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1
PO
CK
ET G
UID
ELIN
E
Hem
ato
logy
Pra
ctical m
anag
em
ent
of chro
nic
m
yelo
id le
uka
em
ia in
Belg
ium
2
PO
CK
ET G
UID
ELIN
E
Hem
ato
logy
Pra
ctic
al m
anag
em
ent
of chro
nic
m
yelo
id le
uka
em
ia in
Belg
ium
A s
ele
ctio
n o
f ke
y ta
ble
s d
eri
ved
fro
m t
he
ori
gin
al p
ap
er:
“ P
rac
tica
l ma
na
ge
me
nt
of
ch
ron
ic m
yelo
id le
uk
ae
mia
in B
elg
ium
”, w
ritt
en
by
F.S
. Be
ng
hia
t, Y
. Be
gu
in, B
. De
ssa
rs,
T. D
evo
s, P
. Le
wa
lle, P
. Min
eu
r, N
. Str
ae
tma
ns,
K. v
an
Eyg
en
, G. V
erh
oe
f, a
nd
L. K
no
op
s,
pu
blis
he
d in
th
e B
elg
ian
Jo
urn
al o
f H
em
ato
log
y, v
olu
me
6, i
ssu
e 1
, Ma
rch
20
15
Pu
blis
he
rA
riez
Inte
rnat
iona
l BV,
Nie
uwew
eg 1
08 A
, 153
1 A
H W
orm
er, T
he N
ethe
rland
sTe
l.: +
31(0
)75
642
94 2
0, F
ax: +
31(0
)75
642
94 2
1, E
-mai
ladr
es: e
dito
r@bj
h.be
, Web
site
: ww
w.a
riez.
nl
Co
pyri
gh
t ©
Cop
yrig
ht 2
015
Arie
z In
tern
atio
nal B
.V.,
Wor
mer
, The
Net
herla
nds.
This
pub
licat
ion
or p
arts
of t
his
pub
licat
ion
may
not
be
used
, cop
ied
or r
epro
duc
ed fo
r com
mer
cial
pur
pos
es b
y ot
her p
artie
s th
an th
e p
ublis
her.
The
opin
ions
sta
ted
in th
is p
ublic
atio
n d
o no
t refl
ect t
he o
pin
ion
of th
e p
ublis
her a
nd a
re n
ot th
e re
spon
sib
ility
of th
e p
ublis
her.
The
resp
onsi
bilit
y of
the
con
tent
of
this
pub
licat
ion
rest
s so
lely
with
the
aut
hors
. Th
e p
ublis
her
cann
ot b
e he
ld r
esp
onsi
ble
and
is n
ot
liab
le fo
r any
dam
age
caus
ed to
third
par
ties
by th
is p
ublic
atio
n an
d re
ject
s an
y cl
aim
s w
ith re
gard
s to
dam
age
that
mig
ht b
e ca
used
or
infli
cted
to th
ird p
artie
s fo
llow
ing
the
cont
ent o
f thi
s p
ublic
atio
n.
The
auth
ors
have
writ
ten
this
pub
licat
ion
with
the
utm
ost a
ttent
ion
and
care
; des
pite
this
fact
, err
ors
in th
e te
xt c
ould
occ
ur. T
he p
ublis
her
cann
ot b
e he
ld r
esp
onsi
ble
or
is n
ot li
able
for
any
tex
tual
err
ors
or p
oten
tial d
amag
e or
cla
ims
conc
erni
ng d
amag
e in
flict
ed t
o ot
her
par
ties
follo
win
g th
e us
e of
this
pub
licat
ion.
1
Intr
od
uc
tio
n
3-4
Ta
ble
I.
5
Sta
ging
of C
ML
acco
rdin
g to
the
ELN
or W
HO
crit
eria
Ta
ble
II.
6
Initi
al W
ork
up
Ta
ble
IV
a.
7-8
Fi
rst a
nd s
econ
d ge
nera
tion
Tyro
sine
Kin
ase
Inhi
bito
rs c
hara
cter
istic
s
Ta
ble
IV
b.
9
-10
N
ew T
yros
ine
Kin
ase
Inhi
bito
rs c
hara
cter
istic
s
Ta
ble
V.
11-1
2
Dru
g in
tera
ctio
ns
Ta
ble
Va
.
13-1
4
List
of C
YP
3A4
indu
cers
and
inhi
bito
rs
Ta
ble
Vb
.
15-1
6
QT
prol
ongi
ng d
rugs
Ta
ble
VI.
17-1
8
Man
agem
ent o
f TK
I adv
erse
eve
nts
Ta
ble
VIII.
19
C
autio
us u
se o
f TK
Is fo
r cer
tain
com
orbi
ditie
s
Ta
ble
IX
.
2
0
Res
ults
of s
tudi
es c
ompa
ring
Imat
inib
firs
t lin
e to
Nilo
tinib
or D
asat
inib
Ta
ble
Xb
.
21-
22
D
efini
tions
of r
espo
nses
and
mon
itorin
g
Ta
ble
XI.
23
D
efini
tion
of th
e re
spon
se to
any
TK
I, fir
st li
ne
Ta
ble
XII.
2
4
Defi
nitio
n of
resp
onse
for 2
nd li
ne tr
eatm
ent,
in c
ase
of fa
ilure
of i
mat
inib
Re
fere
nc
es
25
-28
Ind
ex
2
Intr
od
uc
tio
n
3-4
Ta
ble
I.
5
Sta
ging
of C
ML
acco
rdin
g to
the
ELN
or W
HO
crit
eria
Ta
ble
II.
6
Initi
al W
ork
up
Ta
ble
IV
a.
7-8
Fi
rst a
nd s
econ
d ge
nera
tion
Tyro
sine
Kin
ase
Inhi
bito
rs c
hara
cter
istic
s
Ta
ble
IV
b.
9
-10
N
ew T
yros
ine
Kin
ase
Inhi
bito
rs c
hara
cter
istic
s
Ta
ble
V.
11-1
2
Dru
g in
tera
ctio
ns
Ta
ble
Va
.
13-1
4
List
of C
YP
3A4
indu
cers
and
inhi
bito
rs
Ta
ble
Vb
.
15-1
6
QT
prol
ongi
ng d
rugs
Ta
ble
VI.
17-1
8
Man
agem
ent o
f TK
I adv
erse
eve
nts
Ta
ble
VIII.
19
C
autio
us u
se o
f TK
Is fo
r cer
tain
com
orbi
ditie
s
Ta
ble
IX
.
2
0
Res
ults
of s
tudi
es c
ompa
ring
Imat
inib
firs
t lin
e to
Nilo
tinib
or D
asat
inib
Ta
ble
Xb
.
21-
22
D
efini
tions
of r
espo
nses
and
mon
itorin
g
Ta
ble
XI.
23
D
efini
tion
of th
e re
spon
se to
any
TK
I, fir
st li
ne
Ta
ble
XII.
2
4
Defi
nitio
n of
resp
onse
for 2
nd li
ne tr
eatm
ent,
in c
ase
of fa
ilure
of i
mat
inib
Re
fere
nc
es
25
-28
3
Dea
r Col
leag
ues,
The
treat
men
t of p
atie
nts
with
chr
onic
mye
loid
leuk
emia
(CM
L) is
one
of t
he g
reat
est m
edic
al
succ
ess
stor
ies
of th
e pa
st 3
0 ye
ars.
Tod
ay, t
reat
men
t goa
ls s
houl
d be
to b
ring
our p
atie
nts
life
expe
ctan
cy to
nor
mal
with
min
imal
impa
ct o
n th
eir q
ualit
y of
life
. To
achi
eve
thes
e go
als,
CM
L tre
atm
ent s
houl
d be
indi
vidu
aliz
ed w
ith tr
eatm
ent e
ffici
ency
and
sid
e ef
fect
s ca
refu
lly
mon
itore
d. T
oget
her w
ith th
e co
-aut
hor o
f thi
s po
cket
gui
de, I
hop
e th
at th
ese
prac
tical
tabl
es
will
help
you
to g
ive
the
best
cha
nces
to a
ll C
ML
patie
nts
treat
ed in
Bel
gium
.
With
bes
t wis
hes,
Pro
f. L
aure
nt K
noo
ps,
MD
, PhD
Hem
atol
ogy
unit
Clin
ique
s U
nive
rsita
ires
Sai
nt-L
uc
and
de D
uve
Inst
itute
Uni
vers
ité c
atho
lique
de
Louv
ain
Bru
ssel
s
Intr
od
uc
tio
n
4
Dea
r Col
leag
ues,
The
treat
men
t of p
atie
nts
with
chr
onic
mye
loid
leuk
emia
(CM
L) is
one
of t
he g
reat
est m
edic
al
succ
ess
stor
ies
of th
e pa
st 3
0 ye
ars.
Tod
ay, t
reat
men
t goa
ls s
houl
d be
to b
ring
our p
atie
nts
life
expe
ctan
cy to
nor
mal
with
min
imal
impa
ct o
n th
eir q
ualit
y of
life
. To
achi
eve
thes
e go
als,
CM
L tre
atm
ent s
houl
d be
indi
vidu
aliz
ed w
ith tr
eatm
ent e
ffici
ency
and
sid
e ef
fect
s ca
refu
lly
mon
itore
d. T
oget
her w
ith th
e co
-aut
hor o
f thi
s po
cket
gui
de, I
hop
e th
at th
ese
prac
tical
tabl
es
will
help
you
to g
ive
the
best
cha
nces
to a
ll C
ML
patie
nts
treat
ed in
Bel
gium
.
With
bes
t wis
hes,
Pro
f. L
aure
nt K
noo
ps,
MD
, PhD
Hem
atol
ogy
unit
Clin
ique
s U
nive
rsita
ires
Sai
nt-L
uc
and
de D
uve
Inst
itute
Uni
vers
ité c
atho
lique
de
Louv
ain
Bru
ssel
s
5
Tab
le I.
Sta
ging
of C
ML
acco
rdin
g to
the
ELN
or
WH
O c
riter
ia (b
oth
can
be u
sed)
.26,2
7
Ch
ron
ic
Ph
ase
(CP
)A
ccel
erat
ed P
has
e (A
P)
Bla
st P
has
e (B
P)
EL
N c
rite
ria
Non
e of
the
crite
ria fo
r A
P o
r BP
− B
last
s 15
- 2
9% in
blo
od o
r BM
;−
Bla
sts
+ p
rom
yelo
cyte
s ≥
30%
in b
lood
or B
M;
− B
asop
hilia
≥ 2
0% in
blo
od;
− P
late
lets
< 1
00
x 10
9 /L
unre
late
d to
ther
apy;
− C
lona
l chr
omos
ome
abno
rmal
ities
in P
h+ c
ells
(CC
A/P
h+),
maj
or ro
ute,
on
trea
tmen
t.
≥ 3
0% B
last
s in
blo
od o
r B
M;
Ext
ram
edul
lary
bla
stic
infil -
trate
s ap
art f
rom
sp
leen
.
WH
O
crit
eria
Non
e of
the
crite
ria fo
r A
P o
r BP
− B
last
s 10
-19%
in b
lood
or B
M;
− P
ersi
sten
t thr
omb
ocyt
open
ia (<
10
0 ×
10
9 /L)
unr
elat
ed to
ther
apy
− P
ersi
sten
t thr
omb
ocyt
osis
(> 1
00
0 ×
10
9 /L)
unr
esp
onsi
ve to
ther
apy;
−
Incr
easi
ng w
hite
blo
od c
ells
and
sp
leen
siz
e un
resp
onsi
ve to
ther
apy;
−
Bas
ophi
lia ≥
20%
in b
lood
− C
lona
l chr
omos
ome
abno
rmal
ities
in P
h+ c
ells
(CC
A/P
h+) o
n tre
atm
ent
(clo
nal e
volu
tion)
≥ 2
0% B
last
s in
blo
od o
r B
M;
Ext
ram
edul
lary
bla
stic
infil -
trate
s ap
art f
rom
sp
leen
;La
rge
clus
ters
of b
last
s on
b
one
mar
row
bio
psy
.
