Chronic myeloid leukaemia David Marin, Imperial College London.
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Transcript of Chronic myeloid leukaemia David Marin, Imperial College London.
Chronic myeloid leukaemia
David Marin,
Imperial College London
Time from diagnosis (years)
20181614121086420
Su
rviv
al
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
Survival of 246 patients who received Interferon therapy within the UK Medical Research Council's CML-III trial (1986-1994)
Survival of 224 patients who received first line imatinib therapy therapy in Hammersmith Hospital (2000-2008)
28 May 2001
2001
(From Novartis Pharma)
(C(C3030HH3535NN77SOSO44))
NN
NN
NN
HH
NN
HH
NNNN
NN
OO
NN
Imatinib mesylate (STI571 - Glivec)
1998
Substrate
Imatinib
Bcr-Abl
Y = TyrosineP = Phosphate
Bcr-Abl
ATP
Substrate
PPP
P
Y
Mechanism of action of imatinib
Bosutinib(SK-606)
Ponatinib
Imatinib
(Phos. IC50)
PDGFR
72 nM >Kit
99 nM >BcrAbl
221 nM >Src
>1000 nM
Nilotinib
(Phos. IC50)
BcrAbl
20 nM >PDGFR
75 nM >Kit
209 nM >Src
>1000 nM
Dasatinib
(Phos. IC50)
Src
0.1 nM >BcrAbl
1.8 nM >PDGFR
2.9 nM >Kit
18 nM
Bosutinib
(Phos. IC50)
Src
3 nM >BcrAbl
85 nM >PDGFR
>3000 >Kit
>10000 nM
1. Manley PW, et al. Proc Am Assoc Cancer Res 2007;48:772.2. Weisberg E, et al. Cancer Cell 2005;7:1129.3. Remsing Rix LL, et al. Leukemia 2009;23:477.
Target kinases for the 4 TKIs
Comparison of Kinase Inhibitors: Toxicity
Licensed First Line Second Line
Imatinib 1st and 2nd line Gold standard No published experience
Nilotinib 1st and 2nd line Early data suggest small advantage over Imatinib
40-50% CCyR
Dasatinib 1st and 2nd line Early data suggest small advantage over Imatinib
40-50% CCyR
Bosutinib No (1st line soon) Not yet clear, maybe slightly better than imatinib
40-50% CCyR
Ponatinib No (2nd line soon?) No yet tried 10-30% of responses in 3rd line (T315I active)
Darling, this morning I saw a new
patient with CML and I prescribed him a TKI.
I have done my duty!¿Darling,
Should not you check
whether the patient is
responding?
Marin, Blood 2008
Pro
ba
bil
ity
of
PF
S
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Months from starting imatinib therapy
60544842363024181260
0.1
0.0
Patients who fail to achieve CCyR
progress to advance phase (n=204)
p<0.0001
CCyRNo CCyR
% w
ithou
t pro
gres
sion
0
10
20
30
40
50
60
70
80
90
100
Months since randomization0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Patients who achieve CCyR do well and patients who fail to achieve CCyR do badly (IRIS data)
p<0.001
Estimated rate (95% CI)at 42 months:
n=363 93% (89%, 96%)n=139 74% (66%, 92%)
Time from diagnosis (years)
76543210
Pro
vabi
lity
of O
S
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Interferon controls, n =246, aRR=1
TKI non responders, n= 37aRR= 0.76, p=0.65
Imatinib responders, n= 179,aRR= 0.18, p<0.0001
2G-TKI responders, n=67,aRR=0.05, p=0.003
TKI therapy only prolongs live on those patients who achieve CCyR
Ibrahim, Haematologica 2011
• How we know that the patient has achieved CCyR?
• When the patient has to achieve CCyR?
• How we make sure that the patient remains in CCyR?
Patients must achieve CCyR
• How we know that the patient has achieved CCyR?
• When the patient has to achieve CCyR?
• How we make sure that the patient remains in CCyR?
Patients must achieve CCyR
• How we know that the patient has achieved CCyR?
• When the patient has to achieve CCyR?
