Beruflich Dokumente
Kultur Dokumente
AndrewWei
AlfredHospital
ACUTELEUKAEMIAandMDS
12/06/2014
FBE
12/06/2014
BMAT
Normal
Leukaemia
12/06/2014
Myeloperoxidase
Flow cytometry
Rapid diagnosis of
AML
Lineage designation
Monitoring for residual
disease
12/06/2014
Flow cytometry
Lymphocytes
Monocytes
Granulocytes
Myeloblasts
Lymphoblasts
Rapid diagnosis of
AML
Lineage designation
Monitoring for residual
disease
Is t(15;17) an indicator of
favorable or adverse outcome
12/06/2014
Cytogenetics
100
Survival (%)
Favorable
80
60
Intermediate
Adverse
40
20
0
0
10
Time (years)
Age 16-60; N=1130
12/06/2014
APML4
100
88 %
% surviving
80
Arsenic+
ATRA+Chemo
68 % APML3
ATRA+Chemo
60
40
20
p = 0.012
0
0
2
3
4
5
years from treatment start
6
Harry Iland, ALLG
12/06/2014
Thecytogeneticgap
t(15;17)
11%
Favourable
risk
Normal
33%
t(8;21)
6%
inv(16)
4%
abn(3q)
inv(3)
2%
1%
add(5q), del(5q),
-5
4%
-7,
Intermediate
18%
Complex
7%
Adverse
risk
add(7q)/del(7q)
6%
t(11q23)
t(9;22)4%
-17/abn(17p)
1%
3%
12/06/2014
GeneticarchitectureofAML
Mutation
Karyotype
FAB
De novo (85%)
M0
M1
M2
M3
M4
M5
M6
M7
Secondary
(15%)
MDS
MPD
Favourable (23%)
t(15;17)
t(8;21)
Inv(16)
Intermediate (60%)
Other
Adverse (17%)
Abn (3q)
Inv (3)
Del (5q)/-5
Del (7q)/-7
t(11q23)
t(9;22)
-17/abn(17p)
Complex
(4 abn)
Grimwade, Blood 2010
Mutation
Freq. in AML
(%)
DNMT3A
NPM1
FLT3
TET2
RUNX1
IDH2
CEBPA
IDH1
TP53
NRAS
WT1
KIT
PTPN11
KRAS
U2AF1
SMC3
SMC1A
29
28
27
15
11
10
10
10
9
8
7
5
5
4
4
4
4
N Engl J Med 2013; 369:1472-1473
RecurrentsomaticlesionsinAML
12/06/2014
% Overall survival
100
P<0.0001
80
CEBPAmut
60
No transplant
NPM1mut/FLT3-ITDneg
40
Consider transplant
20
FLT3-ITDpos / triple WT
0
0
10
Time [years]
WHOclassificationinAML
AMLwithrecurrentgeneticabnormalities
AMLwitht(8;21),inv(16)andt(16;16)
AML/APLwitht(15;17)
AMLwitht(9;11),AMLwitht(6;9),AMLwithinv(3)
andt(3;3)
AML(megakaryoblastic)witht(1;22)
AMLwithNPM1
AMLwithmutatedCEBRA
AMLwithMyelodysplasticRelatedChanges
AMLwithmultilineagedysplasia
AMLwithpoorriskCG
MyeloidSarcoma
TherapyrelatedAML
MyeloidproliferationrelatedtoDownSyndrome
AcuteLeukemiasofAmbiguousLineage
10
12/06/2014
FLT3-ITD
11
12/06/2014
CEP701
PKC412
Sorafenib
AC220
Ligand
FLT3
JMD
NPMc
FrequencyinNKAML:35%
Brunangelo Falini, NEJM 2005; 254
WT
MUT
12
12/06/2014
p53mutationsassociatedwithadverserisk
karyotypeAML
13
12/06/2014
DenovoAML
(20%BMblasts)
Myelodysplastic
syndrome
Myeloproliferativesyndrome
