R
Bassan

UOC
Ematologia,
Ospedaledell’Angelo
eOspedale
SS.
Giovanni
e
Paolo,Mestre‐Venezia

SIE
Regionale
Triveneta,
Udine
18
maggio
2012

CAN
BE
OPTIMIZEDCAN
BE
OPTIMIZED

StudyStudy typetype AgeAgegroupsgroups

StudyStudy

parametersparameters

ageage cytogencytogen geneticsgenetics otherother

MRC
(1999) Re/val C,
A,
E ‐ + ‐ CR
cycle
1

NILG
(2000) Pro A ‐ + FLT3 CR
cycle
1 WBC,MDS/sec

AMLSG(2008)

Re A ‐ +
(NK) FLT3,
NPM1,CEBPA

‐

AMLCG(2010)

Re/val(CR)

E + + ‐ FLT3,
NPM1 Temperature,
sec,
Hb,
PLT,LDH,
fibrinogen‐

ELN
(2010) Cons ‐ ‐ + FLT3,
NPM1,CEBPA

‐

AMLSG‐ELN(2011)

Re A,
E ‐ + FLT3,
NPM1,CEBPA

‐

SAL
(2012) Re/val A + + FLT3 MDS/sec,
CD34

ECOG
(2012) Re/val A ‐ + FLT3,
NPM1,CEBPA,
IDH,MLL,
ASXL1,PHF6,
TET2,DNMT3A

‐

Re
=retrospecticeRe/val
=
retrospective
with
validation
cohortPro
=
prospectiveCons
=
consensusC,
A,
E
=
children,
adult,
elderly
AML

incidence

survival

Age

NorthernNorthern ItalyItaly LeukemiaLeukemia GroupGroup

ClinicalTrials.gov Identifier: NCT00495287

Days
from
diagnosis

N
1235
(1351
–
116
APL)Median
age
(range):
62
(17‐90)N
573
to
Random
1
(46.4%)


N
792
>55
yy
(64.1%)

Score 1With cytogenetics/geneticsNPM1/FLT3

Probability of CR: from 12 to 91%Risk of ED : from 6 to 69%

Score 2Without cytogenetics/genetics

(only clinical data: temperature, age, sec. AML, Hb, PLT, fibrinogen, LDH)

Probability of CR : from 21 to 80%Risk of ED: from 7 to 63%

In
HR

cytogenetic/genetic
group,
25%
of
patients
still
have


>40%
CR
probability

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8 10 12years

.

(n=401) 0.43

NILG
AML
01/00

HOVON JPN

MRC
15Australia

EORTC/GIMEMA

Italy

Res

t
of
th

e
world













5‐year
survivalRisk
category Definition* age
15‐34 age
35+

GOOD
 APL
,
CBF 70% 64%STANDARD intermediate,
normal 52% 39%

CR
c1POOR adverse
cytogenetics, 19% 8%

no
CR
c1

*two
parameters:‐cytogenetics‐CR
after
course
1
(c1)

Study
cohort

Validation
cohort

TherapyTherapy

Schlenk
et
al,
NEJM
2008

Rollig
et
al,
JCO
2011

Dohner
et
al,
Blood
2010

Allo‐SCT


favourablefavourable1)1)t(8;21t(8;21))2)2)invinv(16(16),
t(16;16),
del(16q)),
t(16;16),
del(16q)

intermediateintermediate1)1)NORMALNORMAL2)2)OTHER
OTHER
non‐HIGHnon‐HIGH33)
)








UnknownUnknown

unfavourableunfavourable‐‐5/del(5q),
‐7,
t(11q23),
t(9;22),5/del(5q),
‐7,
t(11q23),
t(9;22),abnabn

3q,
9q,
11q,
20q,
21q,3q,
9q,
11q,
20q,
21q,17p17p,
,
isoiso(17q),
t(3;5),
t(6;9),
(17q),
t(3;5),
t(6;9),
t(9;22t(9;22),
complex
(),
complex
(>>3)3)

CYTOGENETICSCYTOGENETICS

WBC
>50x109/l
sec/MDS
CR
cycle
2
FLT‐3,
MLL
FAB
M0,6,7

none

any

HHRR

SRSR

HHRR

SSRR

ClinicalTrials.gov Identifier: NCT00400673

ICE
(c1)IC
(c2)

A8HD
(c2)

CR

res

A20



alloSCT

x3
(monthly)

CD34+
harvest/reinfusion
(1‐2
x106/kg)

A8/20 with
total
Ara‐C
8/20
g/m2


Risk
definition













risk‐oriented
therapy

0.00

0.25

0.50

0.75

1.00

Cum

ulat

ive s

urviv

al

0 2 4 6 8 10 12years

.

5-year probability

SR c1 (n 136) 0.65

SRHR c2 (n 12) 0.49

HR c1 (n 164) 0.43HR c2 (n 24) 0.21

ED/NR

Reference
data
(«3+7») CR
after
cycle
1ECOG
(NEJM
2009)

DNR
45
mg/m2
x3135 121/293
(41.3%) standard
arm
↓ DNR
90
mg/m2
x3270 170/289
(58.8%)

JALSG
(Blood
2011)
 DNR
50
mg/m2
x5250 321/525
(61.1%) IDR
12
mg/m2
x336 341/532
(64.1%) IDR
=
HD
DNR

Personal
data
(«ICE»)NILG
01
(unpublished)

IDR
12
mg/m2
x336 300/401
(74.8%)NILG
02
(unpublished)

IDR
12
mg/m2
x336 192/272
(70.5%) ext.
age
(>70) 
Exp.
arm
(HD) 
220/269
(81.7)

RR

RR

RR

CR
timing No.of
cycles▪ Anthracycline
type/dose,
HD
Ara‐C

Remission
and
relapse
kinetics Blast
cell
clearance▪ PB,
BM▪ Timing

MRD▪ Remission▪ Relapse

…….