• How we make sure that the patient remains in CCyR?
Patients must achieve CCyR
Total num
ber of leukaemia cells2
3
4
5
6
7
8
9
10
11
12
13
0
10
10
10
10
10
10
10
10
10
10
10
10
10
0
0.0001
0.001
0.01
0.1
1
10
100
BC
R-A
BL
/AB
L r
atio
(%
)
Leucocytosis
RT-PCR positive
RT-PCR negative
Ph-chromosome pos
(Ph-negative)
Adapted from Lin et al. Genes Chromosomes and Cancer 1995
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Total num
ber of leukaemia cells
1011
1010
109
108
107
1012
1013High WBC
Ph +
Metaphases
CHR
Ph +
Metaphases
Normal WBC
Transcript level at
diagnosis
PFS and probability of CCyR according to the haematological response at 3 months
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
bab
ilit
y o
f P
FS
Cu
mu
late
in
cid
ence
o
f C
CyR
Months from starting imatinib therapy
PFS: p=0.002
CCyR: p=0.0003
No CHR, n=8
CHR, n=216
Marin, Blood 2008
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Total num
ber of leukaemia cells
1011
1010
109
108
107
1012
1013
Ph +
Metaphases
CHR
MiCyRPh +
Ph -
Metaphases
Transcript level at
diagnosis
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Total num
ber of leukaemia cells
1011
1010
109
108
107
1012
1013
Ph +
Metaphases
MiCyRPh +
Ph -MiCyR
CHR
Ph +
Ph -
Metaphases
MCyR
Transcript level at
diagnosis
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Total num
ber of leukaemia cells
1011
1010
109
108
107
1012
1013
MCyRMCyR
CCyRPh -
Metaphases
Ph +
Metaphases
Ph +
Ph -MiCyR
CHR
Ph +
Ph -
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Total num
ber of leukaemia cells
1011
1010
109
108
107
1012
1013
CCyRCCyR
Ph -
Metaphases
MMR
MCyR
Ph +
Metaphases
Ph +
Ph -MiCyR
CHR
Ph +
Ph -
Ph -
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Total num
ber of leukaemia cells
1011
1010
109
108
107
1012
1013
Ph -
MMRMMR
CMRPh -
Metaphases
CCyR
MCyR
Ph +
Metaphases
Ph +
Ph -MiCyR
CHR
Ph +
Ph -
Ph -
• How we know that the patient has achieved CCyR?
• When the patient has to achieve CCyR?
• How we make sure that the patient remains in CCyR?
Patients must achieve CCyR
605448423630241812600.0
Months from start of imatinib therapy
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Cu
mu
lativ
e in
cid
en
ce o
f re
spo
nse 1-35% Ph+
36-95% Ph+
96-100% Ph+
605448423630241812600.0
Months from start of imatinib therapy
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Cu
mu
lativ
e in
cid
en
ce o
f re
spo
nse 1-35% Ph+
36-95% Ph+
96-100% Ph+
A, 3 months B, 6 months
de Lavallade, JCO 2008
Probability of CCyR according to the cytogenetic response at 3 and 6 months (n=204)
p< 0.0001 p< 0.0001
• How we know that the patient has achieved CCyR?
• When the patient has to achieve CCyR?
• How we make sure that the patient remains in CCyR?
Patients must achieve CCyR
How to monitor the patient and desired responses
10
1
0.1
0.01
0.001
100
0.0001
BC
R/A
BL/
AB
L ra
tio (
%)
CCyR
6 9 15 18 21 24 273
Months from start of imatinib
12
Level of detection
3 log
RQ-PCR
G-Banding•MiCyR?•MCyR?•CCyR?{
•MMR?•Early detection of relapse{
FISH negative
So, what is the best first line
therapy?
