12/06/2014

AndrewWei
AlfredHospital

ACUTELEUKAEMIAandMDS

National Cancer Institute. SEER Cancer Statistics Review. 1975-2000

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FBE

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BMAT

Normal

Leukaemia

How is AML distinguished from

ALL?

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Myeloperoxidase

Flow cytometry

Rapid diagnosis of
AML
Lineage designation
Monitoring for residual
disease

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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

inv(16); t(8;21); t(15;17)

80

60

normal karyotype; all other

Intermediate

inv(3); t(6;9); t(v;11q23)

-5/5q-; -7; abn(17p); complex

Adverse

40

20

0
0

10

Time (years)
Age 16-60; N=1130

Acute promyelocytic leukaemia

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Progress against APML

1957 APML first described (Hillestad)
1973 Anthracycline efficacy 5y DFS 35% (Bernard)
1977 t(15;17)(q22;q21) was identified (Rowley)
1985 ATRA efficacy reported in 6 cases (Huang)
1992 Arsenic efficacy reported (Sun)

APML therapy in Australia

Failure-free survival

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%

What molecular factors are

useful in classifying
cytogenetically normal AML?

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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

N Engl J Med 2013; 369:1472-1473

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Prognostic value of FLT3-ITD, NPM and CEBPA in

normal karyotype AML

% 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]

Schlenk , N Engl J Med. 2008

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

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How is FLT3-ITD detected?

FLT3-ITD

11

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CEP701
PKC412
Sorafenib
AC220

Ligand
FLT3
JMD

NPMc

FrequencyinNKAML:35%
Brunangelo Falini, NEJM 2005; 254

WT

MUT

12

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In which subset is p53 mutation

common in AML?

p53mutationsassociatedwithadverserisk
karyotypeAML

Vera Grossmann, Blood 2012 120: 2963-2972

13

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How is complete remission (CR)

in AML defined?

CR < 5% marrow blasts

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

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What drugs are used for the

treatment of AML?

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

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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

Mayer RJ, et al. N Engl J Med. 1994;896

Who should receive an

allogeneic stem cell transplant
in first remission?

16

12/06/2014

ELN classification in de novo AML (APML, s-AML, t-AML excluded)

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

CALGB n=1550, <60y, no SCT CR1

INT-II
INT-I

Krzysztof Mrzek, ASH 2011; 414

Allogeneic stem cell

matching

17

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Which acute leukemia is most

likely?

18

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ALL: main subtypes

BcellALL /precursorBlymphoblasticleukemia
TcellALL /precursorTlymphoblasticleukemia

ALL incidence is bimodal

7

Males

Females

0
04
59
1014
1519
2024
2529
3034
3539
4044
4549
5054
5559
6064
6569
7074
7579
8084
85+

Age-specific incidence rate

Age group at diagnosis

Australian Institute of Health and Welfare

19

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ALL outcomes for adult regimens

Regimen

Age
(med)

TRM
(age)

CR

OS (age)

Ref

HyperCVAD

288

15-92
(40)

2% (<60)
15% (>60)

92%

51% 5YS (<40)

30% (40-59)
17% (60+)

Kantarjian, Cancer
2004; 2788

HyperCVAD

53

<60

74%

83% 2YS

Xu, Leuk Res 2008;

930

Minimal residual disease

20

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Risk assessment in ALL

Genetic architecture of ALL

Charles Mullighan, ASH 2012

21

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Advances in ALL therapy

Paediatric approaches improve outcome
L-asparaginase
Less cyclophosphamide
Improved compliance
More dexamethasone
Rituximab for CD20+ ALL
MRD guided stem cell transplant decisions

What is the management of

Ph+ ALL

22

12/06/2014

Imatinib:moleculartargetedtherapy
forPhpositiveALL

Imatinib: blocks abl function by

interfering with ATP binding
Bcr-Abl

Substrate
P
P
P

ATP

Y = Tyrosine
P = Phosphate

Goldman et al, Lancet 2000

What are the limitations of TKI

therapy for Ph+ ALL?

23

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Gatekeeper mutation

Are there any new treatments

for B-ALL?

24

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Blinatumomab

What is the diagnosis?

25

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MDS
Concepts
Clonaldisorderofstemcells
Ineffectivehematopoiesis
TransformationtoAML

WHO classification of MDS

26

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IPSS

R-IPSS

27

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RandomisedtrialofazacitidineforMDS

Azacitidine + BSC

Int-2/high risk
MDS

R
A
N
D
O
M
I
S
E

(75 mg/m2/day x 7 days SC

q28 days)

n = 179

BSC, LDAC or high dose chemo

n = 179

Fenaux P et al. Lancet Oncol. 2009

AZA-001 Phase III Study: Azacitidine improves OS

compared to CCR (supportive, 7+3, low dose Ara-C)
1.0

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)

Pierre Fenaux, Lancet 2009

28

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What mutation is linked to

RARS?

Emerging new MDS mutations

Histone modifications

DNA methylation
mRNA splicing

Wahab, ASH 2013

29

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WHO classification of MDS

(SF3B1)

(RPS-14 and miR-145, 146)

(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

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Conclusions

AML, ALL, MDS morphologic syndromes

Therapy to date empirical
Morphologic entities undergoing transformation by
genomic insights
Future goals will be the development of less toxic targetdirected therapies

31