemias/page/0/2
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WHO 2016 revised classification system
Arber D, The 2016 revision to the World Health Organization classification of myeloid neoplasm and acute leukemia., Blood, 19 May 2016, vol 127, number 20.
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Smith ML, et al. Blood Rev. 2011;25:39-51.
Independent Prognostic Variables in AML
MRC/NCRI AML Trials: OS
100
80
40
20
00 1 2
Pa
tie
nts
Ali
ve
(%
)
3 4 5 6 7 8 9 10
t(15;17) (n = 330)t(8;21) (n = 247)inv(16)/t(16;16) (n = 154)CEBPα biallelic (n = 47)FLT3-ITD WT/NPM1 mut (n = 248)Other intermediate (n = 471)FLT3-ITD mut/NPM1 WT (n = 100)Other adverse (n = 130)
76%
58%52%51%
26%
11%
Yrs From Entry
60
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Cytogenetic/Molecular alterations
Core binding factor (CBF) cytogenetically characterized by either the t(8;21) or the
inv.(16)/t(16;16)
APL t(15;17)(q22;q12); PML-RARA.
MLL-AML (11q23)
.
Prada-Arismendy J, et al, Molecular biomarkers in acute myeloid leukemia, Blood Rev (2016),
http://dx.doi.org/10.1016/j.blre.2016.08.005.
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Point mutations in specific genes FLT3
The most important mutation found in this gene is the internal tandem duplication (FLT3-ITD)
NPM1 alterations of this gene are present in high frequency in
AML patients, ranging between 25 and 53%, being more frequent in patients with a normal karyotype (between 46 and 67%).
CEBPA
TP53
DNMT3A
IDH1/2
TET proteins
Prada-Arismendy J, et al, Molecular biomarkers in acute myeloid leukemia, Blood Rev (2016),
http://dx.doi.org/10.1016/j.blre.2016.08.005.
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Prognostic Effect of CEBPα Mutations in AML:OS
Wouters BJ, et al. Blood. 2009;113:3088-3091.
CEBPαmut vs CEBPαwt CEBPαdouble-mut vs CEBPαsingle-mut
vs CEBPαwt
Pro
po
rtio
n R
em
ain
ing
Ali
ve
Pro
po
rtio
n R
em
ain
ing
Ali
ve
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60
Mos
CEBPα mut (n = 38)
CEBPαwt (n = 486)
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48
Mos
CEBPαsingle-mut (n = 12)
CEBPαwt (n = 486)
CEBPαdouble-mut (n = 26)
60
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Epigenetics
Epigenetics
Proteomics
Prada-Arismendy J, et al, Molecular biomarkers in acute myeloid leukemia, Blood Rev (2016),
http://dx.doi.org/10.1016/j.blre.2016.08.005.
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Prada-Arismendy J, et al, Molecular biomarkers in acute myeloid leukemia, Blood Rev (2016),
http://dx.doi.org/10.1016/j.blre.2016.08.005.
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FLT3 inhibitors First generation:
Midostaurin
Lestaurtinib (CEP701)
sunitinib
Sorafenib
Second generation: Quizartinib (AC220)
Tandutinib
Crenolanib
Pexidartinib (PLX3397)
Gilteritinib (ASP2215)
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IDH1/2 inhibitors AG-120 (IDH1)
AG-221 (Enasidenib)-IDH2 inhibitor
AG-881
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Immune check point inhibitors PD-1/PD-L1
Nivolumab
Pembrolizumab
Atezolizumab
Durvalumab
ipilimumab (CTLA-4 inhibitor )
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Other inhibitors BET
ABBV-075
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Papaemmanuil, E, et al. N Engl J Med. 2016; 374: 2209-2221.
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Patel JP, et al. N Engl J Med. 2012;366:1079-1089.
Prognostic Relevance of Integrated Genomic ProfilingGene Overall Frequency, %
FLT3 (ITD, TKD) 37 (30, 7)
NPM1 29
DNMT3A 23
NRAS 10
CEBPα 9
TET2 8
WT1 8
IDH2 8
IDH1 7
KIT 6
RUNX1 5
MLL-PTD 5
ASXL1 3
PHF6 3
KRAS 2
PTEN 2
TP53 2
HRAS 0
EZH2 0
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http://www.targetedonc.com/publications/targeted-therapies-cancer/2017/2017-february/immune-checkpoint-
approaches-in-aml-and-mds-a-next-frontier
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Progress in defining the molecular landscape of AML. Timing of the identification of leukemic
fusion genes and mutations underlying the pathogenesis of AML.
David Grimwade et al. Blood 2016;127:29-41
©2016 by American Society of Hematology
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Monitoring for MRD Multiparameter flow cytometry (MFC)
RT-PCR
Next-generation sequencing
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AML PANEL at Duke Cytogenetics
FISH: AML panel
FLT3
NPM1
CEBPA
IDH1/2
P53
Tumor banking
NGS/Foundation One testing
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QUESTIONS?