ENESTnd: Nilotinib vs Imatinib in CML-CP
Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral)30
Study Design and Endpoints
• Primary endpoint: MMR at 12 months
• Key secondary endpoint: Durable MMR at 24 months
• Other endpoints: CCyR by 12 months, time to MMR and CCyR, EFS, PFS, time to AP/BC on
study treatment, OS including follow-up*Stratification by Sokal risk score
Imatinib 400 mg QD (n = 283)
Nilotinib 300 mg BID (n = 282)
RANDOMIZED*
Nilotinib 400 mg BID (n = 281)• N = 846
• 217 centers
• 35 countries
Follow-up 5 years
31 ASCO 2010, Abstract # LBA6500
Dasatinib Versus Imatinib Study In Treatment-naïve CML: DASISION (CA180-056). Design
● Primary endpoint: Confirmed CCyR by 12 months
● Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival
Follow-up
5 yearsRandomized*
Imatinib 400 mg QD (n=260)
Dasatinib 100 mg QD (n=259)• N=519
• 108 centers
• 26 countries
*Stratified by Hasford risk score
ENESTnd: Nilotinib vs Imatinib in CML-CP
Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral)
80%85%
78% 82%
65%74%
0%
20%
40%
60%
80%
100%
Month 12 Overall
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
CCyR Rates* by 12 Months and Overall
P < .0001
P < .001
% C
CyR
32Data cut-off: 2Jan2010
n = 282 n = 281 n = 283
P < .001
P = .017
• Among patients who had a cytogenetic assessment at 18 months (n = 442/846), the rates of CCyR were:
• 99%, 99%, and 89% for nilotinib 300 mg BID, 400 mg BID, and imatinib*ITT population
n = 282 n = 281 n = 283
33 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib
in CML-CP. CCyR rates (ITT)
54
7378
83
31
5967
72
0
20
40
60
80
100
Mo 3 Mo 6 Mo 9 Mo 12
P=0.0011Dasatinib 100mg QD Imatinib 400mg QD
CCyR(%)
• By analysis of time to CCyR, likelihood of achieving CCyR at any time ~50% higher with dasatinib than with imatinib (stratified log-rank P<0.0001; HR=1.53)
ENESTnd: Nilotinib vs Imatinib in CML-CP
Larson R. A. et al.JCO 28:7s ASCO 2010 (suppl; abs 6501, Oral)
Patient DispositionNilotinib
300 mg BIDn = 282
Nilotinib400 mg BID
n = 281
Imatinib400 mg QDn = 283
Still on treatment 80% 81% 75%Discontinued, % 20 19 25 Disease progression* <1 4
Suboptimal response/ treatment failure*# 6 2 8
Adverse events 5 8
Abnormal lab. values 2 2 1
Death 1 0 0
Protocol violation 2 2 1
Other reason 4 3 3
Data cut-off: 2Jan2010
*Investigator assessment of criteria
#Patients were required to discontinue nilotinib 300 mg BID for suboptimal response but could remain on nilotinib 400 mg BID
<1
10
35 ASCO 2010, Abstract # LBA6500
DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Treatment Discontinuations
*Includes consent withdrawal, pregnancy, lost to follow-up and death
% Patients
Dasatinib 100 mg QDn=258
Imatinib 400 mg QDn=258
Still on treatment 84.5 81.4
Discontinued 15.5 18.6
Treatment failure including progression
5.0 8.9
Study drug toxicity 5.0 4.3
Adverse event unrelated 1.2 0.4
Other reason* 4.2 5.0
48% in CCyR on imatinib
29% in CCyR but not on imatinib
7% alive but not in CCyR
94%
84%
77%
48%
10% death because the CML
6% death non CML
Outcome in 282 patients treated with imatinib first line in Hammersmith Hospital
Outcome in 135 patients treated with second line dasatinib or nilotinib in Hammersmith Hospital
Pro
ba
bil
ity
Time (years) from the onset of second line therapy
OS, 82%
C-CCyRS, 54%
EFS, 35%
Time (years) from the onset of second line therapy
Pro
ba
bil
ity
of
cC
Cy
R-S
p=0.008
CCyR at 12 months, n=48
no CCyR at 12 months, n=51
Outcome in 135 patients treated with second line dasatinib or nilotinib according to the cytogenetic
response achieved at 12 months
Time (years) from the onset of second line therapy
Pro
ba
bil
ity
CCyR at 12 months, n=48
no CCyR at 12 months, n=51
Outcome in 135 patients treated with second line dasatinib or nilotinib according to the cytogenetic
response achieved at 12 months
It is far from certain which is going to be
the best line therapy as the log term
benefit of a modest improvement in the
CCyR rate induced by a given drug may
be easily overcome by a higher therapy
discontinuation rate on that drug
Cu
mu
lati
ve i
nci
de
nce
of
CC
yR
Time from diagnosis (months)
Cumulative incidence of CCyR in patients treated with dasatinib first line therapy in the SPIRIT-II trial according to
the molecular response achieved at 3 months
3 months BCR-ABL/ABL <10%
3 months BCR-ABL/ABL >10%
p=0.02
Time from diagnosis (months)
Cu
mu
lati
ve i
nci
de
nce
of
CC
yR
Dasatinib
Imatinib
Cumulative incidence of CCyR in the SPIRIT-II trial according to the treatment arm and the molecular
response achieved at 3 months
3 months BCR-ABL/ABL <10%
3 months BCR-ABL/ABL >10%
The key principles of therapy are:
1.Promptly identification of the high risk patients
2.Change of therapy according to tolerance and response
What is the best why to detect
who is not doing well?
