Update Diagnostik und Prognostische

Faktoren bei AML

Hartmut Döhner

Ärztlicher Direktor, Klinik für Innere Medizin III

Sprecher, Comprehensive Cancer Center Ulm

Universität Ulm

DGHO Jahrestagung

Hamburg, 11. Oktober 2014

WHO 2008 AML Classification

Swerdlow SH, et al.

Lyon, France: IARC Press. 2008.

AML with recurrent genetic abnormalities:

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1

AML with inv(16)(p13.1q22); CBFB-MYH11

APL with t(15;17)(q22;q12); PML-RARA

AML with t(9;11)(p22;q23); MLLT3-MLL

AML with inv(3)(q21q26.2); RPN1-EVI1

AML with t(6;9)(p23;q34); DEK-NUP214

AML with t(1;22)(p13;q13); RBM15-MKL1

Provisional entity: AML with mutated NPM1

Provisional entity: AML with mutated CEBPA

WHO 2015 AML Classification

AML with recurrent genetic abnormalities:

AML with t(8;21)(q22;q22); RUNX1-RUNX1T1

AML with inv(16)(p13.1q22); CBFB-MYH11

APL with t(15;17)(q22;q12); PML-RARA

AML with t(9;11)(p22;q23); MLLT3-MLL

AML with inv(3)(q21q26.2); RPN1 GATA2-EVI1

AML with t(6;9)(p23;q34); DEK-NUP214

AML with t(1;22)(p13;q13); RBM15-MKL1

Provisional entity: AML with mutated NPM1

Provisional entity: AML with biallelic CEBPA mutation

Provisional entity: AML with RUNX1 mutation

Gröschel S, Sanders MA, et al Cell. 2014;157(2):369-81.

AML with inv(3)(q21q26.2); GATA2-EVI1

Proposed mechanism of EVI1 and GATA2

deregulation in myeloid neoplasms with inv(3)/t(3;3)

EVI1 GATA2

EVI1 GATA2

Normal chr3

inv(3)

Deregulated monoallelic EVI1 expression from inv(3)

Monoallelic GATA2 expression at reduced levels from

normal chromosome 3

Hemizygous mutations of GATA2 in 15% of AML with inv(3) (Gröschel S, Sander MA, et al. Manuscript submitted)

Gröschel S, Sanders MA, et al Cell. 2014;157(2):369-81.

3q21 3q26.2

TAD1 TAD2 BR LZ

42 kDa 30 kDa

DNA-binding and

dimerization

Transcription

activation

• Double (bi-allelic) mutations in ~1/2 of cases (mostly N- and C-

terminal), single (mono-allelic) mutations in ~1/2 of cases

N-term C-term

• Favorable prognosis is only conferred by CEBPA double (but not

single) mutations

Wouters B, et al. Blood. 2009;26;113:3088-91; Pabst T, et al. Br J Cancer. 2009;100:1343-46;

Hou HA, et al. Br J Cancer. 2009;101:738-40; Dufour A, et al. J Clin Oncol. 2010;28:570-7;

Green CL, et al. J Clin Oncol. 2010; 28:2739-47; Taskesen E, et al. Blood. 2011;117:2469-75;

Hollink IHIM, et al. Haematologica. 2011;96;384. Schlenk RF, et al. Blood 2013;122:1576-82;

AMLSG Meta-Database, unpublished.

AML with Mutated CEBPA

AMLSG Meta-Database. Unpublished data (03-2014).

CEBPA mutation status available: n=3510

CEBPAdm n=124 (3.5%)

CEBPAsm n=125 (3.5%)

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

0,09

0,1

1 2 3 4

%dm

%sm

≤45 45-60 60-75 >75

9.2%

4.7% 5.6%

3.6% 1.6%

1.2%

6.7%

5.8%

% dm

% sm

Frequency of All CEBPA Mutations by Age

*Not all cases tested for all mutations

CEBPAdm CEBPAsm p-value n=124* n=125*

NPM1 4 (3%) 48 (40%) <0.001

RUNX1 2 (2%) 10 (12%) 0.014

FLT3-ITD 14 (11%) 34 (30%) <0.001

FLT3-TKD 5 (4%) 3 (2.5%) 0.023

DNMT3A 3 (3%) 26 (33%) <0.001

ASXL1 1 (1%) 8 (10%) 0.026

GATA2 36 (32%) 4 (4%) <0.001

IDH1 2 (2%) 6 (7%) 0.104

IDH2-R140 4 (4%) 8 (10%) 0.232

IDH2-R172 0 1 (1%)

MLL-PTD 2 (2%) 3 (4%) 0.451

TET2 2 (6%) 1 (5%)

Association With Other Gene Mutations

AMLSG Meta-Database. Unpublished data (03-2014).

inv

(16)

t(8;2

1)

t(15;1

7)

AML With CEBPAdm Has a Distinct Gene Expression Profile

t(15;17)

inv(16)

t(8;21)

CEBPAdm

CE

BP

Ad

m

CE

BP

Asm

Unsupervised GEP Analysis

674 AML cases from

AMLSG and HOVON

Taskesen E, Bullinger L, et al. Blood. 2011;117(8):2469-75.

