Transcript Poor Prognostic Factors in Allogeneic SCT in CML

Treatment Approaches in
Relapsed CML
Jorge Cortes, MD
Professor of Medicine
Deputy Chair, Department of Leukemia
The University of Texas
MD Anderson Cancer Center
Houston, TX
Case Study: Question 1
A 50-year old female presented with LUQ pain and
splenomegaly 10 cm/BCM. Her WBC was 105 x 109/L,
Plts 800 x 109/L. BM shows 5% blasts, 4% basophils.
CG show 100% Ph, no clonal evolution. She has a
perfect match brother. Your treatment plan is:
 Allogeneic BMT ASAP
 Imatinib 400 mg QD
 Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Case Study: Question 2
Patient has now received imatinib 400 mg QD for 12
months. CG at 12 months shows Ph+ 10%. You
would now proceed to:
 Allogeneic BMT
 Continue Imatinib 400 mg QD
 Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Case Study: Question 3
Patient has now received imatinib for two years, the
second year at imatinib 800 mg/D. Repeat CG show
Ph+ 0%, QPCR is .15%. You would now proceed with:
 Allogeneic BMT ASAP
 Send sample for mutation studies and
decide accordingly
 Continue Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Case Study: Question 4
Patient is now on imatinib 800 mg/D for the past 40
months. Repeat CG shows Ph+ 40%, and a mutation
screen identifies the T359C mutation. Your next
approach is:
 Allogeneic BMT ASAP
 Consider MK 0457
 Continue Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Case Study: Question 5
The patient achieved a compete cytogenetic
response. One year later, cytogenetic analysis shows
50% Ph+ metaphases. A T315I mutation is detected.
Your approach now is:
 Allogeneic SCT
 Imatinib 400 mg BID
 Increase Dasatinib to 140 mg QD
 Change to Nilotinib 400 mg BID
 Consider Homoharringtonine
Results with Imatinib in Early
CP CML – The IRIS Trial
• 364 (66%) patients on imatinib on study
• Projected results at 6 years:
–CCyR 87%
–Event-free survival 83%
–Transformation-free survival 93%
• If MMR at 12 mos: 100%
• If CCyR, no MMR: 98%
–Survival 88%
• Annual rate of transformation: 1.5%, 2.8%,
1.6%, 0.9%, 0.6%, and 0%
Hochhaus et al; Blood 2007; 110: abst# 25
Criteria for Failure to Imatinib
Time (mo)
3
6
12
18
Any
Response
Failure
Suboptimal
No HR
No CHR
No CHR
≥ 35% Ph+
100% Ph+
≥ 35% Ph+
≥ 5% Ph+
≥ 5% Ph+
No MMR (<3-log 
BCR-ABL/ABL)
Loss of CHR
Clonal Evolution
Loss of CCgR
Loss of MMR
Mutation
Mutation
Baccarani et al. Blood 2006; 108: 1809-20
Survival Post Imatinib Failure by CML Phase
Kantarjian et al. Cancer 2007; 109: 1556-60
Inhibition of Bcr-Abl
ATP-binding
T315I-active
Non-kinase
Inhibition
Bcr-Abl
Abl & Src
Imatinib
Dasatinib
MK-0457
17-AAG
Nilotinib Bosutinib
KW-2449
HDAC
INNO-406
XL228
HHT
AZD 0530
PHA-739358
ATO
ON 012380
Outcome After Imatinib Dose Increase
• 102 patients with imatinib dose escalation after imatinib
failure (N = 85), suboptimal (N = 9), or other (N = 8)
• Dose  from 400800 (N = 86) or 300600 (N = 16)
• Median follow-up after dose : 50 mo (range 3-83)
2-year (%)
% outcome after dose 
from dose 
Loss
CCyR
MMR
EFS TFS
CCyR
Failure
39
8
18
Cytogenetic
49
10
17
85
86
Hematologic
12
4
33
Suboptimal
0/1
1/9 (11)
0
88
100
Other
4/4**
4/8 (50)
0
100 100
• Median time to cytogenetic response 9 mos
Jabbour et al. Blood 2007; 110: abst# 1035