605448423630241812600.0
Months from start of imatinib therapy
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Cu
mu
lativ
e in
cid
en
ce o
f re
spo
nse 1-35% Ph+
36-95% Ph+
96-100% Ph+
605448423630241812600.0
Months from start of imatinib therapy
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Cu
mu
lativ
e in
cid
en
ce o
f re
spo
nse 1-35% Ph+
36-95% Ph+
96-100% Ph+
A, 3 months B, 6 months
de Lavallade, JCO 2008
Probability of CCyR according to the cytogenetic response at 3 and 6 months (n=204)
p< 0.0001 p< 0.0001
We can do better than
that!
We can identify what is the 3 months transcript level that predicts for overall survival with the maximal sensitivity and specify
Pro
ba
bil
ity
of
su
rviv
al
Time from onset of imatinib therapy (years)
BCR-ABL/ABL<10% OS= 93.3%
BCR-ABL/ABL>10% OS= 54%
p<0.0001
Survival in 282 patients treated with imatinib first line in Hammersmith Hospital according to the molecular response
achieved at 3 months
Pro
ba
bil
ity
of
c-C
Cy
RS
Time from onset of imatinib therapy (years)
p =0.0002
Outcome in 282 patients treated with imatinib first line in Hammersmith Hospital according to the molecular response
achieved at 3 months
BCR-ABL/ABL<10%, c-CCyRS= 91%
BCR-ABL/ABL>10% c-CCyRS= 48%
Off Imatinib
CMR
BC
R-A
BL
1/A
BL
1 (
log
)Evolution of the transcript level in 282 patients treated
with imatinib first line therapy
high transcript level at 3 month
low transcript level at 3 month
Cum
ula
tive
inci
denc
e o
f C
MR
Time from onset of therapy (years)
8-year cumulative incidence of CMR on imatinib therapy according to the BCR-ABL1 transcript level at 3 months.
3-month transcript ratio ≤0.61% (n=57), 8-year CI of CMR of 84.7%,
3-month transcript ratio >0.61% (n=222), 8-years CI of CMR of 1.5%
p<0.0001
It is important to achieve MMR?
Molecular responses
10
1
0.1
0.01
0.001
100
0.0001
BC
R/A
BL/
AB
L ra
tio (
%)
CCyR
6 9 15 18 21 24 273
Months from start of imatinib
12
Level of detection
3 log
FISH negative
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
ba
bil
ity
of
PF
S
Months from starting imatinib therapy
CCyR with no MMR, n=91
CCyR with MMR, n= 41
p= 0.4
18 months
Marin et al, Blood 2008
PFS is similar in patients with CCyR regardless of the depth of molecular
response
PFS similar in patients with CCyR regardless of depth of molecular response
Druker BJ, et al. NEJM, 2006;355(25):2408-17.
PFS is similar in patients with CCyR regardless of depth of molecular response
Kantarjian HM, et al. Blood. 2006;108:1835-1840.