674 AML cases

Taskesen E, Bullinger L, et al. Blood. 2011;117(8):2469-75.

Outcome of AML with CEBPAdm vs. CEBPAsm in

Younger Adults with Cytogenetically-Normal AML

1182 CN-AML, 16-60 yrs

*

Multivariate analysis (OS)

HR p-value

CEBPAsm* 0.70 0.10

CEBPAdm 0.36 <0.001

FLT3-ITD 1.78 <0.001

FLT3-TKD 0.84 0.28

NPM1 0.56 <0.001

WBC 1,35 <0.001

Age 1.02 <0.001

* 40% of CEBPAsm have NPM1 mutation

AML with RUNX1 Mutation – A New Entity?

• RUNX1 involved in recurrent balanced rearrangements, such as

t(8;21)(q22;q22) or t(3;21)(q26.2;q22)

• Recurrent intragenic RUNX1 mutations in MDS (5-10%), AML (5-

18%), and T-ALL (18%)

RUNX1 mutations associated with

• MDS/AML after radiation exposure (incl. atomic bomb survivors) Harada H, et al. Blood. 2003 (Hiroshima / Nagasaki); Zharlyganova D, et al. J Radiat Res. 2008 (Semipalatinsk).

• MDS/AML of Fanconi anemia pts. Quentin S, et al. Blood. 2011.

• MDS/AML of congenital neutropenia pts. (64.5%); cooperation with

CSF3R mutations Skokowa J, et al. Blood. 2014.

• Autosomal dominant familial platelet disorder with predisposition to

AML (FPD/AML) (germline) Song WJ, et al. Nat Genet. 1999.

AML with RUNX1mut: Clinical Characteristics

No. of pts. n=2194 n=245 (10%)

Age (yrs) 53.6 59.2 <0.001

Gender (male, %) 51.8 60.0 0.015

RUNX1wt RUNX1mut p-value

Platelets (x109/L) 53.0 67.0 0.007

LDH levels (U/L) 418 322 <0.001

FAB M0 (%) 5.1 13.8 0.046

Type of AML (%)

de novo 88.5 79.5 <0.001

s-AML 5.5 15.6 <0.001

t-AML 6.0 4.9 0.57

Gaidzik V, Teleanu V, et al. Manuscript in preparation.

Increasing Frequency of RUNX1mut with Older Age

75 80 85 90 95 100

<20

20-29

30-39

40-49

50-59

60-69

≥70

%

Age (

Years

)

RUNX1wt RUNX1mut

n=248

n=558

n=675

n=478

n=316

n=137

n=27

n=2439

15%

14%

10%

8%

6%

7%

8% 16-20

RUNX1mut Defines a Distinct Entity of AML

RUNX1 mutations define a cluster, that is, they are almost entirely

mutually exclusive of the other recurrent genetic abnormalities

RUNX1 mutation is the second most frequent lesion in the category

„AML with recurrent genetic abnormalities“

Gaidzik V, Teleanu V, et al. Manuscript in preparation.

Poor Prognostic Impact of RUNX1 Mutation

Tang JL, et al. Blood. 2009;114:5352-5361.

Taiwan National Hospital

Mendler JH, et al. J Clin Oncol. 2012;30:3109-3118.

CALGB

• de novo AML only; younger and older adults

• RUNX1mut = independent poor prognostic factor for OS

• de novo CN-AML only; younger and older adults

• RUNX1mut = independent poor prognostic factor for OS

18-60 yrs >60 yrs

RUNX1mut: A Continuum of Myeloid Neoplasms

MDS AML RAEB I RAEB II

e.g., Papaemmanuil E, et al. Blood. 2013;21:3616-3627.

Bejar R, et al. N Engl J Med. 2011;364:2496-2506.

Haferlach T, et al. Leukemia. 2014;28:241-247.

e.g., Mendler JH, et al. J Clin Oncol. 2012;30:3109-3118.

Gaidzik V, et al. J Clin Oncol. 2011;29:1364-72.

Tang JL, et al. Blood. 2009;114:5352-5361.

Myeloid neoplasm with RUNX1 mutation

Myeloid neoplasm with RUNX1mut / ASXL1mut genotype

…

Schlenk RF, Döhner K, et al. N Engl J Med. 2008;358(18):1909-18.

Impact of Allogeneic HSCT in CN-AML

Molecular favorable genotypes

AML with NPM1mut / FLT3-ITDneg

Molecular unfavorable genotypes

e.g. AML with FLT3-ITD

Schlenk RF, et al. Blood. 2014 Sept 30. [Epub ahead of print].