(ET,PRV,MF,CML)
Secondar
y AML
CMML
Previous chemotherapy
Previous radiotherapy
Therapy
related
AML
I
N
D
U
C
T
I
O
N
C
O
N
S
O
L
I
D
A
T
I
O
N
C
O
N
S
O
L
I
D
A
T
I
O
N
A
L
L
O
G
R
A
R
F
I
T
S
K
I
F
H
I
G
H
14
12/06/2014
Evolutionofmodernchemotherapy forAML
Regimen
6-MP and PNL
Daunorubicin 45mg/m2 x 3d
Ara-C 100 mg/m2 IVI x 7d
CR
0%
25%
25%
Ref
MRC 1966
Bernard 1967
Ellison 1968
7+3in1973
YatesandWallace
16 patients
Cytarabine 100 mg/m2 x 7 days, by cont. IVI
Daunorubicin 45 mg/m2 x 3 days
Complete remission achieved in
5/8 (untreated AML)
2/8 (previously treated)
J.Bernard,PresseMed.75(1967)951955
EllisonandHolland,AcuteLeukemiaGroupB
JYates,CancerChemother.Rep.57(1973)485488
15
12/06/2014
HiDACconsolidationimprovesOSinyoungerAML
7+3
Ara-C d1-5
200mg/m2 IVI
x4
Ara-C (d1,3,5)
400mg/m2 bd
x4
HiDAC
3g/m2 bd d1,3,5
x4
16
12/06/2014
ELN
(Dhner,Blood2010;
453)
FAV
CBF
NPMc
CEBPAm
INTI
FLT3ITD+
FLT3/NPM
INTII
t(9;11)
OtherCG
ADV
inv(3)/t(3;3);t(6;9);
t(v;11)(v;q23);5or
del(5q);7;abn(17p);
complexkaryotype
INT-II
INT-I
17
12/06/2014
18
12/06/2014
Males
Females
0
04
59
1014
1519
2024
2529
3034
3539
4044
4549
5054
5559
6064
6569
7074
7579
8084
85+
19
12/06/2014
Regimen
Age
(med)
TRM
(age)
CR
OS (age)
Ref
HyperCVAD
288
15-92
(40)
2% (<60)
15% (>60)
92%
Kantarjian, Cancer
2004; 2788
HyperCVAD
53
<60
74%
83% 2YS
20
12/06/2014
21
12/06/2014
22
12/06/2014
Imatinib:moleculartargetedtherapy
forPhpositiveALL
Substrate
P
P
P
ATP
Y = Tyrosine
P = Phosphate
23
12/06/2014
Gatekeeper mutation
24
12/06/2014
Blinatumomab
25
12/06/2014
MDS
Concepts
Clonaldisorderofstemcells
Ineffectivehematopoiesis
TransformationtoAML
26
12/06/2014
IPSS
R-IPSS
27
12/06/2014
RandomisedtrialofazacitidineforMDS
Azacitidine + BSC
Int-2/high risk
MDS
R
A
N
D
O
M
I
S
E
n = 179
Proportion Surviving
0.9
0.8
0.7
0.6
24.4 months
0.5
0.4
15 months
AZA
0.3
CCR
0.2
0.1
0.0
0
10
15
20
25
30
35
40
Months
Transfusion independence (50%)
Improves quality of life
PBS for int-2 and high risk MDS (Feb 2012)
28
12/06/2014
DNA methylation
mRNA splicing
29
12/06/2014
(SF3B1)
(SETBP1)
(PTPN11)
(JAK2 V617F)
5q Syndrome
The 5q-syndrome is characterized by:
Macrocytosis
Anemia
Thrombocytosis
Erythroblastopenia
Megakaryocyte hyperplasia with nuclear
hypolobation
Interstitial deletion of chromosome 5
Females of advanced age
Low risk of leukemic transformation
Responds to lenalidomide 60%
transfusion independence
30
12/06/2014
Conclusions
31