Probability of loss of CCyR according Probability of loss of CCyR according to the level of molecular response to the level of molecular response
Marin et al, Blood 2008
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0P
rob
abil
ity
of
los
s o
f C
Cy
R
Months from starting imatinib therapy
CCyR with no MMR, n=91
CCyR with MMR, n= 41
p= 0.006
18 months
24.6%
0%
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0P
rob
abil
ity
of
los
s o
f C
Cy
R
Months from starting imatinib therapy
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0P
rob
abil
ity
of
los
s o
f C
Cy
R
Months from starting imatinib therapy
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
60544842363024181260 60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0P
rob
abil
ity
of
los
s o
f C
Cy
R
Months from starting imatinib therapy
CCyR with no MMR, n=91
CCyR with MMR, n= 41
p= 0.006
18 months
24.6%
0%
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
bab
ilit
y o
f lo
ss
of
CC
yR
Months from starting imatinib therapy
CCyR with no MMR, n= 92
CCyR with MMR, n= 32
p= 0.04
12 months
23.9%
2.6%
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
bab
ilit
y o
f lo
ss
of
CC
yR
Months from starting imatinib therapy
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
bab
ilit
y o
f lo
ss
of
CC
yR
Months from starting imatinib therapy
60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
60544842363024181260 60544842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
bab
ilit
y o
f lo
ss
of
CC
yR
Months from starting imatinib therapy
CCyR with no MMR, n= 92
CCyR with MMR, n= 32
p= 0.04
12 months
23.9%
2.6%
The definition of MMR is
wrong
Do not be silly!
Problems with MMR
• The depth of the molecular response in a given patient is basically driven by the patient’s adherence to therapy
• The definition of MMR is arbitrary
Problems with MMR
• The depth of the molecular response in a given patient is basically driven by the patient’s adherence to therapy
• The definition of MMR is arbitrary
10
1
0.1
0.01
0.001
100
BC
R-A
BL/
AB
L ra
tio (
%)
Time from start of imatinib
CCyR
3 log
There is a great variability in the response to imatinib. I wonder why
0.0001
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Study design
Time from start of imatinib• hOCT1 level• MDR-1 polymorphisms• BCR-ABL transcript type• BCR-ABL transcript level• Sokal score• Hb• WBC• Sex• Age
We correlated all these variables with the molecular response achieved by the patient
MEMS
Imatinib plasma
level
TKD mutations
• Records the time of opening the container
• Most reliable method of measuring adherence
• Our patients: not told about the chip
Microelectronic Monitoring System (MEMS 6 Trackcap)
≥100%95–99%90–95%80–90%<80%
90
80
70
60
50
40
30
20
10
0
Pro
port
ion
of p
atie
nts
(%)
Percentage of intended dose
13.8% 12.6%8%
25.3%
40.2%
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Long term adherence to imatinib
Percentage of intended dose≥100%95–99%90–95%80–90%<80%
Pro
port
ion
of p
atie
nts
(%)
100
90
80
70
60
50
40
30
20
10
0
Self reporting
Pill count
MEMS
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Lack of adherence is underestimated by conventional methods
Well, some patients miss a
few doses, so what?