Evaluation of the prognostic and predictive impact of FLT3-ITD

allelic ratio and insertion site of FLT3 internal tandem

duplications, as well as concurrent gene mutations with regard

to type of postremission therapy

323 patients with FLT3-ITD, age 18-60 yrs

Assessment of FLT3-ITD allelic ratio and insertion site

Postremission therapy:

Intensive chemotherapy n=121

Autologous transplantation n=17

Allogeneic transplantation n=93

Impact of allelic ratio and insertion site of

FLT3-ITD with respect to allogeneic SCT

n=138

FLT3-ITD Allelic Ratio and Outcome

Schlenk RF, et al. Blood. 2014 Sept 30. [Epub ahead of print].

0 0.2 0.4 0.6 0.8 1.0

0.5

1.0

1.5

2.0

2.5

3.0

Allelic Ratio

Sta

nd

ard

ize

d lo

g-r

an

k s

tati

sti

cs

Optimal cut-point for the

allelic ratio by maximally

selected log-rank statistics

Overall survival according

to FLT3-ITD allelic ratio

(excl. allogeneic SCT)

Schlenk RF, et al. Blood. 2014 Sept 30. [Epub ahead of print].

Time (years)

Overa

ll surv

ival (%

)

0 1 2 3 4 5 6 7 8 9 10

0

25

50

75

100

Allogeneic HSCT

n=48

p=0.64

Allelic ratio <0.51

FLT3-ITD Allelic Ratio and Outcome

Time (years)

Overa

ll surv

ival (%

)

0 1 2 3 4 5 6 7 8 9 10

0

25

50

75

100

Allogeneic HSCT

n=45

p=0.03

Allelic ratio ≥0.51

Allogeneic hematopoietic stem-cell transplantation (HSCT) in

first complete remission is superior compared to

chemotherapy/autologous HSCT in patients (n=630) with

intermediate-risk cytogenetics acute myeloid leukemia

lacking mutations in NPM1, FLT3-ITD, and CEBPA:

A joint study of AMLSG, CETLAM and Acute Leukemia

Working Party of EBMT.

Jordi Esteve1, Myriam Labopin2, Marta Pratcorona1, Felicitas Thol3,

Salut Brunet4, Michael Heuser5, Gudrun Göhring6, Arnold Ganser5,

Konstanze Döhner3, Peter Paschka3, Verena Gaidzik3, Arnaud

Pigneux7, Gerard Socié8, Jan Cornelissen9, Michel Attal10, Jean Henri

Bouhris11, John Maertens12, Didier Blaise13, Mar Tormo14, Josep

Maria Ribera15, Montserrat Hoyos4, Jordi Sierra4, Mohamad Mohty2,

Arnon Nagler16, Hartmut Döhner3, and Richard Schlenk3

Presentation at ASH 2014

Genetic Biomarker Stratification

Fav t(8;21)(q22;q22); RUNX1-RUNX1T1

inv(16)(p13.1q22); CBFB-MYH11

Mutated NPM1 without FLT3-ITD (nl karyotype)

Mutated CEBPA (nl karyotype)

Int-I Mutated NPM1 and FLT3-ITD (nl karyotype)

Wild type NPM1 and FLT3-ITD (nl karyotype)

Wild type NPM1 without FLT3-ITD (nl karyotype)

Int-II t(9;11)(p22;q23); MLLT3-MLL;

cytogenetic abnormalities not classified as favorable or

adverse

Adv inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1

t(6;9)(p23;q34); DEK-NUP214; t(v;11q23); MLL rearranged;

-5 or del(5q); -7; abn(17p); complex karyotype (≥3)

International AML Recommendations (ELN)

Blood. 2010;115:453-474.

Only NPM1, CEBPA, and FLT3 in clinical practice …

Diagnosis/

Prognosis

ASXL1

DNMT3A

RUNX1

TP53

…

Therapy

FLT3

KIT

IDH1

IDH2

MLL

ELN 2015

E. Papaemmanuil

M. Gestung

P. Campbell

Cambridge

J. Krauter

M. Heuser

G. Göhring

F. Thol

B. Schlegelberger

A. Ganser

MHH, Hannover

A. Corbacioglu

A. Dolnik

S. Gröschel

S. Kapp-Schwörer

J. Krönke

F. Kuchenbauer

M. Kühn

F. Rücker

D. Späth

F. Theis

V. Teleanu

L. Bullinger

K. Döhner

V. Gaidzik

P. Paschka

R.F. Schlenk

Ulm University

R. Larson

G. Marcucci

C. Bloomfield

CALGB

R. Delwel

P. Valk

B. Löwenberg

Rotterdam

A. Gedman

I. Radtke

J. Downing

Memphis