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Chronic myeloid leukaemia

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Title: Chronic myeloid leukaemia


1
Chronic myeloid leukaemia
  • David Marin,
  • Imperial College London

2
Survival of 246 patients who received Interferon
therapy within the UK Medical Research Council's
CML-III trial (1986-1994)
3
28 May 2001
2001
4
Imatinib mesylate (STI571 - Glivec)
1998
(From Novartis Pharma)
5
Mechanism of action of imatinib
Bcr-Abl
Bcr-Abl
Substrate
Substrate
P
P
P
Y
ATP
Imatinib
P
Y Tyrosine P Phosphate
6
(No Transcript)
7
Selectivity of Tyrosine Kinase Inhibitors
Target kinases for the 4 TKIs
Imatinib (Phos. IC50) PDGFR 72 nM gt Kit 99 nM gt BcrAbl 221 nM gt Src gt1000 nM
Nilotinib (Phos. IC50) BcrAbl 20 nM gt PDGFR 75 nM gt Kit 209 nM gt Src gt1000 nM
Dasatinib (Phos. IC50) Src 0.1 nM gt BcrAbl 1.8 nM gt PDGFR 2.9 nM gt Kit 18 nM
Bosutinib (Phos. IC50) Src 3 nM gt BcrAbl 85 nM gt PDGFR gt3000 gt Kit gt10000 nM
1. Manley PW, et al. Proc Am Assoc Cancer Res
200748772. 2. Weisberg E, et al. Cancer Cell
200571129. 3. Remsing Rix LL, et al. Leukemia
200923477.
8
Comparison of Kinase Inhibitors Toxicity
Imatinib (STI571) Gleevec Nilotinib (AMN 107) Tasigna Dasatinib (BMS354825) Sprycel Bosutinib (SK606)
Hematologic
Pleural Effusions - -
Hepatic
Pancreatitis - - -
GI Bleeding - - -
Platelet Function - - ?
Immune - - ?
Diarrhea
Q-Tc - ?
9
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)
10
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?
11
Patients who fail to achieve CCyR progress to
advance phase (n204)
plt0.0001
Marin, Blood 2008
12
Patients who achieve CCyR do well and patients
who fail to achieve CCyR do badly (IRIS data)
plt0.001
13
TKI therapy only prolongs live on those patients
who achieve CCyR
2G-TKI responders, n67, aRR0.05, p0.003
Imatinib responders, n 179, aRR 0.18, plt0.0001
Interferon controls, n 246, aRR1
TKI non responders, n 37 aRR 0.76, p0.65
Ibrahim, Haematologica 2011
14
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?

15
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?

16
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?

17
13
10
Leucocytosis
12
100
10
Ph-chromosome pos
11
10
10
10
1
10
RT-PCR positive
9
0.1
10
BCR-ABL/ABL ratio ()
(Ph-negative)
8
0.01
10
7
0.001
10
Total number of leukaemia cells
6
0.0001
10
5
10
4
10
RT-PCR negative
3
10
2
10
10
0
0
Adapted from Lin et al. Genes Chromosomes and
Cancer 1995
18
Normal WBC
CHR
19
PFS and probability of CCyR according to the
haematological response at 3 months
CHR, n216
Probability of PFS Cumulate incidence of CCyR
No CHR, n8
PFS p0.002 CCyR p0.0003
Months from starting imatinib therapy
Marin, Blood 2008
20
CHR
MiCyR
21
CHR
MiCyR
MiCyR
MCyR
22
CHR
MiCyR
MCyR
MCyR
CCyR
23
CHR
MiCyR
MCyR
CCyR
CCyR
MMR
24
CHR
MiCyR
MCyR
CCyR
MMR
MMR
CMR
25
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?

26
Probability of CCyR according to the cytogenetic
response at 3 and 6 months (n204)
plt 0.0001
plt 0.0001
de Lavallade, JCO 2008
27
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?

28
How to monitor the patient and desired responses
G-Banding
  • MMR?
  • Early detection
  • of relapse

RQ-PCR
100
10
CCyR
1
3 log
0.1
BCR/ABL/ABL ratio ()
FISH negative
0.01
0.001
Level of detection
0.0001
6
9
15
18
21
24
27
3
12
Months from start of imatinib
29
So, what is the best first line therapy?
30
Study Design and Endpoints
R A N D O M I Z ED
Nilotinib 300 mg BID (n 282)
  • N 846
  • 217 centers
  • 35 countries

Nilotinib 400 mg BID (n 281)
Imatinib 400 mg QD (n 283)
Follow-up 5 years
  • 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

30
Stratification by Sokal risk score
31
Dasatinib Versus Imatinib Study In
Treatment-naïve CML DASISION (CA180-056). Design
  • N519
  • 108 centers
  • 26 countries

Follow-up 5 years
Randomized
Stratified by Hasford risk score
  • 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