6-year probability of response
Adherence rate n MMR (%) 4-log (%) CMR (%)
100%<99%
3651
p=0.0191.158.6
p=0.0279.938.6
p=0.0246.722.7
>95%<95%
5730
p<0.00194.529.3
p<0.00177.215.0
p=0.00245.28.2
>90%<90%
6423
p<0.00193.713.9
p<0.00176.04.3
p=0.00243.8
0
>85%<85%
6918
p<0.00185.811.8
p=0.00169.25.6
p=0.00740.8
0
>80%<80%
7512
p=0.00181.2
0
p=0.00563.8
0
p=0.0437.1
0
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Achievement of a molecular response is related to the adherence to imatinib therapy
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
6-year probability of MMR according to the measured adherence rate
p<0.001
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
6-year probability of CMR according to the measured adherence rate
p=0.002
Variables n MMR (%) 4-log (%) CMR (%)
Hemoglobin ≤115 g/l>115 g/lRR
4047
p=0.03659.280.7
1.186, p=0.012
p=0.0339.569.1
1.323, p=0.01
p=0.01114.747.6
1.209, p=0.07
Leukocytes ≤140 x 109/l>140 x 109/lRR
4443
p=0.01278.863.1
0.996, p=0.008
p=0.02256.737.6
0.996, p=0.015
p=0.1735.428.1
0.996, p=0.11
BCR-ABL1/ABL1 ratio≤100%>100%RR
4443
p=0.2571.452.6
0.996, p=0.44
p=0.03853.026.6
0.971, p=0.002
p=0.132.78.4
0.979, p=0.13
hOCT1 transcript level ≤0.16>0.16RR
3030
p<0.00155.281.4
2.199, p<0.001
p=0.0142.064.8
1.990, p=0.001
p=0.0216.645.3
1.665, p=0.04
Imatinib plasma level ≤1 g/ml>1 g/mlRR
4341
p=0.0260.183.2
2.11, p=0.01
p=0.0753.068.0
2.50, p=0.06
p=0.1423.344.4
2.25, p=0.09
Adherence rate>90%≤90%RR
6423
p<0.00193.713.9
1.093, p<0.001
p<0.00176.04.3
1.104, p=0.002
p=0.00243.8
0RR= 1.135, p=0.012
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Other variables are also predictive for the achievement of molecular response
But adherence to therapy is the critical factor for achieving molecular response
• MMR– adherence to imatinib therapy, RR=11.17 (p=0.001) – hOCT1 transcript level, RR=1.79 (p=0.038)
• CMR– adherence to imatinib therapy, RR=19.35 (p=0.004)
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Imatinib plasma levels are not an independent predictor of molecular response
Total population Adherent patients
Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388.
Who will sustain CCyR?
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Study design
Time from start of imatinib• hOCT1 level• MDR-1 polymorphisms• BCR-ABL transcript type• BCR-ABL transcript level• Sokal score• Hb• WBC• Sex• Age
We correlated all these variables with the molecular response achieved by the patient
MEMS
Cu
mu
late
inci
den
ce o
f lo
ss o
f C
CyR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
Adherence rate ≤85%, n=18
Adherence rate >85%, n=69
Cu
mu
late
inci
den
ce o
f lo
ss o
f C
CyR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
Cu
mu
late
inci
den
ce o
f lo
ss o
f C
CyR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
Adherence rate ≤85%, n=18
Adherence rate >85%, n=69
Pro
bab
ility
of
imat
inib
fai
lure
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
Adherence rate ≤85%, n=18
Adherence rate >85%, n=69
Pro
bab
ility
of
imat
inib
fai
lure
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
Pro
bab
ility
of
imat
inib
fai
lure
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
Adherence rate ≤85%, n=18
Adherence rate >85%, n=69
Poor adherent patients have a higher probability of losing the CCyR and a lower EFS
Ibrahim, Blood 2011
On multivariate analysis, the adherence rate and
having failed to achieve a major molecular
response are the only independent predictors for
loss of CCyR and discontinuation of imatinib
therapy.