“maj
or ro
utes
” ab
norm
aliti
es in
clud
e :
tris
omy
8, a
dditi
onal
Ph
(+de
r(22)
t(9;2
2)(q
34;q
11) o
r ide
r(22)
(q10
)t(9;
22)(q
34;q
11)),
isoc
hrom
osom
e 17
, and
tris
omy
19.2
6
Tab
le II
. Ini
tial W
ork
up.
His
tory
Med
ical
his
tory
and
exh
aust
ive
med
icat
ion
list
His
tory
of c
ardi
ovas
cula
r eve
nts
Phy
sica
l ex
amin
atio
nS
ple
en s
ize
(cm
bel
ow c
osta
l mar
gin)
in o
rder
to c
alcu
late
a p
rogn
ostic
sco
reS
pec
ial a
ttent
ion
to h
yper
tens
ion
Blo
od
An
alys
isC
BC
, diff
eren
tial c
ount
, per
iphe
ral b
lood
sm
ear
PC
R fo
r BC
R-A
BL1
Ele
ctro
lyte
, ren
al a
nd h
epat
ic fu
nctio
nLi
pas
e, A
myl
ase,
TS
H, g
lyca
emia
, HbA
1c a
nd li
pid
pro
file
if N
ilotin
ib c
onsi
der
ed fo
r ini
tial t
reat
-m
ent
ß-H
CG
for w
omen
of c
hild
bea
ring
age
Bo
ne
Mar
row
A
spir
atio
nD
iffer
entia
l cou
ntC
ytog
enet
ic a
naly
sis
FIS
H fo
r BC
R-A
BL1
(if P
CR
for B
CR
-AB
L1 n
egat
ive)
EK
GTo
exc
lud
e lo
ng Q
T sy
ndro
me
bef
ore
star
ting
Nilo
tinib
or D
asat
inib
Ech
oca
rdio
gra
phy
To r
ule
out p
ulm
onar
y ar
teria
l hyp
erte
nsio
n b
efor
e st
artin
g D
asat
inib
Ch
est
X-r
ayTo
exc
lud
e p
leur
al e
ffusi
on b
efor
e st
artin
g D
asat
inib
Ab
do
min
al U
ltra
sou
nd
To e
valu
ate
sple
en s
ize
if cl
inic
al a
sses
smen
t is
not p
ossi
ble
(ob
ese
pat
ient
s)
7
Tab
le IV
a. F
irst a
nd s
econ
d ge
nera
tion
Tyro
sine
Kin
ase
Inhi
bito
rs c
hara
cter
istic
s.
(ww
w.e
ma.
euro
pa.e
u)
Imat
inib
(Gliv
ec®)
Nilo
tin
ib (
Tasi
gn
a®)
Das
atin
ib (S
pry
cel®
)
Do
sin
gC
P
AP
BP
400
mg
1x/d
400
mg
2x/
d
400
mg
2x/
d
30
0 m
g 2
x/d
in 1
st li
ne40
0 m
g 2x
/d i
n 2nd
line
afte
r fa
ilure
400
mg
2x/
d
400
mg
2x/
d
100
mg
1x/d
140
mg
1x/d
140
mg
1x/d
Ad
min
istra
tion
Onc
e d
aily
with
a m
eal a
nd
a la
rge
glas
s of
wat
er.
12 h
ours
ap
art.
On
empt
y st
omac
h, a
t lea
st 2
h b
efor
e an
d 1h
afte
r foo
d.
Onc
e d
aily
with
out r
egar
d to
food
.
Pha
rmac
okin
etic
pro
per
ties
Met
abol
ism
mai
nly
hep
atic
;M
inim
al re
nal e
xcre
tion
(13%
)M
etab
olis
m m
ainl
y he
pat
ic;
No
rena
l exc
retio
nM
etab
olis
m m
ainl
y he
pat
ic;
Min
imal
rena
l exc
retio
n (4
%)
Dos
e ad
just
men
t for
live
r d
ysfu
nctio
nU
se w
ith c
autio
n. M
axim
um
reco
mm
end
ed d
ose
of
400
mg/
d as
sta
rtin
g d
ose.
R
educ
e d
ose
if no
t tol
e-ra
ted.
Adj
ustm
ent m
ay n
ot b
e re
qui
red
how
ever
use
with
ca
utio
n. A
LT o
r AS
T >
2.
5xU
LN o
r tot
al b
ilirub
in
> 1
.5xU
LN w
ere
excl
uded
fro
m c
linic
al tr
ials
.
Adj
ustm
ent m
ay n
ot b
e re
qui
red
how
ever
use
with
ca
utio
n. A
LT o
r AS
T >
2.
5xU
LN o
r tot
al b
ilirub
in >
2
xULN
wer
e ex
clud
ed fr
om
clin
ical
tria
ls.
Dos
e ad
just
men
t for
rena
l d
ysfu
nctio
nR
enal
dys
func
tion
or o
n di
alys
is: u
se w
ith c
autio
n.
Max
imum
reco
mm
ende
d do
se o
f 40
0 m
g/d
as s
tart -
ing
dos
e. R
educ
e d
ose
if no
t tol
erat
ed. I
f tol
erat
ed,
incr
ease
dos
e fo
r lac
k of
ef
ficac
y.
Not
stu
died
in p
atie
nts
with
se
rum
cre
atin
ine
> 1
.5x
ULN
. A
djus
tmen
ts m
ay n
ot b
e ne
cess
ary.
Not
stu
died
in p
atie
nts
with
se
rum
cre
atin
ine
> 3
x U
LN.
Adj
ustm
ents
may
not
be
nece
ssar
y.
Mo
nit
ori
ng
CB
CE
lect
roly
teLi
ver T
ests
Ren
al fu
nctio
n
Afte
r 1 w
eek,
then
1x/
2 w
eeks
for t
he 1
st 3
mon
ths,
then
at e
ach
BC
R-A
BL1
PC
R te
stin
g
Mo
nit
ori
ng
Oth
er te
sts
Wei
ght a
nd fl
uid
stat
us.
Lip
id p
rofil
e, G
lyca
emia
; P
ancr
eatic
func
tion
test
s;E
KG
(D+1
and
D+
8 af
ter i
nitia
tion
or d
osag
e ad
just
men
t);TS
H (1
x/m
onth
for 4
mon
ths,
th
en e
very
3 m
onth
s).
Wei
ght a
nd fl
uid
stat
us;
Che
st x
-ray
if s
usp
icio
n of
p
leur
al e
ffusi
on;
EK
G if
at r
isk
of Q
T p
rolo
ngat
ion
(arr
hyth
mia
, ant
iarr
hyth
mic
m
edic
atio
ns,…
).
8
Tab
le IV
a. F
irst a
nd s
econ
d ge
nera
tion
Tyro
sine
Kin
ase
Inhi
bito
rs c
hara
cter
istic
s.
(ww
w.e
ma.
euro
pa.e
u)
Imat
inib
(Gliv
ec®)
Nilo
tin
ib (
Tasi
gn
a®)
Das
atin
ib (S
pry
cel®
)
Do
sin
gC
P
AP
BP
400
mg
1x/d
400
mg
2x/
d
400
mg
2x/
d
30
0 m
g 2
x/d
in 1
st li
ne40
0 m
g 2x
/d i
n 2nd
line
afte
r fa
ilure
400
mg
2x/
d
400
mg
2x/
d
100
mg
1x/d
140
mg
1x/d
140
mg
1x/d
Ad
min
istra
tion
Onc
e d
aily
with
a m
eal a
nd
a la
rge
glas
s of
wat
er.
12 h
ours
ap
art.
On
empt
y st
omac
h, a
t lea
st 2
h b
efor
e an
d 1h
afte
r foo
d.
Onc
e d
aily
with
out r
egar
d to
food
.
Pha
rmac
okin
etic
pro
per
ties
Met
abol
ism
mai
nly
hep
atic
;M
inim
al re
nal e
xcre
tion
(13%
)M
etab
olis
m m
ainl
y he
pat
ic;
No
rena
l exc
retio
nM
etab
olis
m m
ainl
y he
pat
ic;
Min
imal
rena
l exc
retio
n (4
%)
Dos
e ad
just
men
t for
live
r d
ysfu
nctio
nU
se w
ith c
autio
n. M
axim
um
reco
mm
end
ed d
ose
of
400
mg/
d as
sta
rtin
g d
ose.
R
educ
e d
ose
if no
t tol
e-ra
ted.
Adj
ustm
ent m
ay n
ot b
e re
qui
red
how
ever
use
with
ca
utio
n. A
LT o
r AS
T >
2.
5xU
LN o
r tot
al b
ilirub
in
> 1
.5xU
LN w
ere
excl
uded
fro
m c
linic
al tr
ials
.
Adj
ustm
ent m
ay n
ot b
e re
qui
red
how
ever
use
with
ca
utio
n. A
LT o
r AS
T >
2.
5xU
LN o
r tot
al b
ilirub
in >
2
xULN
wer
e ex
clud
ed fr
om
clin
ical
tria
ls.
Dos
e ad
just
men
t for
rena
l d
ysfu
nctio
nR
enal
dys
func
tion
or o
n di
alys
is: u
se w
ith c
autio
n.
Max
imum
reco
mm
ende
d do
se o
f 40
0 m
g/d
as s
tart -
ing
dos
e. R
educ
e d
ose
if no
t tol
erat
ed. I
f tol
erat
ed,
incr
ease
dos
e fo
r lac
k of
ef
ficac
y.
Not
stu
died
in p
atie
nts
with
se
rum
cre
atin
ine
> 1
.5x
ULN
. A
djus
tmen
ts m
ay n
ot b
e ne
cess
ary.
Not
stu
died
in p
atie
nts
with
se
rum
cre
atin
ine
> 3
x U
LN.
Adj
ustm
ents
may
not
be
nece
ssar
y.
Mo
nit
ori
ng
CB
CE
lect
roly
teLi
ver T
ests
Ren
al fu
nctio
n
Afte
r 1 w
eek,
then
1x/
2 w
eeks
for t
he 1
st 3
mon
ths,
then
at e
ach
BC
R-A
BL1
PC
R te
stin
g
Mo
nit
ori
ng
Oth
er te
sts
Wei
ght a
nd fl
uid
stat
us.
Lip
id p
rofil
e, G
lyca
emia
; P
ancr
eatic
func
tion
test
s;E
KG
(D+1
and
D+
8 af
ter i
nitia
tion
or d
osag
e ad
just
men
t);TS
H (1
x/m
onth
for 4
mon
ths,
th
en e
very
3 m
onth
s).
Wei
ght a
nd fl
uid
stat
us;
Che
st x
-ray
if s
usp
icio
n of
p
leur
al e
ffusi
on;
EK
G if
at r
isk
of Q
T p
rolo
ngat
ion
(arr
hyth
mia
, ant
iarr
hyth
mic
m
edic
atio
ns,…
).
9
Tab
le IV
b. N
ew T
yros
ine
Kin
ase
Inhi
bito
rs c
hara
cter
istic
s. (w
ww
.em
a.eu
ropa
.eu)
Bo
suti
nib
(Bo
sulif
®)
Po
nat
inib
(Icl
usi
g®)
Do
sin
gC
P –
AP
– B
P50
0 m
g 1x
/dD
ose
to b
e re
defi
ned
to m
inim
ize
card
iova
scul
ar r
isk.