32
CCyR Rates by 12 Months and Overall
P lt .001
P lt .0001
P .017
P lt .001
CCyR
n 282 n 281 n 283
n 282 n 281 n 283
  • 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

Data cut-off 2Jan2010
ITT population
32
33
DASISION First-Line Dasatinib vs. Imatinib in
CML-CP. CCyR rates (ITT)
P0.0011
CCyR ()
Mo 3 Mo 6 Mo 9 Mo 12
  • By analysis of time to CCyR, likelihood of
    achieving CCyR at any time 50 higher with
    dasatinib than with imatinib (stratified log-rank
    Plt0.0001 HR1.53)

34
Patient Disposition
Nilotinib 300 mg BID n 282
Nilotinib 400 mg BID n 281
Imatinib 400 mg QD n 283
Still on treatment
80
81
75
Discontinued,
20
19
25
Disease progression
lt1
4
lt1
Suboptimal response/ treatment failure
6
2
8
Adverse events
5
8
10
Abnormal lab. values
2
2
1
Death
1
0
0
Protocol violation
2
2
1
Other reason
4
3
3
Investigator assessment of criteria Patients
were required to discontinue nilotinib 300 mg BID
for suboptimal response but could remain on
nilotinib 400 mg BID
Data cut-off 2Jan2010
35
DASISION First-Line Dasatinib vs. Imatinib in
CML-CP. Treatment Discontinuations
Patients Patients
Dasatinib 100 mg QD n258 Imatinib 400 mg QD n258
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
Includes consent withdrawal, pregnancy, lost to
follow-up and death
36
Outcome in 282 patients treated with imatinib
first line in Hammersmith Hospital
94
6 death non CML
10 death because the CML
84
7 alive but not in CCyR
77
29 in CCyR but not on imatinib
48
48 in CCyR on imatinib
37
Outcome in 135 patients treated with second line
dasatinib or nilotinib in Hammersmith Hospital
38
Outcome in 135 patients treated with second line
dasatinib or nilotinib according to the
cytogenetic response achieved at 12 months
39
Outcome in 135 patients treated with second line
dasatinib or nilotinib according to the
cytogenetic response achieved at 12 months
40
  • 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

41
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 lt10
3 months BCR-ABL/ABL gt10
p0.02
42
Cumulative incidence of CCyR in the SPIRIT-II
trial according to the treatment arm and the
molecular response achieved at 3 months
Dasatinib
Imatinib
43
The key principles of therapy are
  1. Promptly identification of the high risk patients
  2. Change of therapy according to tolerance and
    response

44
What is the best why to detect who is not doing
well?
45
Probability of CCyR according to the cytogenetic
response at 3 and 6 months (n204)
plt 0.0001
plt 0.0001
de Lavallade, JCO 2008
46
We can do better than that!
47
We can identify what is the 3 months transcript
level that predicts for overall survival with the
maximal sensitivity and specify
48
Survival in 282 patients treated with imatinib
first line in Hammersmith Hospital according to
the molecular response achieved at 3 months
BCR-ABL/ABLlt10 OS 93.3
BCR-ABL/ABLgt10 OS 54
Probability of survival
plt0.0001
Time from onset of imatinib therapy (years)
49
Outcome in 282 patients treated with imatinib
first line in Hammersmith Hospital according to
the molecular response achieved at 3 months
BCR-ABL/ABLlt10, c-CCyRS 91
Probability of c-CCyRS
BCR-ABL/ABLgt10 c-CCyRS 48
p 0.0002
Time from onset of imatinib therapy (years)
50
Evolution of the transcript level in 282 patients
treated with imatinib first line therapy
51
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 (n57), 8-year
CI of CMR of 84.7,
plt0.0001
3-month transcript ratio gt0.61 (n222), 8-years
CI of CMR of 1.5
52
It is important to achieve MMR?
53
Molecular responses
54
PFS is similar in patients with CCyR regardless
of the depth of molecular response
Marin et al, Blood 2008
55
PFS similar in patients with CCyR regardless of
depth of molecular response
Druker BJ, et al. NEJM, 2006355(25)2408-17.
56
PFS is similar in patients with CCyR regardless
of depth of molecular response
Kantarjian HM, et al. Blood. 20061081835-1840.
57
Probability of loss of CCyR according to the
level of molecular response
Marin et al, Blood 2008
58
The definition of MMR is wrong
Do not be silly!
59
Problems with MMR
  • The depth of the molecular response in a given
    patient is basically driven by the patients
    adherence to therapy
  • The definition of MMR is arbitrary

60
Problems with MMR
  • The depth of the molecular response in a given
    patient is basically driven by the patients
    adherence to therapy
  • The definition of MMR is arbitrary

