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?