Pos
sib
ly 3
0 m
g/d
ay, t
o b
e d
ecre
ased
to 1
5 m
g/d
whe
n p
atie
nt w
ith M
MR
Ad
min
istra
tion
Onc
e d
aily
with
food
. O
nce
dai
ly w
ithou
t reg
ard
to fo
od.
Dos
e ad
just
men
t for
live
r dys
func
tion
Chi
ld A
-B-C
: 20
0 m
g Q
DN
ot s
tudi
ed. M
etab
olis
m m
ainl
y he
pat
ic. U
se w
ith
caut
ion.
Dos
e ad
just
men
t for
rena
l dys
func
tion
Cre
atin
ine
> 1
.5xU
NL
wer
e ex
clud
ed fr
om
CM
L st
udie
s.
Not
stu
died
. Min
imal
rena
l exc
retio
n.
Adj
ustm
ent m
ay n
ot b
e ne
cess
ary
if cr
eatin
ine
clea
r -an
ce ≥
50
mL/
min
. Use
with
cau
tion
if cr
eatin
ine
clea
ranc
e <
50
mL/
min
.
Mo
nit
ori
ng
CB
CE
lect
roly
teLi
ver F
unct
ion
Test
s
1x/2
wee
ks fo
r the
1st
2 m
onth
s, th
en 1
x/3
mon
ths
Oth
er te
sts
Ren
al fu
nctio
n;W
eigh
t and
flui
d st
atus
.D
iarr
hoea
Bas
elin
e E
KG
; Gly
caem
ia; L
ipas
e; U
ric a
cid;
Wei
ght
and
fluid
sta
tus;
Blo
od p
ress
ure;
Car
diac
func
tion;
H
aem
orrh
age;
Sig
ns o
f thr
omb
oem
bol
ism
; G
astro
-inte
stin
al p
erfo
ratio
n.
Dru
g In
tera
ctio
ns
CY
P3A
4 In
duc
ers
and
Inhi
bito
rs [c
f.
Lis
t]
Avo
id c
onco
mita
nt u
se.
Avo
id c
onco
mita
nt u
se.
Dru
gs fo
r gas
tric
aci
dity
Ant
acid
s, H
2-an
tago
-ni
sts:
sep
arat
e ad
min
i-st
ratio
n by
sev
eral
ho
urs.
P
PI:
Avo
id.
Ant
acid
s, P
PI:
avo
id, m
ay d
ecre
ase
Pon
atin
ib s
erum
co
ncen
tratio
n.
Car
diac
Dru
gsA
void
QT
pro
long
ing
agen
ts [c
f.lis
t]S
erio
us h
eart
failu
re a
nd a
rrhy
thm
ias
wer
e re
por
ted
with
Pon
atin
ib. M
onito
r for
sig
ns o
f hea
rt fa
ilure
and
ar
rhyt
hmia
s.
Ant
icoa
gula
nts
Vita
min
K a
ntag
onis
ts: M
onito
r IN
R c
lose
ly.
Par
ticu
lar
AE
Gas
tro-in
test
inal
: dia
r -rh
oea,
nau
sea,
vom
iting
Car
diov
ascu
lar:
Hyp
erte
nsio
n, a
rteria
l thr
ombo
tic e
ven-
ts, s
troke
.S
kin:
Dry
ski
n, ra
sh
Cau
tio
us
use
fo
r ce
rtai
n co
mo
r -b
idit
ies
Long
QT
synd
rom
eC
ardi
ovas
cula
r ris
k fa
ctor
s Is
chem
ic c
ardi
ac d
isea
seH
yper
tens
ion
10
Tab
le IV
b. N
ew T
yros
ine
Kin
ase
Inhi
bito
rs c
hara
cter
istic
s. (w
ww
.em
a.eu
ropa
.eu)
Bo
suti
nib
(Bo
sulif
®)
Po
nat
inib
(Icl
usi
g®)
Do
sin
gC
P –
AP
– B
P50
0 m
g 1x
/dD
ose
to b
e re
defi
ned
to m
inim
ize
card
iova
scul
ar r
isk.
Pos
sib
ly 3
0 m
g/d
ay, t
o b
e d
ecre
ased
to 1
5 m
g/d
whe
n p
atie
nt w
ith M
MR
Ad
min
istra
tion
Onc
e d
aily
with
food
. O
nce
dai
ly w
ithou
t reg
ard
to fo
od.
Dos
e ad
just
men
t for
live
r dys
func
tion
Chi
ld A
-B-C
: 20
0 m
g Q
DN
ot s
tudi
ed. M
etab
olis
m m
ainl
y he
pat
ic. U
se w
ith
caut
ion.
Dos
e ad
just
men
t for
rena
l dys
func
tion
Cre
atin
ine
> 1
.5xU
NL
wer
e ex
clud
ed fr
om
CM
L st
udie
s.
Not
stu
died
. Min
imal
rena
l exc
retio
n.
Adj
ustm
ent m
ay n
ot b
e ne
cess
ary
if cr
eatin
ine
clea
r -an
ce ≥
50
mL/
min
. Use
with
cau
tion
if cr
eatin
ine
clea
ranc
e <
50
mL/
min
.
Mo
nit
ori
ng
CB
CE
lect
roly
teLi
ver F
unct
ion
Test
s
1x/2
wee
ks fo
r the
1st
2 m
onth
s, th
en 1
x/3
mon
ths
Oth
er te
sts
Ren
al fu
nctio
n;W
eigh
t and
flui
d st
atus
.D
iarr
hoea
Bas
elin
e E
KG
; Gly
caem
ia; L
ipas
e; U
ric a
cid;
Wei
ght
and
fluid
sta
tus;
Blo
od p
ress
ure;
Car
diac
func
tion;
H
aem
orrh
age;
Sig
ns o
f thr
omb
oem
bol
ism
; G
astro
-inte
stin
al p
erfo
ratio
n.
Dru
g In
tera
ctio
ns
CY
P3A
4 In
duc
ers
and
Inhi
bito
rs [c
f.
Lis
t]
Avo
id c
onco
mita
nt u
se.
Avo
id c
onco
mita
nt u
se.
Dru
gs fo
r gas
tric
aci
dity
Ant
acid
s, H
2-an
tago
-ni
sts:
sep
arat
e ad
min
i-st
ratio
n by
sev
eral
ho
urs.
P
PI:
Avo
id.
Ant
acid
s, P
PI:
avo
id, m
ay d
ecre
ase
Pon
atin
ib s
erum
co
ncen
tratio
n.
Car
diac
Dru
gsA
void
QT
pro
long
ing
agen
ts [c
f.lis
t]S
erio
us h
eart
failu
re a
nd a
rrhy
thm
ias
wer
e re
por
ted
with
Pon
atin
ib. M
onito
r for
sig
ns o
f hea
rt fa
ilure
and
ar
rhyt
hmia
s.
Ant
icoa
gula
nts
Vita
min
K a
ntag
onis
ts: M
onito
r IN
R c
lose
ly.
Par
ticu
lar
AE
Gas
tro-in
test
inal
: dia
r-rh
oea,
nau
sea,
vom
iting
Car
diov
ascu
lar:
Hyp
erte
nsio
n, a
rteria
l thr
ombo
tic e
ven-
ts, s
troke
.S
kin:
Dry
ski
n, ra
sh
Cau
tio
us
use
fo
r ce
rtai
n co
mo
r-b
idit
ies
Long
QT
synd
rom
eC
ardi
ovas
cula
r ris
k fa
ctor
s Is
chem
ic c
ardi
ac d
isea
seH
yper
tens
ion
11
Tab
le V
. Dru
g in
tera
ctio
ns.*30
(ww
w.fd
a.go
v)
Dru
g in
tera
ctio
ns
Imat
inib
Nilo
tin
ibD
asat
inib
CY
P3A
4 S
trong
Ind
ucer
s (m
ay d
ecre
ase
TKI p
lasm
a le
vels
)[c
f. L
ist]
Avo
id.
If ca
nnot
be
avoi
ded
, in -
crea
se Im
atin
ib d
ose
by a
t le
ast 5
0% w
ith c
aref
ul m
oni-
torin
g. C
onsi
der
Imat
inib
p
lasm
a le
vel d
osag
e.
Avo
id
An
incr
ease
d d
ose
of N
i -lo
tinib
is
not
like
ly to
com
pen
sate
fo
r dec
reas
ed e
xpos
ure.
Avo
id.
If re
qui
red,
con
sid
er in
cre -
asin
g th
e D
asat
inib
dos
e w
ith c
aref
ul m
onito
ring.
CY
P3A
4 S
trong
Inhi
bito
rs
(may
incr
ease
TK
I pla
sma
leve
ls)
[cf.
Lis
t]
Avo
idIf
req
uire
d, c
onsi
der
Imat
inib
d
ose
red
uctio
n (n
o fo
rmal
re
com
men
dat
ions
)C
onsi
der
Imat
inib
pla
sma
leve
l dos
age
(no
form
al re
com
men
dat
ion)
Avo
id.
If re
qui
red:
Con
sid
er re
duc
-in
g N
ilotin
ib to
20
0 m
g/d
(CP
) or 3
00
mg/
d (A
P) w
ith
care
ful m
onito
ring
of th
e Q
T in
terv
al.
Whe
n th
e st
rong
inhi
bito
r is
disc
ontin
ued,
allo
w a
was
h ou
t per
iod
(1 w
eek)
prio
r to
adj
ustin
g N
ilotin
ib d
ose
upw
ard.
If
not t
oler
ated
, dis
cont
inue
C
YP
3A4
inhi
bito
r or w
ithho
ld
Nilo
tinib
tem
por
arily
.
Avo
id.
If re
qui
red:
Con
sid
er re
duc
-in
g D
asat
inib
to 2
0 m
g/d
(CP
) or 4
0 m
g/d
(AP
).
Whe
n th
e st
rong
inhi
bito
r is
disc
ontin
ued,
allo
w a
was
h ou
t per
iod
(1 w
eek)
prio
r to
adju
stin
g D
asat
inib
dos
e up
war
d.If
not t
oler
ated
, dis
cont
inue
C
YP
3A4
inhi
bito
r or w
ithho
ld
Das
atin
ib te
mp
orar
ily.
Dru
gs fo
r gas
tric
aci
dity
PP
I : ↑
Imat
inib
exp
osur
eP
PI:
↓ N
ilotin
ib a
bso
rptio
n →
Avo
id
Ant
acid
s, H
2-an
tago
nist
s:
sepa
rate
adm
inis
tratio
n by
se
vera
l hou
rs.
H2-
anta
goni
sts
and
PP
I: ↓
Das
atin
ib a
bso
rptio
n →
A
void
.A
ntac
ids:
sep
arat
e ad
min
i -st
ratio
n by
sev
eral
hou
rs.
Car
diac
Dru
gsC
alci
um c
hann
el b
lock
ers
(CC
B):
↑ C
CB
exp
osur
e.D
igox
in: ↓
dig
oxin
abs
orpt
ion
Avo
id Q
T p
rolo
ngin
g ag
ents
[c
f.lis
t]↑
CC
B e
xpos
ure.
Avo
id Q
T P
rolo
ngin
g ag
ents
[c
f.lis
t]↑
CC
B e
xpos
ure.
Ant
icoa
gula
nts
Ant
ipla
tele
t dru
gsN
SA
IDs
Vita
min
K a
ntag
onis
ts:
cont
rol I
NR
dur
ing
the
first
w
eeks
follo
win
g in
itiat
ion
of
Imat
inib
NS
AID
s: ↑
NS
AID
s ex
pos
ure.