Dasatinib in CML Chronic Phase After
Imatinib Failure (START-C)
•
387 pts; IM resistance 74%; median CML
duration 61 mos; dasatinib 70 mg BID
• Parameter
Percent
CHR
91
MCyR / CCyR
62 / 53
MMR
47
24-mos PFS / OS
80 / 94
• Dose reductions 73%; median dose 101 mg/d
• Grade 3-4 ↓ plts 49%, neuts 50%; pleural
effusions 26% (grade 3-4 9%)
Stone et al. Blood 2007; 110: abst# 734
Duration of MCyR to Dasatinib in CML CP
Imatinib Resistance
Imatinib Intolerance
100
80
80
% without loss of MCyR
100
97%
84%
60
60
24-month response rates
40
20
0
0
MCyR
CCyR
MMR
55%
45%
37%
3
6
9
12
15 18
21
24
24-month response rates
40
20
27
30
CCyR
MMR
82%
78%
78%
0
0
Months
MCyR
3
6
9
12
15
18
21
24
27
30
Months
Stone et al. Blood 2007; 110: abst# 734
PFS and Overall Survival with Dasatinib in CML
CP by Imatinib Failure
Imatinib Resistance
96%
100
Imatinib Intolerance
100%
98%
94%
100
92%
88%
80
100%
80
75%
60
60
40
40
Overall Survival
20
20
Progression-Free Survival
0 0
3
6
9
12
15
18
21
24
27
30
33 0 0
3
6
9
12
15
18
21
24
27
30
33
Months
Months
Progression was defined as increasing WBC count, loss of CHR / MCyR, AP / BP, or death
Stone et al. Blood 2007; 110: abst# 734
Phase II Studies of Dasatinib
After Imatinib Failure
Percent by Disease Stage
Response
CP
AP
MyBP LyBP ALL
N = 387 N = 174 N = 109
Hematologic
N = 48
N = 46
91
64
50
39
49
CHR
91
50
26
29
35
NEL
-
14
7
6
7
Cytogenetic
62
40
47
58
62
Complete
53
33
27
46
54
Partial
9
7
7
6
2
ASH 2007; abst# 470, 734
PFS with Dasatinib in CML After Imatinib Failure
100
100
CP
80
88%
80
75%
60
60
40
40
20
20
0
0
0
3
6
9
12
100
AP
15 18 21
Months
24
27
46%
0
30 33
3
6
9
12
100
BP
80
64%
15 18 21
Months
24
27
30 33
ALL
80
60
60
MyBP (Median 5.6 mo)
40
40
20
20
0
All (Median 3.3 mo)
LyBP (Median 3.1 mo)
0
3
6
9
12 15 18
Months
Non T315I (Median 5.7 mo)
0
21
24
27 30
0
3
6
9
12 15 18
Months
21
24
27 30
Dasatinib vs HD Imatinib in CML (START-R)
• 150 pts post failure of IM 400-600 mg/d
• Randomized (2:1) to dasatinib 70 mg BID vs IM 400
mg BID; median FU 15 mos
• Endpoint: CG response at 12 weeks  crossover
Percent Response
• Outcome
Dasatinib HD IM P value
CHR
93
82
0.03
MCyR
53
33
0.017
CCyR
44
18
0.002
MMR
29
12
0.028
•
•
PFS better with dasatinib (HR 0.14; p<0.0001)
More grade 3-4  plts (57% vs 14%) and neuts (63% vs
39%), and pl. effusions (17% vs 0%) with dasatinib
Kantarjian et al. Blood 2007; 110: abst# 736
PFS with Dasatinib vs HD IM by
Prior Imatinib Dose
100
P=0.0562
Per cent PFS
80
P=0.0033
60
Prior imatinib dose: 400 mg
40
Prior imatinib dose: 600 mg
Dasatinib
20
Imatinib
0
0
3
6
9
12
15
18
Months
21
24
27
30
33
Kantarjian et al. Blood 2007; 110: abst# 736
Optimal Dose and Schedule of Dasatinib
IN CML CP after Imatinib Failure
Parameter
MCyR
CCyR
Anemia
Neutropenia
Thrombocytopenia
Pleural effusion
Interruption
Reduction
100mg 50mg 140mg 70mg
PQD
BID
QD
BID value
N = 166 N = 166 N = 163 N = 167
64
46
10
34
22
10
58
33
58
46
18
46
34
16
66
45
62
47
19
43
40
20
69
54
58
50
17
43
38
18
71
57
NS
NS
0.105
0.123
0.003
NS
0.047
<0.001
Shah et al. JCO 2007; 25; (Abst # 7004)
Better Outcome on Dasatinib with Earlier
Intervention
•
Patients on dasatinib studies analyzed by failure
status on imatinib: loss of CG response vs loss
of CHR
• Status at IM Failure
Loss of MCyR
Loss of CHR
No.
