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Donna B. Adams ANP-BC, ONCDivision of Cellular Therapy
April 21, 2017
FAB Classification
Risk Stratification and Prognosis
Risk Stratification and Prognosis
http://www.cancernetwork.com/cancer-management/acute-leukemias/page/0/2
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.
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
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.
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.
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
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.
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.
FLT3 inhibitors First generation:
Midostaurin
Lestaurtinib (CEP701)
sunitinib
Sorafenib
Second generation: Quizartinib (AC220)
Tandutinib
Crenolanib
Pexidartinib (PLX3397)
Gilteritinib (ASP2215)
IDH1/2 inhibitors AG-120 (IDH1)
AG-221 (Enasidenib)-IDH2 inhibitor
AG-881
Immune check point inhibitors PD-1/PD-L1
Nivolumab
Pembrolizumab
Atezolizumab
Durvalumab
ipilimumab (CTLA-4 inhibitor )
Other inhibitors BET
ABBV-075
Papaemmanuil, E, et al. N Engl J Med. 2016; 374: 2209-2221.
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
http://www.targetedonc.com/publications/targeted-therapies-cancer/2017/2017-february/immune-checkpoint-
approaches-in-aml-and-mds-a-next-frontier
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
Monitoring for MRD Multiparameter flow cytometry (MFC)
RT-PCR
Next-generation sequencing
AML PANEL at Duke Cytogenetics
FISH: AML panel
FLT3
NPM1
CEBPA
IDH1/2
P53
Tumor banking
NGS/Foundation One testing
QUESTIONS?