Vita
min
K a
ntag
onis
ts:
cont
rol I
NR
dur
ing
the
first
w
eeks
follo
win
g in
itiat
ion
of
Nilo
tinib
.N
SA
IDs:
↑ N
SA
IDs
ex
pos
ure.
Ant
ipla
tele
t effe
ct o
f Das
atin
ib:
Enh
ance
d ris
k of
ble
edin
g,
use
with
cau
tion.
*Wor
d of
war
ning
: Non
-exh
aust
ive
list o
f dru
g-in
tera
ctio
ns. P
leas
e ch
eck
bef
ore
pre
scrib
ing.
12
Tab
le V
. Dru
g in
tera
ctio
ns.*30
(ww
w.fd
a.go
v)
Dru
g in
tera
ctio
ns
Imat
inib
Nilo
tin
ibD
asat
inib
CY
P3A
4 S
trong
Ind
ucer
s (m
ay d
ecre
ase
TKI p
lasm
a le
vels
)[c
f. L
ist]
Avo
id.
If ca
nnot
be
avoi
ded
, in -
crea
se Im
atin
ib d
ose
by a
t le
ast 5
0% w
ith c
aref
ul m
oni-
torin
g. C
onsi
der
Imat
inib
p
lasm
a le
vel d
osag
e.
Avo
id
An
incr
ease
d d
ose
of N
i -lo
tinib
is
not
like
ly to
com
pen
sate
fo
r dec
reas
ed e
xpos
ure.
Avo
id.
If re
qui
red,
con
sid
er in
cre -
asin
g th
e D
asat
inib
dos
e w
ith c
aref
ul m
onito
ring.
CY
P3A
4 S
trong
Inhi
bito
rs
(may
incr
ease
TK
I pla
sma
leve
ls)
[cf.
Lis
t]
Avo
idIf
req
uire
d, c
onsi
der
Imat
inib
d
ose
red
uctio
n (n
o fo
rmal
re
com
men
dat
ions
)C
onsi
der
Imat
inib
pla
sma
leve
l dos
age
(no
form
al re
com
men
dat
ion)
Avo
id.
If re
qui
red:
Con
sid
er re
duc
-in
g N
ilotin
ib to
20
0 m
g/d
(CP
) or 3
00
mg/
d (A
P) w
ith
care
ful m
onito
ring
of th
e Q
T in
terv
al.
Whe
n th
e st
rong
inhi
bito
r is
disc
ontin
ued,
allo
w a
was
h ou
t per
iod
(1 w
eek)
prio
r to
adj
ustin
g N
ilotin
ib d
ose
upw
ard.
If
not t
oler
ated
, dis
cont
inue
C
YP
3A4
inhi
bito
r or w
ithho
ld
Nilo
tinib
tem
por
arily
.
Avo
id.
If re
qui
red:
Con
sid
er re
duc
-in
g D
asat
inib
to 2
0 m
g/d
(CP
) or 4
0 m
g/d
(AP
).
Whe
n th
e st
rong
inhi
bito
r is
disc
ontin
ued,
allo
w a
was
h ou
t per
iod
(1 w
eek)
prio
r to
adju
stin
g D
asat
inib
dos
e up
war
d.If
not t
oler
ated
, dis
cont
inue
C
YP
3A4
inhi
bito
r or w
ithho
ld
Das
atin
ib te
mp
orar
ily.
Dru
gs fo
r gas
tric
aci
dity
PP
I : ↑
Imat
inib
exp
osur
eP
PI:
↓ N
ilotin
ib a
bso
rptio
n →
Avo
id
Ant
acid
s, H
2-an
tago
nist
s:
sepa
rate
adm
inis
tratio
n by
se
vera
l hou
rs.
H2-
anta
goni
sts
and
PP
I: ↓
Das
atin
ib a
bso
rptio
n →
A
void
.A
ntac
ids:
sep
arat
e ad
min
i -st
ratio
n by
sev
eral
hou
rs.
Car
diac
Dru
gsC
alci
um c
hann
el b
lock
ers
(CC
B):
↑ C
CB
exp
osur
e.D
igox
in: ↓
dig
oxin
abs
orpt
ion
Avo
id Q
T p
rolo
ngin
g ag
ents
[c
f.lis
t]↑
CC
B e
xpos
ure.
Avo
id Q
T P
rolo
ngin
g ag
ents
[c
f.lis
t]↑
CC
B e
xpos
ure.
Ant
icoa
gula
nts
Ant
ipla
tele
t dru
gsN
SA
IDs
Vita
min
K a
ntag
onis
ts:
cont
rol I
NR
dur
ing
the
first
w
eeks
follo
win
g in
itiat
ion
of
Imat
inib
NS
AID
s: ↑
NS
AID
s ex
pos
ure.
Vita
min
K a
ntag
onis
ts:
cont
rol I
NR
dur
ing
the
first
w
eeks
follo
win
g in
itiat
ion
of
Nilo
tinib
.N
SA
IDs:
↑ N
SA
IDs
ex
pos
ure.
Ant
ipla
tele
t effe
ct o
f Das
atin
ib:
Enh
ance
d ris
k of
ble
edin
g,
use
with
cau
tion.
*Wor
d of
war
ning
: Non
-exh
aust
ive
list o
f dru
g-in
tera
ctio
ns. P
leas
e ch
eck
bef
ore
pre
scrib
ing.
13
Tab
le V
a. L
ist o
f CY
P3A
4 in
duce
rs a
nd in
hibi
tors
.*31
(ww
w.le
xi.c
om; w
ww
.upt
odat
e.co
m, a
dapt
ed to
the
Bel
gian
situ
atio
n)
Str
on
g In
du
cers
Mo
der
ate
Ind
uce
rsS
tro
ng
Inh
ibit
ors
Mo
der
ate
Inh
ibit
ors
Car
bam
azep
ine
Ap
rep
itant
Ata
zana
vir
Ab
irate
rone
Dex
amet
haso
neA
rtem
ethe
rB
ocep
revi
rA
mio
dar
one
Enz
alut
amid
eB
exar
oten
eC
hlor
amp
heni
col
Ap
rep
itant
Mito
tane
Bos
enta
nC
larit
hrom
ycin
Bic
alut
amid
e
Nev
irap
ine
Cal
citr
iol
Cob
icis
tat
Cim
etid
ine
Oxc
arb
azep
ine
Clo
baz
amD
arun
avir
Cip
roflo
xaci
n
Pen
tob
arb
ital
Dab
rafe
nib
Del
avird
ine
Clo
trim
azol
e
Phe
nyto
inD
efer
asiro
xFo
sam
pre
navi
rC
rizot
inib
Prim
idon
eEf
avire
nzG
rape
fruit
Cyc
losp
orin
e
Rifa
but
inEt
ravi
rine
Indi
navi
rD
anaz
ol
Rifa
mp
icin
Felb
amat
eItr
acon
azol
eD
asat
inib
Rifa
pen
tine
Fluc
loxa
cillin
Ket
okon
azol
eD
iltia
zem
Rifa
mp
icin
Fosa
prep
itant
Lop
inav
irEf
avire
nz
Rifa
pen
tine
Hyd
roco
rtiso
neN
elfin
avir
Eryt
hrom
ycin
St J
ohn’
s w
ort
Mod
afini
lN
icar
dipi
neFl
ucon
azol
e
Naf
cillin
Pos
acon
azol
eFo
sapr
epita
nt
Pac
litax
elR
itona
vir
Imat
inib
Topi
ram
ate
Saq
uina
vir
Met
roni
dazo
le
Tram
etin
ibTe
lapr
evir
Mic
onaz
ole
Vem
uraf
enib
Telit
hrom
ycin
Nor
floxa
cin
Voric
onaz
ole
Tetra
cycl
ine
Vera
pam
il
*Wor
d of
war
ning
: Non
-exh
aust
ive
list o
f dru
g-in
tera
ctio
ns. P
leas
e ch
eck
bef
ore
pre
scrib
ing.
14
Tab
le V
a. L
ist o
f CY
P3A
4 in
duce
rs a
nd in
hibi
tors
.*31
(ww
w.le
xi.c
om; w
ww
.upt
odat
e.co
m, a
dapt
ed to
the
Bel
gian
situ
atio
n)
Str
on
g In
du
cers
Mo
der
ate
Ind
uce
rsS
tro
ng
Inh
ibit
ors
Mo
der
ate
Inh
ibit
ors
Car
bam
azep
ine
Ap
rep
itant
Ata
zana
vir
Ab
irate
rone
Dex
amet
haso
neA
rtem
ethe
rB
ocep
revi
rA
mio
dar
one
Enz
alut
amid
eB
exar
oten
eC
hlor
amp
heni
col
Ap
rep
itant
Mito
tane
Bos
enta
nC
larit
hrom
ycin
Bic
alut
amid
e
Nev
irap
ine
Cal
citr
iol
Cob
icis
tat
Cim
etid
ine
Oxc
arb
azep
ine
Clo
baz
amD
arun
avir
Cip
roflo
xaci
n
Pen
tob
arb
ital
Dab
rafe
nib
Del
avird
ine
Clo
trim
azol
e
Phe
nyto
inD
efer
asiro
xFo
sam
pre
navi
rC
rizot
inib
Prim
idon
eEf
avire
nzG
rape
fruit
Cyc
losp
orin
e
Rifa
but
inEt
ravi
rine
Indi
navi
rD
anaz
ol
Rifa
mp
icin
Felb
amat
eItr
acon
azol
eD
asat
inib
Rifa
pen
tine
Fluc
loxa
cillin
Ket
okon
azol
eD
iltia
zem
Rifa
mp
icin
Fosa
prep
itant
Lop
inav
irEf
avire
nz
Rifa
pen
tine
Hyd
roco
rtiso
neN
elfin
avir
Eryt
hrom
ycin
St J
ohn’
s w
ort
Mod
afini
lN
icar
dipi
neFl
ucon
azol
e
Naf
cillin
Pos
acon
azol
eFo
sapr
epita
nt
Pac
litax
elR
itona
vir
Imat
inib
Topi
ram
ate
Saq
uina
vir
Met
roni
dazo
le
Tram
etin
ibTe
lapr
evir
Mic
onaz
ole
Vem
uraf
enib
Telit
hrom
ycin
Nor
floxa
cin
Voric
onaz
ole
Tetra
cycl
ine
Vera
pam
il
*Wor
d of
war
ning
: Non
-exh
aust
ive
list o
f dru
g-in
tera
ctio
ns. P
leas
e ch
eck
bef
ore
pre
scrib
ing.