61
There is a great variability in the response to
imatinib. I wonder why
CCyR
3 log
0.0001
Time from start of imatinib
62
Study design
63
Microelectronic Monitoring System (MEMS 6
Trackcap)
  • Records the time of opening the container
  • Most reliable method of measuring adherence
  • Our patients not told about the chip


64
(No Transcript)
65
Long term adherence to imatinib
90
80
70
60
50
Proportion of patients ()
40.2
40
30
25.3
20
13.8
12.6
8
10
0
100
9599
9095
8090
lt80
Percentage of intended dose
Marin D, et al. J Clin Oncol 2010 28(14)
23812388.
66
Lack of adherence is underestimated by
conventional methods
Marin D, et al. J Clin Oncol 2010 28(14)
23812388.
67
(No Transcript)
68
Well, some patients miss a few doses, so what?
69
Achievement of a molecular response is related
to the adherence to imatinib therapy
6-year probability of response 6-year probability of response 6-year probability of response 6-year probability of response 6-year probability of response
Adherence rate n MMR () 4-log () CMR ()
100 lt99 36 51 p0.01 91.1 58.6 p0.02 79.9 38.6 p0.02 46.7 22.7
gt95 lt95 57 30 plt0.001 94.5 29.3 plt0.001 77.2 15.0 p0.002 45.2 8.2
gt90 lt90 64 23 plt0.001 93.7 13.9 plt0.001 76.0 4.3 p0.002 43.8 0
gt85 lt85 69 18 plt0.001 85.8 11.8 p0.001 69.2 5.6 p0.007 40.8 0
gt80 lt80 75 12 p0.001 81.2 0 p0.005 63.8 0 p0.04 37.1 0
Marin D, et al. J Clin Oncol 2010 28(14)
23812388.
70
6-year probability of MMR according to the
measured adherence rate
plt0.001
Marin D, et al. J Clin Oncol 2010 28(14)
23812388.
71
6-year probability of CMR according to the
measured adherence rate
p0.002
Marin D, et al. J Clin Oncol 2010 28(14)
23812388.
72
Other variables are also predictive for the
achievement of molecular response
Variables n MMR () 4-log () CMR ()
Hemoglobin 115 g/l gt115 g/l RR 40 47 p0.036 59.2 80.7 1.186, p0.012 p0.03 39.5 69.1 1.323, p0.01 p0.011 14.7 47.6 1.209, p0.07
Leukocytes 140 x 109/l gt140 x 109/l RR 44 43 p0.012 78.8 63.1 0.996, p0.008 p0.022 56.7 37.6 0.996, p0.015 p0.17 35.4 28.1 0.996, p0.11
BCR-ABL1/ABL1 ratio 100 gt100 RR 44 43 p0.25 71.4 52.6 0.996, p0.44 p0.038 53.0 26.6 0.971, p0.002 p0.1 32.7 8.4 0.979, p0.13
hOCT1 transcript level 0.16 gt0.16 RR 30 30 plt0.001 55.2 81.4 2.199, plt0.001 p0.01 42.0 64.8 1.990, p0.001 p0.02 16.6 45.3 1.665, p0.04
Imatinib plasma level 1 ?g/ml gt1 ?g/ml RR 43 41 p0.02 60.1 83.2 2.11, p0.01 p0.07 53.0 68.0 2.50, p0.06 p0.14 23.3 44.4 2.25, p0.09
Adherence rate gt90 90 RR 64 23 plt0.001 93.7 13.9 1.093, plt0.001 plt0.001 76.0 4.3 1.104, p0.002 p0.002 43.8 0 RR 1.135, p0.012
Marin D, et al. J Clin Oncol 2010 28(14)
23812388.
73
But adherence to therapy is the critical factor
for achieving molecular response
  • MMR
  • adherence to imatinib therapy, RR11.17 (p0.001)
  • hOCT1 transcript level, RR1.79 (p0.038)
  • CMR
  • adherence to imatinib therapy, RR19.35 (p0.004)

Marin D, et al. J Clin Oncol 2010 28(14)
23812388.
74
Imatinib plasma levels are not an independent
predictor of molecular response
Total population
Marin D, et al. J Clin Oncol 2010 28(14)
23812388.
75
Who will sustain CCyR?
76
Study design
MEMS
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
77
Poor adherent patients have a higher probability
of losing the CCyR and a lower EFS
Ibrahim, Blood 2011
78
  • 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
79
Adherence and the achievement of MMR are the only
independent predictors for outcome
Ibrahim, Blood 2011
80
Problems with MMR
  • The depth of the molecular response in a given
    patient is basically driven by the patients
    adherence to therapy
  • The definition of MMR is arbitrary