Induction
























consolidation
/
SCT







































FUP

MRD
threshold
(

Early prediction of response to standard induction in a“clinically relevant time”

NRNR

CRCR

1012

108

109

1010

1011

Neo

pla

stic

cell

s

Bone Marrowat diagnosis

Bone Marrowat recovery (Day 28)

Induction Aplasia

Peripheralblood

Bone Marrowat day 14

courtesy
G
Gianfaldoni,
F
Mannelli
(FI)

0 1 2 3 4 5 6 76

54

32

10

day

Log

Red

uctio

nNCRCR

Overall

0 1 2 3 4 5 6 7

65

43

21

0

day

Log

Red

uctio

n Low Risk

0 1 2 3 4 5 6 7

65

43

21

0

day

Log

Red

uctio

n Intermediate Risk

0 1 2 3 4 5 6 76

54

32

10

day

Log

Red

uctio

n High Risk

RESULTS: PILOT STUDY

In some pts (mainly CR), peripheral blasts not detectable at days 6-8Analysis restricted to days 1-5

BJH, 2006

PBC: predictive value on CR

DAY 5: CUT-OFF = 2 LOG

< 2 LOG: CR 1/20 (5%)

> 2 LOG: CR 31/41 (76%)

NCR CR RankSumDay Median (95% CI) Median (95% CI) W P

2 0.18 (0.04, 0.17) 0.46 (0.46, 0.54) 149.5 .0123 0.58 (0.17, 0.58) 1.19 (0.95, 1.80) 132.5 .0044 1.19 (0.32, 1.26) 2.26 (1.90, 3.07) 93 .0005 1.70 (0.61, 1.86) 2.93 (2.79, 3.69) 75 .000

Specificity 67%

Sensibility 97%

Blood, 2008

Predictive value of PBC independent of baseline PB burden

R1

ICE

HDS 2/1

D1 D4

D1 D4

BM DG

BM D28

Northern Italy Northern Italy LeukemiaLeukemia Group (NILG) Group (NILG)AML 02-06 protocolAML 02-06 protocol

Endpoints: To confirm results on a larger cohort adjusting cut-off

To verify the feasibility in a multicenter setting

To study PBC along with 2 induction regimens

0.00

0.25

0.50

0.75

1.00

Cum

ulat

ive s

urviv

al

0 2 4 6 8 10 12years

.

SR

ED/NR

for allo-SCTSR,
late
CRHR
HR,
late
CR

CR

Noconsolidation(early
relapse/death,toxicity)

Allo‐SCT Chemotherapy

314 58
(18.4%) 112
(35.6%) 144
(46%)

0.00

0.25

0.50

0.75

1.00

0 2 4 6 8 10 12analysis time

.

CHT
(n
144)


0.37

SCT
(n
112)


0.55

P


RD
SCT
(n
69) CR‐SCT
interval
(mos.) 
3.5
 (0.7‐10)

URD
SCT
(n
40) CR‐SCT
interval
(mos.) 5.9
 (0.6‐13)

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20months

.

Incidence
of
relapse
in
HR
AML(n=202)25%
at
5
mos.50%
at
10
mos.

Incidence
of
SCT
in
HR
AML(n=109)

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20months

.

Incidence
of
relapse(n=202)

Incidence
ofRD
SCT URD
SC(n=69) 
 (n=40)

25%
after
~40
%
relapse
incidence50%
after
>25%
relapse
incidence


CenterCenter No.
No.
PtsPts.. MedianMedian((mosmos.).)

Max.
(Max.
(mosmos.).)

11 99 3.73.7 5.95.9

22 99 8.28.2 1313

33 88 55 1313

44 44 44 9.29.2

55 33 6.56.5 6.76.7

66 33 1111 1111

77 22 6.96.9 77

88 22 7.97.9 8.78.7

Many
markers
and
models,
few
universalAGE,
CYTOGENETICS,
GENETICSflt3,
npm1,
cebpa

Therapy‐related
issues CR time,
frequency
(drug/regimen) MRD how/when/why SCT actual
v
planned

Marker‐therapy
relationship:
of
interest FLT3+
(midostaurin,
lestaurtinib…) C‐kit
(dasatinib) NPM1
(ATRA) NK/CBF
(mylotarg,
demethylating,
hystone
deacetylase
inhib.)

«it
is
plausible
that
regulatory
agencies
will
approve
XXX
or
YYY
foruse
in
AML.

While
I
would
have
no
problem
with
such
approval,I
think
it
would
be
unfortunate
if
these
drugs
were
regarded
as
the‘standard
of
care’
for
such
patients
if
this
phrase
meant
nota
standard
of
comparison
for
future
trials,
but
a
mandate
to
use
thesedrugs
as
initial
therapy,
rather
than
placing
a
patienton
a
clinical
trial,
such
as
one
using
these
drugs
as
‘epigenetic
priming’»

Estey,
LEUKEMIA
2012