15
Tab
le V
b. Q
T pr
olon
ging
dru
gs.*
(ww
w.c
bip.
be)
Gen
eric
Nam
esB
ran
d N
ames
An
tiar
rhyt
hm
ics
Dis
opyr
amid
eQ
uini
dine
Am
iod
aron
eS
otal
olFl
ecai
nid
e
Ryt
hmod
an®
-
(not
ava
ilab
le in
Bel
gium
)C
ord
aron
e®
Sot
alex
®
Tam
boc
or®, A
poc
ard
®
An
tiem
etic
sD
omp
erid
one
(cau
tion
whe
n >
30
mg/
d)O
ndan
setro
n (m
ainl
y I.V
., m
ax. 1
6 m
g/d
ose)
Mot
ilium
®
Zofra
n®
An
alg
esic
Met
hado
neM
ephe
non®
An
tip
sych
oti
csD
rop
erid
olP
imoz
ide
Ser
tind
olH
alop
erid
ol
Deh
ydro
ben
zper
idol
®
Ora
p®
Ser
dol
ect®
Hal
dol
®
An
tid
epre
ssan
tsTr
icyc
lic a
ntid
epre
ssan
ts (m
ainl
y in
cas
e of
ov
erd
ose)
Cita
lop
ram
Es
cita
lop
ram
Cip
ram
il®
Sip
rale
xa®
CN
S s
tim
ula
nt
Ato
mox
etin
eS
tratte
ra®
An
tim
icro
bia
lsE
ryth
rom
ycin
e (m
ainl
y I.V
.)C
larit
hrom
ycin
eTe
lithr
omyc
ine
/ A
zith
rom
ycin
eM
oxifl
oxac
ine
/ Le
voflo
xaci
ne /
Oflo
xaci
neA
mp
hote
ricin
e B
Chl
oroq
uine
Art
émét
her +
Lum
éfan
trin
e A
rtén
imol
+ P
ipér
aqui
ne
Pen
tam
idin
e A
taza
navi
r / L
opin
avir
/ S
aqui
navi
r
Ery
thro
cine
®
Bic
lar®
, Hel
icla
r®, M
acla
r®, M
onoc
lariu
m®
Ket
ek® /
Zitr
omax
®
Ave
lox®
, Pro
flox®
/ T
avan
ic® /
Tar
ivid
®
Ab
elce
t®, A
mb
isom
e®
Niv
aqui
ne®
Ria
met
®
Eura
rtes
im®
Pen
taca
rinat
®
Rey
ataz
® /
Kal
etra
® /
Invi
rase
®
An
ti-t
um
ou
r ag
ents
Tore
mife
neTr
ioxy
de
d’ar
seni
cTK
Is :
Bos
utin
ib /
Das
atin
ib /
Géfi
tinib
/
Imat
inib
/ L
apat
inib
/ N
ilotin
ib /
Paz
opan
ib /
S
oraf
énib
/ S
uniti
nib
Not
ava
ilab
le in
Bel
gium
Tris
enox
®
TKIs
: Bos
ulif®
/ S
pry
cel®
/ Ir
essa
® /
Gliv
ec®
/ Ty
verb
® /
Tas
igna
® /
Vot
rient
® /
Nex
avar
® /
S
uten
t®
*Wor
d of
war
ning
: Non
-exh
aust
ive
list o
f dru
g-in
tera
ctio
ns. P
leas
e ch
eck
bef
ore
pre
scrib
ing.
16
Tab
le V
b. Q
T pr
olon
ging
dru
gs.*
(ww
w.c
bip.
be)
Gen
eric
Nam
esB
ran
d N
ames
An
tiar
rhyt
hm
ics
Dis
opyr
amid
eQ
uini
dine
Am
iod
aron
eS
otal
olFl
ecai
nid
e
Ryt
hmod
an®
-
(not
ava
ilab
le in
Bel
gium
)C
ord
aron
e®
Sot
alex
®
Tam
boc
or®, A
poc
ard
®
An
tiem
etic
sD
omp
erid
one
(cau
tion
whe
n >
30
mg/
d)O
ndan
setro
n (m
ainl
y I.V
., m
ax. 1
6 m
g/d
ose)
Mot
ilium
®
Zofra
n®
An
alg
esic
Met
hado
neM
ephe
non®
An
tip
sych
oti
csD
rop
erid
olP
imoz
ide
Ser
tind
olH
alop
erid
ol
Deh
ydro
ben
zper
idol
®
Ora
p®
Ser
dol
ect®
Hal
dol
®
An
tid
epre
ssan
tsTr
icyc
lic a
ntid
epre
ssan
ts (m
ainl
y in
cas
e of
ov
erd
ose)
Cita
lop
ram
Es
cita
lop
ram
Cip
ram
il®
Sip
rale
xa®
CN
S s
tim
ula
nt
Ato
mox
etin
eS
tratte
ra®
An
tim
icro
bia
lsE
ryth
rom
ycin
e (m
ainl
y I.V
.)C
larit
hrom
ycin
eTe
lithr
omyc
ine
/ A
zith
rom
ycin
eM
oxifl
oxac
ine
/ Le
voflo
xaci
ne /
Oflo
xaci
neA
mp
hote
ricin
e B
Chl
oroq
uine
Art
émét
her +
Lum
éfan
trin
e A
rtén
imol
+ P
ipér
aqui
ne
Pen
tam
idin
e A
taza
navi
r / L
opin
avir
/ S
aqui
navi
r
Ery
thro
cine
®
Bic
lar®
, Hel
icla
r®, M
acla
r®, M
onoc
lariu
m®
Ket
ek® /
Zitr
omax
®
Ave
lox®
, Pro
flox®
/ T
avan
ic® /
Tar
ivid
®
Ab
elce
t®, A
mb
isom
e®
Niv
aqui
ne®
Ria
met
®
Eura
rtes
im®
Pen
taca
rinat
®
Rey
ataz
® /
Kal
etra
® /
Invi
rase
®
An
ti-t
um
ou
r ag
ents
Tore
mife
neTr
ioxy
de
d’ar
seni
cTK
Is :
Bos
utin
ib /
Das
atin
ib /
Géfi
tinib
/
Imat
inib
/ L
apat
inib
/ N
ilotin
ib /
Paz
opan
ib /
S
oraf
énib
/ S
uniti
nib
Not
ava
ilab
le in
Bel
gium
Tris
enox
®
TKIs
: Bos
ulif®
/ S
pry
cel®
/ Ir
essa
® /
Gliv
ec®
/ Ty
verb
® /
Tas
igna
® /
Vot
rient
® /
Nex
avar
® /
S
uten
t®
*Wor
d of
war
ning
: Non
-exh
aust
ive
list o
f dru
g-in
tera
ctio
ns. P
leas
e ch
eck
bef
ore
pre
scrib
ing.
17
Tab
le V
I. M
anag
emen
t of T
KI a
dver
se e
vent
s.3,
32
Ad
vers
e ev
ent
Man
agem
ent
Nau
sea
Imat
inib
and
Das
atin
ib :
take
med
icat
ion
with
a m
eal a
nd la
rge
glas
s of
wat
erN
ilotin
ib :
antie
met
ic if
nec
essa
ry, a
void
dom
per
idon
e
Dia
rrh
oea
Lop
eram
ide
Ab
do
min
al P
ain
Ant
acid
s, H
2-an
tago
nist
s : s
epar
ate
adm
inis
tratio
n by
sev
eral
hou
rsP
roto
n P
ump
Inhi
bito
rs :
avoi
d
Flu
id r
eten
tio
n (I
mat
inib
an
d
Das
atin
ib)
Per
iphe
ral o
edem
a
Per
iorb
ital o
edem
a
Ple
ural
or c
ardi
ac e
ffusi
on
Diu
retic
s, s
alt r
estr
ictio
n.
Ste
roid
-con
tain
ing
crea
m.
Ob
serv
atio
n if
min
imal
. With
hold
and
rein
itiat
e at
dec
reas
ed d
ose
whe
n ef
fusi
on
reso
lves
. Con
sid
er p
red
niso
ne 2
0 m
g/d
for 3
day
s an
d di
uret
ics.
Tho
raco
cent
esis
if
not r
esol
ving
or l
arge
and
sym
ptom
atic
.
Pu
lmo
nar
y hy
per
ten
sio
n
(Das
atin
ib)
Per
man
ent d
isco
ntin
uatio
n/sw
itch.
Car
dio
vasc
ula
r co
mp
licat
ion
sC
aref
ul e
xam
inat
ion
of th
e p
ossi
ble
cau
salit
y of
the
TKI,
par
ticul
arly
for P
onat
inib
an
d N
ilotin
ib. P
ros
and
cons
of c
ontin
uing
/sw
itchi
ng th
erap
y.
Ski
n ra
shTo
pic
al s
tero
ids
(clo
bet
asol
, bet
amet
haso
ne, d
ifluc
orto
lone
), oc
casi
onal
ly s
yste
mic
st
eroi
ds, a
ntih
ista
min
es, m
inim
ize
sun
expo
sure
. If s
ever
e: d
ose
redu
ctio
n, in
ter-
rupt
ion
or d
isco
ntin
uatio
n.
Mu
scu
losk
elet
al c
om
pla
ints
Pai
n, m
yalg
ia, a
rthr
algi
a
Mus
cle
cram
ps
Usu
ally
mild
to m
oder
ate,
dec
reas
e af
ter a
few
mon
ths.
NS
AID
if n
ot c
ontra
indi
cate
d.N
SA
ID s
houl
d be
use
d w
ith c
autio
n in
Das
atin
ib tr
eate
d pa
tient
s be
caus
e of
the
risk
of b
leed
ing.
Cal
cium
sup
ple
men
t, el
ectro
lyte
rep
lace
men
t if n
eed
ed (e
.g.,
mag
nesi
um, p
otas
-si
um),
toni
c w
ater
, qui
nine
sul
pha
te.
Hyp
erg
lyce
mia
(Nilo
tin
ib)
Usu
ally
mild
, tra
nsie
nt a
nd m
anag
eab
le. I
f gra
de
≥ 3
, res
tart
ther
apy
whe
n re
cov -
ered
to g
rad
e 1
with
red
uced
dos
e. A
djus
tmen
t of t
he a
ntid
iab
etic
trea
tmen
t.
Hep
atic
To
xici
ties
Mon
itor i
f gra
de
1 or
2. I
nter
rupt
ther
apy
if gr
ade
3; re
star
t a lo
wer
dos
e w
hen
re-
cove
red
to g
rad
e 1.
Eva
luat
e fo
r oth
er h
epat
otox
ic d
rugs
that
may
be
cont
ribut
ing
to
toxi
city
. Per
man
ent d
isco
ntin
uatio
n/sw
itch
if se
vere
.
Pan
crea
tic
Toxi
citi
es (N
iloti
nib
)Li
pas
e or
am
ylas
e >
2 x
ULN
: w
ithho
ld u
ntil
≤ 1
.5 x
ULN
then
sw
itch
or re
sum
e N
ilotin
ib a
t 30
0 or
40
0 m
g 1x
/d. P
erm
anen
t dis
cont
inua
tion/
switc
h in
cas
e of
pan
-cr
eatit
is.
Hem
ato
log
ic t
oxi
citi
esA
NC
< 1
00
0/m
L or
pla
tele
ts <
50
x 10
9 /L:
with
hold
. If
AN
C >
10
00/
mL
and
pla
tele
ts >
50
x 10
9 /L
with
in 2
wee
ks: r
esum
e at
prio
r dos
e.
If A
NC
< 1
00
0/m
L or
pla
tele
ts <
50
x 10
9 /L
for >
2 w
eeks
, res
ume
at lo
wer
dos
e.
Con
sid
er fi
lgra
stim
if re
curr
ent/
per
sist
ent o
r sep
sis.
For g
rade
3/4
ana
emia
, CM
S a
nd F
DA
do n
ot s
uppo
rt th
e us
e of
ery
thro
poie
sis-
stim
u-la
ting
agen
ts.
QT
pro
lon
gat
ion
(Nilo
tin
ib, D
a-sa
tin
ib)
QT
prol
onga
tion
> 4
80 m
sec:
with
hold
, cor
rect
pot
assi
um a
nd m
agne
sium
leve
ls,
revi
ew c
urre
nt m
edic
atio
ns.
If Q
T <
450
mse
c w
ithin
2 w
eeks
: res
ume
at p
rior d
ose.
If Q
T 45
0-4
80 m
sec
afte
r 2 w
eeks
: res
ume
at lo
wer
dos
e.If
QT
> 4
80 m
sec
afte
r dos
age
redu
ctio
n: s
top
treat
men
t.