81
CHR
MiCyR
MCyR
CCyR
CCyR
MMR
82
166 out of 282 patients who received imatinib as
first line therapy were in CCyR at 12 months
Transcript level OS () EFS ()
gt0.1 lt0.1 125 41 p0.5 94.2 96.3 p0.08 80.4 93.7
83
166 out of 282 patients who received imatinib as
first line therapy were in CCyR at 12 months
Transcript level OS () EFS ()
gt0.1 lt0.1 125 41 p0.5 94.2 96.3 p0.08 80.4 93.7
gt0.53 lt0.53 20 146 p0.01 81.5 94.4 plt0.0001 29.5 74.3
84
It can not be a talk about CML without mentioning
KD mutations
85
I am going to try to challenge the orthodox view
about kinase domain mutations
86
(No Transcript)
87
The points I want to make are
  • The meaning of KD mutations is often
    misunderstood
  • The uses in clinical practice are very limited

88
Sensitivity studies help us to choose the best
antibiotic. Similarly mutation analysis help us
to choose the best TKI
Are you sure?
89
Figure 3. MCyR rates in patients with or without
a baseline BCR-ABL mutation
Any BCR-ABL mutation
No BCR-ABL mutation
80
70
67
66
67
11
8
10
56
PCyR
60
55
12
54
CCyR
48
8
14
22
11

40
58
58
57
54
46
41
20
37
34
0
100 mg once daily (n49)
70 mg BID (n50)
140 mg once daily (n50)
50 mg BID (n63)
100 mg once daily (n98)
70 mg BID (n96)
140 mg once daily (n89)
50 mg BID (n86)
90
Group A, High transcript levels- mutant clone
predominates
100
75
50
Percentage of mutant transcripts
BCR/ABL/ABL ratio ()
25
0
800
Imatinib 400
1000
600
M244V
Time since the onset of imatinib therapy (months)
Interval from diagnosis to start of imatinib 4
months
Khorashad, Leukemia 2006
91
Group B, Low transcript levels- mutant clone
predominates
100
100
10
75
Percentage of mutant transcripts
1
50
25
0.1
BCR/ABL/ABL ratio ()
0
0.01
Imatinib 400
600
400
0.001
S438C
0.0001
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)
Interval from diagnosis to start of imatinib 2
months
Khorashad, Leukemia 2006
92
Group C, Variable transcript levels- mutant
clone is rare
100
75
Percentage of mutant transcripts
50
25
BCR/ABL/ABL ratio ()
0
Imatinib 400
G250E
Time since the onset of imatinib therapy (months)
Interval from diagnosis to start of imatinib 36
months
Khorashad, Leukemia 2006
93
What is the biological significance of KD
mutations?
94
In order to answer this question we
systematically screened all our CP (n319)
patients treated with imatinib for mutations
regardless of whether or not they shown any sign
of resistance
95
Mutation screening
18 m
12 m
Khorashad et al, JCO, 2008
96
Cumulative Incidence of KD Mutations
Cumulative incidence of KD mutations
13.9
Months from starting imatinib therapy
Khorashad et al, JCO, 2008
97
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
98
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
  • RR3.8, p0.005

Khorashad et al, JCO, 2008
99
Example 1
100
Example 2
101
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
102
Prognostic Impact on PFS
  • Multivariate analysis in the whole population
    (m319), showed that KD mutations and the
    achievement of CCyR are the only independent
    predictor for PFS
  • CCyR (RR0.15, plt0.0001)
  • Mutation detection (RR2.3, p0.014)

Khorashad et al, JCO, 2008
103
Landmark at 2 Years, PFS
CCyR vs no CCyR
Mutation vs. no mutation
84
35
-- CCyR (n143) -- no CCyR (n107)
Probability of PFS
Probability of PFS
--no mutation group (n225) --mutation group
(n25)
Plt 0.0001
P 0.0001
Months from starting imatinib therapy
Months from starting imatinib therapy
Khorashad et al, JCO, 2008
104
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
105
How should we use the mutation screening in
practice?
106
  • 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
  • Perform mutation analysis only at the moment of
    switching therapy

107
Frequency of baseline BCR-ABL mutations by in
vitro IC50 to dasatinib (N1043)
Unknown IC50 to dasatinib (n83) 43 different
BCR-ABL mutations
8
IC50 3 nM (n254) M244V, G250E, Y253F/H/K,
F311L, M351T, E355G, F359C/I/V, V379I, L387M,
H396P/R
No BCR-ABL mutation (n641) 61
24
lt1 V299L (n1)
IC50 gt3 nM (n44) 4
1 Q252H (n6)
1 F317L (n14)
2 E255K/V (n25)
2 T315I (n21) IC50 gt200 nM
Müller M, et al. ASH 2008 Abstract 449.
108
2G-TKD mutations
  • Dasatinib T315I, T315A, V299L F317V, F317L
  • Nilotinib T315I, Y253F, Y253H, E255V, E255K

109
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

110
Thanks to John Goldman and other friends who are
too numerous to be mentioned individually
David, Thankfully your patients fare better than
your plants
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