Ibrahim, Blood 2011
Pro
bab
ility
of
imat
inib
fai
lure
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
CCyR, no MMR, Adherence Rate ≤85%, n=11
MMR, n=53
CCyR, no MMR, Adherence Rate >85%, n=23
p=0.003
p<0.0001
Cu
mu
late
inci
den
ce o
f lo
ss o
f C
CyR
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Months from enrolment0
0.0
2418126
p<0.0001
CCyR, no MMR, Adherence Rate ≤85%, n=11
MMR, n=53
CCyR, no MMR, Adherence Rate >85%, n=23
p=0.0009
p<0.0001
Adherence and the achievement of MMR are the only independent predictors for outcome
Ibrahim, Blood 2011
Problems with MMR
• The depth of the molecular response in a given patient is basically driven by the patient’s adherence to therapy
• The definition of MMR is arbitrary
10
1
0.1
0.01
0.001
100
BC
R/A
BL/
AB
L ra
tio (
%)
Total num
ber of leukaemia cells
1011
1010
109
108
107
1012
1013
CCyRCCyR
Ph -
Metaphases
MMR
MCyR
Ph +
Metaphases
Ph +
Ph -MiCyR
CHR
Ph +
Ph -
Ph -
166 out of 282 patients who received imatinib as first line therapy were in CCyR at 12 months
Transcript level
OS
(%)
EFS
(%)
>0.1%
<0.1%
125
41
p=0.5
94.2
96.3
p=0.08
80.4
93.7
166 out of 282 patients who received imatinib as first line therapy were in CCyR at 12 months
Transcript level
OS
(%)
EFS
(%)
>0.1%
<0.1%
125
41
p=0.5
94.2
96.3
p=0.08
80.4
93.7
>0.53
<0.53
20
146
p=0.01
81.5
94.4
p<0.0001
29.5
74.3
It can not be a talk about CML
without mentioning KD
mutations
I am going to try to challenge the orthodox view about kinase domain mutations
The points I want to make are:
• The meaning of KD mutations is often misunderstood
• The uses in clinical practice are very limited
Sensitivity studies help us to choose the best antibiotic. Similarly mutation analysis help us to
choose the best TKI
Are you sure?
ASH 2008
Dasatinib 100 mg QD in CML-CP: 24-month data (034)
Figure 3. MCyR rates in patients with or without a baseline BCR-ABL mutation
PCyR
CCyR
%
100 mg once daily
(n=49)
55
41
14
70 mg BID
(n=50)
54
46
8
140 mg once daily
(n=50)
56
34
22
50 mg BID
(n=63)
48
37
11
100 mg once daily
(n=98)
66
54
12
70 mg BID
(n=96)
67
58
8
140 mg once daily
(n=89)
70
58
11
50 mg BID
(n=86)
67
57
10
0
20
40
60
80 Any BCR-ABL mutation No BCR-ABL mutation
10
1
0.1
0.01
0.001
100
0.0001
BC
R/A
BL/
AB
L ra
tio (
%)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Time since the onset of imatinib therapy (months)
Imatinib: 400 1000 800 600
100
75
50
25
0
Percen
tage o
f mutant transcripts
Interval from diagnosis to start of imatinib: 4 months
M244V
Group A, High transcript levels- mutant clone predominates
Khorashad, Leukemia 2006
10
1
0.1
0.01
0.001
100
0.0001
BC
R/A
BL/
AB
L ra
tio (
%)
0 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45
Time since the onset of imatinib therapy (months)
100
75
50
25
0
Percen
tage o
f mutant transcripts
Imatinib: 400 600 400
Group B, Low transcript levels- mutant clone predominates
S438C
Interval from diagnosis to start of imatinib: 2 months
Khorashad, Leukemia 2006
10
1
0.1
0.01
0.001
100
0.0001
BC
R/A
BL/
AB
L ra
tio (
%)
0 3 6 9 12 15 18 21 24 27 30 33 35 36 39 42 45
Time since the onset of imatinib therapy (months)
Imatinib: 400
100
75
50
25
0
Percen
tage o
f mutant transcripts
Interval from diagnosis to start of imatinib: 36 months
Group C, Variable transcript levels- mutant clone is rare
G250E
Khorashad, Leukemia 2006
What is the biological significance of KD mutations?