18
Tab
le V
I. M
anag
emen
t of T
KI a
dver
se e
vent
s.3,
32
Ad
vers
e ev
ent
Man
agem
ent
Nau
sea
Imat
inib
and
Das
atin
ib :
take
med
icat
ion
with
a m
eal a
nd la
rge
glas
s of
wat
erN
ilotin
ib :
antie
met
ic if
nec
essa
ry, a
void
dom
per
idon
e
Dia
rrh
oea
Lop
eram
ide
Ab
do
min
al P
ain
Ant
acid
s, H
2-an
tago
nist
s : s
epar
ate
adm
inis
tratio
n by
sev
eral
hou
rsP
roto
n P
ump
Inhi
bito
rs :
avoi
d
Flu
id r
eten
tio
n (I
mat
inib
an
d
Das
atin
ib)
Per
iphe
ral o
edem
a
Per
iorb
ital o
edem
a
Ple
ural
or c
ardi
ac e
ffusi
on
Diu
retic
s, s
alt r
estr
ictio
n.
Ste
roid
-con
tain
ing
crea
m.
Ob
serv
atio
n if
min
imal
. With
hold
and
rein
itiat
e at
dec
reas
ed d
ose
whe
n ef
fusi
on
reso
lves
. Con
sid
er p
red
niso
ne 2
0 m
g/d
for 3
day
s an
d di
uret
ics.
Tho
raco
cent
esis
if
not r
esol
ving
or l
arge
and
sym
ptom
atic
.
Pu
lmo
nar
y hy
per
ten
sio
n
(Das
atin
ib)
Per
man
ent d
isco
ntin
uatio
n/sw
itch.
Car
dio
vasc
ula
r co
mp
licat
ion
sC
aref
ul e
xam
inat
ion
of th
e p
ossi
ble
cau
salit
y of
the
TKI,
par
ticul
arly
for P
onat
inib
an
d N
ilotin
ib. P
ros
and
cons
of c
ontin
uing
/sw
itchi
ng th
erap
y.
Ski
n ra
shTo
pic
al s
tero
ids
(clo
bet
asol
, bet
amet
haso
ne, d
ifluc
orto
lone
), oc
casi
onal
ly s
yste
mic
st
eroi
ds, a
ntih
ista
min
es, m
inim
ize
sun
expo
sure
. If s
ever
e: d
ose
redu
ctio
n, in
ter-
rupt
ion
or d
isco
ntin
uatio
n.
Mu
scu
losk
elet
al c
om
pla
ints
Pai
n, m
yalg
ia, a
rthr
algi
a
Mus
cle
cram
ps
Usu
ally
mild
to m
oder
ate,
dec
reas
e af
ter a
few
mon
ths.
NS
AID
if n
ot c
ontra
indi
cate
d.N
SA
ID s
houl
d be
use
d w
ith c
autio
n in
Das
atin
ib tr
eate
d pa
tient
s be
caus
e of
the
risk
of b
leed
ing.
Cal
cium
sup
ple
men
t, el
ectro
lyte
rep
lace
men
t if n
eed
ed (e
.g.,
mag
nesi
um, p
otas
-si
um),
toni
c w
ater
, qui
nine
sul
pha
te.
Hyp
erg
lyce
mia
(Nilo
tin
ib)
Usu
ally
mild
, tra
nsie
nt a
nd m
anag
eab
le. I
f gra
de
≥ 3
, res
tart
ther
apy
whe
n re
cov-
ered
to g
rad
e 1
with
red
uced
dos
e. A
djus
tmen
t of t
he a
ntid
iab
etic
trea
tmen
t.
Hep
atic
To
xici
ties
Mon
itor i
f gra
de
1 or
2. I
nter
rupt
ther
apy
if gr
ade
3; re
star
t a lo
wer
dos
e w
hen
re-
cove
red
to g
rad
e 1.
Eva
luat
e fo
r oth
er h
epat
otox
ic d
rugs
that
may
be
cont
ribut
ing
to
toxi
city
. Per
man
ent d
isco
ntin
uatio
n/sw
itch
if se
vere
.
Pan
crea
tic
Toxi
citi
es (N
iloti
nib
)Li
pas
e or
am
ylas
e >
2 x
ULN
: w
ithho
ld u
ntil
≤ 1
.5 x
ULN
then
sw
itch
or re
sum
e N
ilotin
ib a
t 30
0 or
40
0 m
g 1x
/d. P
erm
anen
t dis
cont
inua
tion/
switc
h in
cas
e of
pan
-cr
eatit
is.
Hem
ato
log
ic t
oxi
citi
esA
NC
< 1
00
0/m
L or
pla
tele
ts <
50
x 10
9 /L:
with
hold
. If
AN
C >
10
00/
mL
and
pla
tele
ts >
50
x 10
9 /L
with
in 2
wee
ks: r
esum
e at
prio
r dos
e.
If A
NC
< 1
00
0/m
L or
pla
tele
ts <
50
x 10
9 /L
for >
2 w
eeks
, res
ume
at lo
wer
dos
e.
Con
sid
er fi
lgra
stim
if re
curr
ent/
per
sist
ent o
r sep
sis.
For g
rade
3/4
ana
emia
, CM
S a
nd F
DA
do n
ot s
uppo
rt th
e us
e of
ery
thro
poie
sis-
stim
u-la
ting
agen
ts.
QT
pro
lon
gat
ion
(Nilo
tin
ib, D
a-sa
tin
ib)
QT
prol
onga
tion
> 4
80 m
sec:
with
hold
, cor
rect
pot
assi
um a
nd m
agne
sium
leve
ls,
revi
ew c
urre
nt m
edic
atio
ns.
If Q
T <
450
mse
c w
ithin
2 w
eeks
: res
ume
at p
rior d
ose.
If Q
T 45
0-4
80 m
sec
afte
r 2 w
eeks
: res
ume
at lo
wer
dos
e.If
QT
> 4
80 m
sec
afte
r dos
age
redu
ctio
n: s
top
treat
men
t.
19
Tab
le V
III.
Cau
tious
use
of T
KIs
for
cert
ain
com
orbi
ditie
s.
Imat
inib
Nilo
tin
ibD
asat
inib
Car
dio
-vas
cula
r d
isea
ses
Car
diac
dys
func
tion
Isch
emic
car
diac
dis
ease
Long
QT
synd
rom
eP
erip
hera
l art
eria
l dis
ease
Isch
emic
car
diac
dis
ease
Long
QT
synd
rom
eP
ulm
onar
y hy
per
tens
ion
Pu
lmo
nar
y d
isea
ses
Ple
ural
effu
sion
Poo
r pul
mon
ary
func
tion
Liv
er d
isea
seH
epat
ic im
pai
rmen
tH
epat
ic im
pai
rmen
tH
epat
ic im
pai
rmen
t
Gas
tro
inte
stin
al d
isea
ses
Pan
crea
titis
Tota
l gas
trect
omy
Lact
ose
into
lera
nce
Lact
ose
into
lera
nce
En
do
crin
op
ath
ies
Dia
bet
esD
yslip
idem
ia
Ren
al d
isea
ses
Ren
al fa
ilure
Not
stu
died
in re
nal f
ailu
reN
ot s
tudi
ed in
rena
l fai
lure
20
Tab
le IX
. Res
ults
of s
tudi
es c
ompa
ring
Imat
inib
firs
t lin
e to
Nilo
tinib
or
Das
atin
ib (E
NES
T-nd
and
Das
isio
n ar
e di
ffere
nt s
tudi
es, r
esul
ts c
an n
ot b
e di
rect
ly c
ompa
red
be
twee
n th
e tw
o st
udie
s).
CM
L –
CP
– 1
st li
ne
trea
tmen
tE
NE
STn
d6
Das
isio
n7
Imat
inib
40
0 Q
DN
iloti
nib
30
0 B
DIm
atin
ib 4
00
QD
Das
atin
ib 1
00 Q
D
CC
yR 1
y65
%8
0%72
%83
%
MM
R 1
y27
%50
%23
%46
%
MR
4.5
4y3
3,3
423
%40
%3
0%37
%
OS
4y3
3,3
493
.3%
94.3
%92
%93
%
21
Tab
le X
b. D
efini
tions
of r
espo
nses
and
mon
itorin
g.2
Res
po
nse
Defi
nit
ion
sM
on
ito
rin
g**
Hem
ato
log
icC
omp
lete
(CH
R)
Pla
tele
t cou
nt <
450
x10
9 /L
WB
C c
ount
< 1
0 x
109 /
LN
o im
mat
ure
gran
uloc
ytes
Bas
ophi
ls <
5%
Non
pal
pab
le s
ple
en
Ever
y 15
day
s un
til C
HR
has
bee
n co
nfirm
ed
then
eve
ry 3
mon
ths
or a
s re
qui
red.
Cyt
og
enet
ic*
Com
ple
te
(CC
yR)
Par
tial (
PC
yR)
Min
orM
inim
alN
one
No
Ph+
met
apha
ses
1-35
% P
h+ m
etap
hase
s36
-65%
Ph+
met
apha
ses
66
-95%
Ph+
met
apha
ses
> 9
5% P
h+ m
etap
hase
s
At 3
, 6 a
nd e
very
6 m
onth
s un
til a
CC
yR h
as
been
con
firm
ed. O
nce
a C
CyR
is a
chie
ved,
FI
SH
on
bloo
d ce
lls c
an b
e us
ed. I
f an
ade-
quat
e m
olec
ular
mon
itorin
g ca
n be
ass
ured
, cy
toge
netic
s ca
n be
spa
red
afte
r ach
ieve
men
t of
CC
yR.
Cyt
ogen
etic
s is
requ
ired
only
in c
ase
of fa
ilure
, un
expl
aine
d cy
tope
nias
and
if m
olec
ular
test
ing
is
not a
vaila
ble.
Mo
lecu
lar
Maj
or (M
MR
or
MR
3.0
)
MR
4.0
MR
4.5
Tran
scrip
t by
RT-
Q-P
CR
in b
lood
sam
ple
of a
de -
qua
te q
ualit
y (s
ensi
tivity
> 1
04 )
Rat
io B
CR
-AB
L1 to
AB
L1 (o
r oth
er h
ouse
keep
ing
gene
) ≤ 0
.1%
on
the
inte
rnat
iona
l sca
le (I
S)
(1) d
etec
tab
le d
isea
se w
ith <
0.0
1% B
CR
-AB
L1 IS
OR
(2) u
ndet
ecta
ble
dis
ease
in c
DN
A w
ith >
10.
00
0 A
BL1
tran
scrip
ts in
the
sam
e vo
lum
e of
cD
NA
us
ed to
test
for B
CR
-AB
L1.
(1) d
etec
tab
le d
isea
se w
ith <
0.0
032
% B
CR
-AB
L1 IS
OR
(2) u
ndet
ecta
ble
dis
ease
in c
DN
A w
ith >
32.
00
0 A
BL1
tran
scrip
ts in
the
sam
e vo
lum
e of
cD
NA
us
ed to
test
for B
CR
-AB
L1.
Rea
l Tim
e Q
uant
itativ
e (R
T-Q
) PC
R o
n th
e p
e-rip
hera
l blo
od:
Ever
y 3
mon
ths
until
MM
R h
as b
een
confi
rmed
th
en e
very
3 to
6 m
onth
s.
*Onl
y ch
rom
osom
e ba
ndin
g an
alys
is (C
BA
) of m
arro
w c
ell m
etap
hase
s ca
n be
use
d to
ass
ess
the
degr
ee o
f CyR
, with
at
leas
t 20
met
apha
ses
anal
ysed
. FIS
H o
f blo
od in
terp
hase
cel
l nuc
lei c
ould
be
subs
titut
ed fo
r CB
A o
f mar
row
cel
l met
a-ph
ases
onl
y w
hen
a C
CyR
has
bee
n ac
hiev
ed.
**Th
e re
spon
se s
houl
d be
ass
esse
d w
ith a
mol
ecul
ar te
st (o
r a c
ytog
enet
ic te
st if
mol
ecul
ar te
sts
are
not a
vaila
ble
in s
ome
coun
tries
), bu
t bot
h ar
e re
com
men
ded
whe
neve
r pos
sibl
e. N
otic
e th
at M
MR
(MR
3.0
or b
ette
r) is
opt
imal
for s
urvi
val,
but
that
a d
eepe
r res
pons
e is
like
ly to
be
requ
ired
for a
suc
cess
ful d
isco
ntin
uatio
n of
trea
tmen
t. Th
e cu
rren
t pric
e of
a c
hrom
o-so
me
band
ing
anal
ysis
(CB
A),
acco
rdin
g to
the
“Art
icle
33”
, is
arou
nd 2
92 e
uros
(B28
9) a
nd, n
owad
ays,
INA
MI/R
IZIV
reim
-bu
rses
6 te
sts
per y
ear d
urin
g th
e fir
st y
ear,
4 du
ring
year
s 2
to 5
and
1 te
st p
er y
ear a
fter t
he 5
th y
ear.
The
curr
ent p
rice
of a
FI
SH
ana
lysi
s, a
ccor
ding
to th
e “A
rtic
le 3
3”, i
s ar
ound
182
eur
os (B
180)
and
, now
aday
s, IN
AM
I/RIZ
IV re
imbu
rses
6 te
sts
per
year
dur
ing
the
first
yea
r, 4
durin
g ye
ars
2 to
5 a
nd 1
test
per
yea
r afte
r the
5th y
ear.
FIS
H a
naly
sis
is re
imbu
rsed
onl
y if
CB
A
is n
ot c
ontri
butiv
e. T
he c
urre
nt p
rice
of a
BC
R-A
BL1
mol
ecul
ar te
stin
g, a
ccor
ding
to th
e “A
rtic
le 3
3bis
” is
aro
und
125
euro
s B
300
0), a
nd, n
owad
ays,
INA
MI/R
IZIV
reim
burs
es 4
test
s pe
r yea
r.
22
Tab
le X
b. D
efini
tions
of r
espo
nses
and
mon
itorin
g.2
Res
po
nse
Defi
nit
ion
sM
on
ito
rin
g**
Hem
ato
log
icC
omp
lete
(CH
R)
Pla
tele
t cou
nt <
450
x10
9 /L
WB
C c
ount
< 1
0 x
109 /
LN
o im
mat
ure
gran
uloc
ytes
Bas
ophi
ls <
5%
Non
pal
pab
le s
ple
en
Ever
y 15
day
s un
til C
HR
has
bee
n co
nfirm
ed
then
eve
ry 3
mon
ths
or a
s re
qui
red.
Cyt
og
enet
ic*
Com
ple
te
(CC
yR)
Par
tial (
PC
yR)
Min
orM
inim
alN
one
No
Ph+
met
apha
ses
1-35
% P
h+ m
etap
hase
s36
-65%
Ph+
met
apha
ses
66
-95%
Ph+
met
apha
ses
> 9
5% P
h+ m
etap
hase
s
At 3
, 6 a
nd e
very
6 m
onth
s un
til a
CC
yR h
as
been
con
firm
ed. O
nce
a C
CyR
is a
chie
ved,
FI
SH
on
bloo
d ce
lls c
an b
e us
ed. I
f an
ade-
quat
e m
olec
ular
mon
itorin
g ca
n be
ass
ured
, cy
toge
netic
s ca
n be
spa
red
afte
r ach
ieve
men
t of
CC
yR.
Cyt
ogen
etic
s is
requ
ired
only
in c
ase
of fa
ilure
, un
expl
aine
d cy
tope
nias
and
if m
olec
ular
test
ing
is
not a
vaila
ble.
Mo
lecu
lar
Maj
or (M
MR
or
MR
3.0
)
MR
4.0
MR
4.5
Tran
scrip
t by
RT-
Q-P
CR
in b
lood
sam
ple
of a
de-
qua
te q
ualit
y (s
ensi
tivity
> 1
04 )
Rat
io B
CR
-AB
L1 to
AB
L1 (o
r oth
er h
ouse
keep
ing
gene
) ≤ 0
.1%
on
the
inte
rnat
iona
l sca
le (I
S)
(1) d
etec
tab
le d
isea
se w
ith <
0.0
1% B
CR
-AB
L1 IS
OR
(2) u
ndet
ecta
ble
dis
ease
in c
DN
A w
ith >
10.
00
0 A
BL1
tran
scrip
ts in
the
sam
e vo
lum
e of
cD
NA
us
ed to
test
for B
CR
-AB
L1.
(1) d
etec
tab
le d
isea
se w
ith <
0.0
032
% B
CR
-AB
L1 IS
OR
(2) u
ndet
ecta
ble
dis
ease
in c
DN
A w
ith >
32.
00
0 A
BL1
tran
scrip
ts in
the
sam
e vo
lum
e of
cD
NA
us
ed to
test
for B
CR
-AB
L1.
Rea
l Tim
e Q
uant
itativ
e (R
T-Q
) PC
R o
n th
e p
e-rip
hera
l blo
od:
Ever
y 3
mon
ths
until
MM
R h
as b
een
confi
rmed
th
en e
very
3 to
6 m
onth
s.
*Onl
y ch
rom
osom
e ba
ndin
g an
alys
is (C
BA
) of m
arro
w c
ell m
etap
hase
s ca
n be
use
d to
ass
ess
the
degr
ee o
f CyR
, with
at
leas
t 20
met
apha
ses
anal
ysed
. FIS
H o
f blo
od in
terp
hase
cel
l nuc
lei c
ould
be
subs
titut
ed fo
r CB
A o
f mar
row
cel
l met
a-ph
ases
onl
y w
hen
a C
CyR
has
bee
n ac
hiev
ed.
**Th
e re
spon
se s
houl
d be
ass
esse
d w
ith a
mol
ecul
ar te
st (o
r a c
ytog
enet
ic te
st if
mol
ecul
ar te
sts
are
not a
vaila
ble
in s
ome
coun
tries
), bu
t bot
h ar
e re
com
men
ded
whe
neve
r pos
sibl
e. N
otic
e th
at M
MR
(MR
3.0
or b
ette
r) is
opt
imal
for s
urvi
val,
but
that
a d
eepe
r res
pons
e is
like
ly to
be
requ
ired
for a
suc
cess
ful d
isco
ntin
uatio
n of
trea
tmen
t. Th
e cu
rren
t pric
e of
a c
hrom
o-so
me
band
ing
anal
ysis
(CB
A),
acco
rdin
g to
the
“Art
icle
33”
, is
arou
nd 2
92 e
uros
(B28
9) a
nd, n
owad
ays,
INA
MI/R
IZIV
reim
-bu
rses
6 te
sts
per y
ear d
urin
g th
e fir
st y
ear,
4 du
ring
year
s 2
to 5
and
1 te
st p
er y
ear a
fter t
he 5
th y
ear.
The
curr
ent p
rice
of a
FI
SH
ana
lysi
s, a
ccor
ding
to th
e “A
rtic
le 3
3”, i
s ar
ound
182
eur
os (B
180)
and
, now
aday
s, IN
AM
I/RIZ
IV re
imbu
rses
6 te
sts
per
year
dur
ing
the
first
yea
r, 4
durin
g ye
ars
2 to
5 a
nd 1
test
per
yea
r afte
r the
5th y
ear.
FIS
H a
naly
sis
is re
imbu
rsed
onl
y if
CB
A
is n
ot c
ontri
butiv
e. T
he c
urre
nt p
rice
of a
BC
R-A
BL1
mol
ecul
ar te
stin
g, a
ccor
ding
to th
e “A
rtic
le 3
3bis
” is
aro
und
125
euro
s B
300
0), a
nd, n
owad
ays,
INA
MI/R
IZIV
reim
burs
es 4
test
s pe
r yea
r.
23
Tab
le X
I. D
efini
tion
of th
e re
spon
se to
any
TK
I, fir
st li
ne.2
The
defi
nitio
ns a
re th
e sa
me
for
patie
nts
in C
P, A
P, a
nd B
P, a
nd a
pply
als
o to
2nd
line
trea
tmen
t, w
hen
1st li
ne
trea
tmen
t was
cha
nged
for
into
lera
nce.
In c
ase
of c
ytog
enet
ic o
r m
olec
ular
dat
a cl
ose
to th
e in
dica
ted
va-
lues
, a r
epet
ition
of t
he te
sts
is r
ecom
men
ded
.
Tim
eO
pti
mal
War
nin
gs
Fai
lure
Bas
elin
eN
AH
igh
risk
scor
es o
r C
CA
/Ph+
, “m
ajor
rout
e” a
bnor
mal
ities
*N
A
3 m
on
ths
Ph+
≤ 35
% a
nd B
CR
-AB
L1 ≤
10%
Ph+
36-
95%
and
/or B
CR
-AB
L1 >
10%
No
CH
R a
nd/o
r Ph+
> 9
5%
6 m
on
ths
Ph+
= 0
% a
nd B
CR
-AB
L1 <
1%
Ph+
1-3
5% a
nd/o
r BC
R-A
BL1
1-1
0%P
h+ >
35%
and
/or B
CR
-AB
L1 >
10%
12 m
ont
hs
BC
R-A
BL1
≤ 0
.1%
BC
R-A
BL1
0.1
– 1
%P
h+ >
0 %
and
/or B
CR
-AB
L1 >
1%
Th
en a
nd
at
any
ti
me
BC
R-A
BL1
≤ 0
.1%
CC
A/P
h- (-
7 or
7q-
)Lo
ss o
f CH
RLo
ss o
f CC
yRC
onfir
med
loss
of M
MR
**M
utat
ions
CC
A/P
h+
*“M
ajor
rout
e” a
bno
rmal
ities
incl
udes
tris
omy
8, t
risom
y P
h [+
der
(22)
t(9;2
2)(q
34;
q11)
],iso
chro
mos
ome
17 [i
(17)
(q10
)], tr
isom
y 19
, and
id
er(2
2)(q
10)t(
9;22
)(q3
4;q1
1).
Not
e th
at c
hrom
osom
e 9
del
etio
ns a
nd v
aria
nt tr
ansl
ocat
ion
at d
iagn
osis
hav
e no
pro
gnos
tic v
alue
.
**In
tw
o co
nsec
utiv
e te
sts,
of w
hich
one
with
a B
CR
-AB
L1 tr
ansc
ript l
evel
s ≥
1%
.N
A: N
ot a
pp
licab
le. C
CA
/Ph+
: Clo
nal C
hrom
osom
e A
bno
rmal
ities
in P
h+ c
ells
; defi
ne a
n ac
cele
rate
d p
hase
in T
KI-
naiv
e p
atie
nts,
d
efine
a c
lona
l evo
lutio
n an
d a
ther
apy
failu
re in
TK
I-tre
ated
pat
ient
s. C
CA
/Ph-
: Clo
nal C
hrom
osom
e A
bno
rmal
ities
in P
h- c
ells
; no
effe
ct
on o
utco
me
in th
e ab
senc
e of
dys
pla
sia,
with
the
exce
ptio
n of
ab
norm
aliti
es o
f chr
omos
ome
7. M
MR
= B
CR
-AB
L1 IS
≤ 0
.1%
.
24
Tab
le X
I. D
efini
tion
of th
e re
spon
se to
any
TK
I, fir
st li
ne.2
The
defi
nitio
ns a
re th
e sa
me
for
patie
nts
in C
P, A
P, a
nd B
P, a
nd a
pply
als
o to
2nd
line
trea
tmen
t, w
hen
1st li
ne
trea
tmen
t was
cha
nged
for
into
lera
nce.