In order to answer this question we systematically screened all our CP (n=319) patients treated with imatinib for mutations regardless of whether or not they shown any sign of resistance
18 m12 m
Mutation=M244V, 55%
undetectable 5%
Mutation=0
20%
Mutation screening
Khorashad et al, JCO, 2008
13.9%
Cumulative Incidence of KD Mutations
Cum
ula
tive
inci
denc
e o
f K
D m
utat
ions
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.060544842363024181260
Months from starting imatinib therapy
Khorashad et al, JCO, 2008
Mutations in Patients who Achieved CCyR
214 CCyR patients: 6 (3%) with mutations
All of them lost CCyR T315I, L387M, S417F, E459K, G459K, and M351T
Median interval from mutation detection to loss of CCyR: 20.8 months
Median interval from mutation detection to any change in the BCR-ABL transcript level: 12 months
Khorashad et al, JCO, 2008
The Development of Mutation Predicts for the Loss of CCyR
KD mutation was the only predictive factor for loss of CCyR in the multivariate analysis:
RR=3.8, p=0.005
Khorashad et al, JCO, 2008
10
1
0.1
0.01
0.001
100
0.0001
BC
R/A
BL/
AB
L ra
tio (
%, b
lue)
Time since the onset of imatinib therapy (months)
100%
75%
50%
25%
0%
Percentage of m
utant transcripts (%, red)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
CCyR
Loss of CCyR
BP
Panel A, patient 34 (E459K)
Doubling transcript levels
First detection of mutation
Example 1
Example 2
10
1
0.1
0.01
0.001
100
0.0001
BC
R/A
BL/
AB
L ra
tio (
%, b
lue)
Time since the onset of imatinib therapy (months)
100%
75%
50%
25%
0%
Percentage of m
utant transcripts (%, red)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
v
v
CCyR Loss of CCyR
Panel B, patient 29 (M351T)
Doubling transcript levels
First detection of mutation
Prognostic Impact on PFS
Among 319 patients, 49 (15%) progressed to advanced phase 17 of 49 (35%) had a mutation detected before progression
14 of 17 had a mutation detected while still in CHR median interval (detection-progression): 16.3 months median interval (detection-loss of CHR): 13.7 months
Khorashad et al, JCO, 2008
Prognostic Impact on PFS
Multivariate analysis in the whole population (m=319), showed that KD mutations and the achievement of CCyR are the only independent predictor for PFS CCyR (RR=0.15, p<0.0001) Mutation detection (RR=2.3, p=0.014)
Khorashad et al, JCO, 2008
Landmark at 2 Years, PFS
84%
35%
90%
66%
8478726660524842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
ba
bili
ty o
f P
FS
Months from starting imatinib therapy
-- CCyR (n=143)-- no CCyR (n=107)
P< 0.0001
8478726660524842363024181260
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
ba
bili
ty o
f P
FS
Months from starting imatinib therapy
P= 0.0001
--’no mutation’ group (n=225)--’mutation’ group (n=25)
CCyR vs no CCyR Mutation vs. no mutation
Khorashad et al, JCO, 2008
Conclusion
TKD mutations are mere surrogate markers for genetic instability and in many cases are not the real reason for resistance
Khorashad et al, JCO, 2008
How should we use the mutation screening in practice?
A. Perform a mutation analysis on a regular basis (i.e every 3 months) regardless of any sign of resistance
– Caveat: it is extremely cost ineffective
B. Perform mutation analysis only at the moment of switching therapy
BCR-ABL mutation status before starting dasatinib.EHA 2009
Frequency of baseline BCR-ABL mutationsby in vitro IC50 to dasatinib (N=1043)
IC50 ≤3 nM (n=254)
M244V, G250E, Y253F/H/K, F311L, M351T, E355G, F359C/I/V, V379I, L387M, H396P/R
Unknown IC50 to dasatinib (n=83)43 different BCR-ABL mutations
No BCR-ABLmutation(n=641)
61%
IC50 >3 nM(n=44)
4%
2% T315I (n=21)IC50 >200 nM
1% Q252H (n=6)
1% F317L (n=14)
<1% V299L (n=1)
2% E255K/V (n=25)
24%
8%
Müller M, et al. ASH 2008: Abstract 449.
2G-TKD mutations
• Dasatinib: T315I, T315A, V299L F317V, F317L
• Nilotinib: T315I, Y253F, Y253H, E255V, E255K
You agree with me if you think that:
1.What matters is whether the patient is resistant, not if a mutation is present.
2.Mutation analysis may be helpful in choosing a 2G-TKI in 5%-10% of the cases
3.Mutations are surrogate marker for genomic instability
Thanks to John Goldman and other friends who are too numerous to be
mentioned individually
David, Thankfully your patients fare better than your
plants