In c
ase
of c
ytog
enet
ic o
r m
olec
ular
dat
a cl
ose
to th
e in
dica
ted
va-
lues
, a r
epet
ition
of t
he te
sts
is r
ecom
men
ded
.
Tim
eO
pti
mal
War
nin
gs
Fai
lure
Bas
elin
eN
AH
igh
risk
scor
es o
r C
CA
/Ph+
, “m
ajor
rout
e” a
bnor
mal
ities
*N
A
3 m
on
ths
Ph+
≤ 35
% a
nd B
CR
-AB
L1 ≤
10%
Ph+
36-
95%
and
/or B
CR
-AB
L1 >
10%
No
CH
R a
nd/o
r Ph+
> 9
5%
6 m
on
ths
Ph+
= 0
% a
nd B
CR
-AB
L1 <
1%
Ph+
1-3
5% a
nd/o
r BC
R-A
BL1
1-1
0%P
h+ >
35%
and
/or B
CR
-AB
L1 >
10%
12 m
ont
hs
BC
R-A
BL1
≤ 0
.1%
BC
R-A
BL1
0.1
– 1
%P
h+ >
0 %
and
/or B
CR
-AB
L1 >
1%
Th
en a
nd
at
any
ti
me
BC
R-A
BL1
≤ 0
.1%
CC
A/P
h- (-
7 or
7q-
)Lo
ss o
f CH
RLo
ss o
f CC
yRC
onfir
med
loss
of M
MR
**M
utat
ions
CC
A/P
h+
*“M
ajor
rout
e” a
bno
rmal
ities
incl
udes
tris
omy
8, t
risom
y P
h [+
der
(22)
t(9;2
2)(q
34;
q11)
],iso
chro
mos
ome
17 [i
(17)
(q10
)], tr
isom
y 19
, and
id
er(2
2)(q
10)t(
9;22
)(q3
4;q1
1).
Not
e th
at c
hrom
osom
e 9
del
etio
ns a
nd v
aria
nt tr
ansl
ocat
ion
at d
iagn
osis
hav
e no
pro
gnos
tic v
alue
.
**In
tw
o co
nsec
utiv
e te
sts,
of w
hich
one
with
a B
CR
-AB
L1 tr
ansc
ript l
evel
s ≥
1%
.N
A: N
ot a
pp
licab
le. C
CA
/Ph+
: Clo
nal C
hrom
osom
e A
bno
rmal
ities
in P
h+ c
ells
; defi
ne a
n ac
cele
rate
d p
hase
in T
KI-
naiv
e p
atie
nts,
d
efine
a c
lona
l evo
lutio
n an
d a
ther
apy
failu
re in
TK
I-tre
ated
pat
ient
s. C
CA
/Ph-
: Clo
nal C
hrom
osom
e A
bno
rmal
ities
in P
h- c
ells
; no
effe
ct
on o
utco
me
in th
e ab
senc
e of
dys
pla
sia,
with
the
exce
ptio
n of
ab
norm
aliti
es o
f chr
omos
ome
7. M
MR
= B
CR
-AB
L1 IS
≤ 0
.1%
.
Tab
le X
II. D
efini
tion
of r
espo
nse
for
2nd li
ne tr
eatm
ent,
in c
ase
of fa
ilure
of i
mat
inib
.2
Thes
e d
efini
tions
can
not a
pply
to th
e ev
alua
tion
of th
e re
spon
se to
3rd li
ne tr
eatm
ent.
Tim
eO
pti
mal
War
nin
gs
Fai
lure
Bas
elin
eN
AN
o C
HR
or
Loss
of C
HR
on
Imat
inib
or
Lack
to C
yR to
1st li
ne T
KI o
rH
igh
risk
NA
3 m
on
ths
Ph+
< 6
5% a
nd/o
r BC
R-A
BL1
≤ 1
0%Ph
+ 65
-95%
and
/or B
CR
-AB
L1 >
10%
No
CH
R o
r Ph+
> 9
5% o
r New
m
utat
ions
6 m
on
ths
Ph+
< 3
5% a
nd/o
r BC
R-A
BL1
≤ 1
0%P
h+ 3
5-65
%P
h+ >
65%
and
/or B
CR
-AB
L1
> 1
0% a
nd/o
r New
mut
atio
ns
12 m
ont
hsP
h+ =
0%
and
/or B
CR
-AB
L1 ≤
1%
Ph+
1-3
5% a
nd/o
r BC
R-A
BL1
1-1
0%P
h+ >
35
% a
nd/o
r BC
R-A
BL1
>
10%
and
/or N
ew m
utat
ions
Th
en a
nd
at
any
ti
me
BC
R-A
BL1
≤ 0
.1%
CC
A/P
h- (-
7 or
7q-
) or B
CR
-AB
L1 >
0.1
%Lo
ss o
f CH
R o
rLo
ss o
f CC
yR o
r PC
yR o
rC
onfir
med
loss
of M
MR
* or
New
mut
atio
ns o
rC
CA
/Ph+
*In t
wo
cons
ecut
ive
test
s, o
f whi
ch o
ne w
ith a
BC
R-A
BL1
tran
scrip
t lev
els
≥ 1
%.
25
1. S
chiff
er C
A. B
CR-
ABL
tyro
sine
kin
ase
inhi
-bi
tors
for
chro
nic
mye
loge
nous
leuk
emia
. N E
ngl J
M
ed 2
007;
357:
258-
65.
2. B
acca
rani
M, D
eini
nger
MW
, Ros
ti G
, et a
l. E
urop
ean
Leuk
emia
Net
rec
omm
enda
tion
s fo
r th
e m
anag
emen
t of c
hron
ic m
yelo
id le
ukem
ia: 2
013.
Bl
ood
2013
;122
:872
-84.
3. C
orte
s J,
Kan
tarj
ian
H. H
ow I
trea
t new
ly d
iag-
nose
d ch
roni
c ph
ase
CM
L.B
lood
201
2;12
0:13
90-7
.4.
Dru
ker
BJ, G
uilh
ot F
, O’B
rien
SG
, et a
l. Fi
ve- y
ear
follo
w-u
p of
pat
ient
s rec
eivi
ng im
atin
ib fo
r ch
roni
c m
yelo
id le
ukem
ia. N
Eng
l J M
ed 2
006;
355:
2408
-17.
5. d
e La
valla
de H
, App
erle
y JF
, Kho
rash
ad JS
, et
al.
Imat
inib
for
new
ly d
iagn
osed
pat
ient
s w
ith
chro
nic
mye
loid
leuk
emia
: inc
iden
ce o
f sus
tain
ed
resp
onse
s in
an
inte
ntio
n-to
-tre
at a
naly
sis.
J C
lin
Onc
ol 2
008;
26:3
358-
63.
6. S
aglio
G, K
im D
W, I
ssar
agri
sil S
, et a
l. N
ilotin
ib
vers
us im
atin
ib fo
r ne
wly
dia
gnos
ed c
hron
ic m
ye-
loid
leuk
emia
. N E
ngl J
Med
201
0;36
2:22
51-9
.
7. K
anta
rjia
n H
, Sha
h N
P, H
ochh
aus
A, e
t al.
Das
atin
ib v
ersu
s im
atin
ib in
new
ly d
iagn
osed
ch
roni
c-ph
ase
chro
nic
mye
loid
leuk
emia
. N E
ngl J
M
ed 2
010;
362:
2260
-70.
8. H
asfo
rd J,
Bac
cara
ni M
, Hof
fman
n V,
et a
l. Pr
edic
ting
com
plet
e cy
toge
neti
c re
spon
se a
nd s
ub-
sequ
ent p
rogr
essi
on-f
ree
surv
ival
in 2
060
pati
ents
w
ith C
ML
on im
atin
ib tr
eatm
ent:
the
EU
TOS
scor
e. B
lood
201
1;11
8:68
6-92
.9.
Jabb
our
E, C
orte
s J, N
azha
A, e
t al.
EUTO
S sc
ore
is n
ot p
redi
ctiv
e fo
r su
rviv
al a
nd o
utco
me
in p
atie
nts
with
ear
ly c
hron
ic p
hase
chr
onic
mye
loid
leuk
emia
tr
eate
d w
ith ty
rosi
ne k
inas
e in
hibi
tors
: a s
ingl
e in
sti-
tutio
n ex
peri
ence
. Blo
od 2
012;
119:
4524
-6.
10. C
orte
s JE
, Kim
DW
, Pin
illa-
Ibar
z J,
et a
l. A
pha
se 2
tria
l of p
onat
inib
in P
hila
delp
hia
chro
mos
ome-
posi
tive
leuk
emia
s. N
Eng
l J M
ed
2013
;369
:178
3-96
.11
. Mar
in D
, Ibr
ahim
AR
, Luc
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mon
ths
is th
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ly r
equi
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ent f
or p
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g ou
tcom
e fo
r pa
tien
ts w
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ho h
ave
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olec
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t 2 y
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r re
mis
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ic m
yelo
id le
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win
g da
satin
ib c
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mia
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ree
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060
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S sc
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al a
nd o
utco
me
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nts
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ic p
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chr
onic
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loid
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ne k
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R-A
BL1
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vels
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ths
is th
e on
ly r
equi
rem
ent f
or p
redi
ctin
g ou
tcom
e fo
r pa
tien
ts w
ith c
hron
ic m
yelo
id le
ukem
ia tr
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d
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ase
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14. M
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ot J,
et a
l. D
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f im
atin
ib in
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ient
s w
ith c
hron
ic
mye
loid
leuk
aem
ia w
ho h
ave
mai
ntai
ned
com
plet
e m
olec
ular
rem
issi
on fo
r at
leas
t 2 y
ears
: the
pro
s -pe
ctiv
e, m
ulti
cent
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top
Imat
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l. La
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15. R
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PA, G
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J, M
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A,
Seym
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JF, G
rigg
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Dur
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plet
e m
ole -
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r re
mis
sion
of c
hron
ic m
yelo
id le
ukem
ia fo
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win
g da
satin
ib c
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, des
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e im
atin
ib m
esyl
ate
in p
atie
nts
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iagn
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d ph
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nic
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17. H
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t CM
L bl
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y J.
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k Z
K, M
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uz R
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man
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ic m
yelo
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pa M
, Dor
liac-
Llac
er P
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ul
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nanc
ies
in a
wom
an w
ith c
hron
ic m
yelo
id le
u-ke
mia
exp
osed
to n
ilotin
ib d
urin
g th
e fir
st tr
imes
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r of
her
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ond
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chr
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201
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, tr
ansi
ent i
nhib
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CR-
ABL
with
das
atin
ib 1
00
mg
daily
ach
ieve
s ra
pid
and
dura
ble
cyto
gene
tic r
es-
pons
es a
nd h
igh
tran
sfor
mat
ion-
free
sur
viva
l rat
es
in c
hron
ic p
hase
chr
onic
mye
loid
leuk
emia
pat
ient
s w
ith r
esis
tanc
e, s
ubop
timal
res
pons
e or
into
lera
nce
to im
atin
ib. H
aem
atol
ogic
a 20
10;9
5:23
2-40
.
38. C
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s JE
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tarj
ian
HM
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mm
endo
rf T
H,
et a
l. Sa
fety
and
effi
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of b
osut
inib
(SK
I-60
6) in
ch
roni
c ph
ase
Phila
delp
hia
chro
mos
ome-
posi
tive
chro
nic
mye
loid
leuk
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pat
ient
s w
ith r
esis
tanc
e or
into
lera
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to im
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ib. B
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