% CCyR
% 1-yr PFS
152
50-83
[69]
87-100
[95]
147
14-50
[24]
58-93
[84]
Kantarjian et al. Blood 2007; 110: abst# 1036
•
Nilotinib in CML Chronic Phase Post
Imatinib Failure
320 pts with imatinib resistance (71%) or
intolerance (29%)
• Median age 58 yrs; median CML duration 58 mo
• Nilotinib 400 mg PO BID ≥ 6 mos
• Outcome
Percent
- CHR
77
- CG response
76
MCyR / CCyR
57 / 41
- 18-month OS / PFS
91 / 64
• Median dose 790 mg/d
• Grade 3-4 ↓ plts 28%, neuts 30%; lipase elevation
15% (pancreatitis <1%), bilirubin 8%
Kantarjian et al. Blood 2007; 110: abst# 735
Nilotinib in CML-CP
Duration of Major CG Response
Without Loss of MCyR, %
89%
84%
Total = 184
Failed = 23
lll = Censored observations
Months
Kantarjian et al. Blood 2007; 110: abst# 735
Phase II Studies of Nilotinib
After Imatinib Failure
Percentage
Response
CP
AP
N = 321
N = 129
N = 105
N = 31
N = 39
77
54
22
19
29
77
26
11
13
26
Major
57
31
38
48
51
Complete
41
19
29
32
34
HR
CHR
MyBP LyBP Ph+ALL
Cytogenetic
ASH 2007
Time to Progression with Nilotinib
in CML After Imatinib Failure
CP
AP
78%
70%
64%
57%
Months
Months
le Coutre et al. Blood 2007; 110: abst# 471
Bosutinib (SKI–606) in CML and Ph+ ALL
• Src-Abl inhibitor; 30x more potent than IM
– No inhibition of PDGFR, c-kit
• 152 CP pts; median time from Dx 65 mos; 76%
•
•
•
•
•
IM resistant
Bosutinib 400-600 mg/d; Phase II 500 mg/d
Response in CP (N=56)
%
CHR
89
Cytogenetic
81
– Major
41
– Complete
30
G 3-4 toxicity: rash 7%, thrombocytopenia
14%, neutropenia 9%
Cortes et al. Blood 2007; 110: abst# 733
Phase I INNO-406
• Abl/Lyn kinase inhibitor 25-55x more potent
than imatinib
• Inhibits 17/18 Bcr-Abl mutants
• Not MDR dependent; good CNS penetration;
active against F317C/L/V
• 41 pts: 21 CP, 7 AP, 6 BP, 7 ALL
• 32 pts received ≥ 2 TKIs
• INNO-406 30 mg SD → 480 mg BID
• Responses:
–2 CG CR + 1 CG major + 1 CG minor / 7 CP
post IM failure
–1 CG CR + 2 HR in ≥ 2 TKI failures
• DLT transient LFT ; phase II 240 mg P.O. BID
Kantarjian et al. Blood 2007; 110: abst# 469
Survival Post Imatinib Failure in CP by Treatment
Kantarjian et al. Cancer 2007; 109: 1556-60
Survival Post Imatinib Failure in AP by Treatment
Kantarjian et al. Cancer 2007; 109: 1556-60
Time to Response to 2nd Generation TKI
• 113 pts with CML CP receiving nilotinib (N = 43) or
dasatinib (N = 70) after imatinib failure.
1 .0
% AP/BP/Death/CHR loss
Next Year
Response at 12 mo
.8
MCyR or CCyR
3%
mCyR or CHR
17%
P = 0.003
.6
Eve nt
mCyR or CHR (27)
.4
.2
MCyR or CCR (59)
0 .0
0
12
24
36
Mo n t h s
• Failure to achieve mCyR by 3 or 6 mos = 3-7%
chance of reaching MCyR at 12 mo (vs > 50% if
mCyR at 3-6 mos).
Tam et al. Blood 2007; 110: abst# 1931
Hematologic Response to 2nd Generation TKI
in Advanced Stage CML After IM Failure
• 136 pts: CML AP (N = 87), BP (N = 60) or Ph+ ALL (N = 7)
treated with dasatinib (N = 73) or nilotinib (N = 81) after
imatinib failure
• MCyR 35%; 46% no CHR at time of MCyR
• Most common causes of no CHR: thrombocytopenia (88%),
neutropenia (35%), immature cells (31%)
1.0
1.0
0.9
0.8
0.8
0.7
0.6
0.6
0.5
0.4
0.4
0.3
0.2
MCyR, with CHR
MCyR, no CHR
No MCyR
0.1
No.
31
26
97
Dead (%)
6 (19)
14 (54)
55 (57)
0.2
MCyR, w ith CHR
MCyR, never CHR
MCyR, later CHR
No MCyR
p=0.0003
0.0
0.0
0
1
2
Years
3
4
0
1
No.
31
13
13
97
Dead (%)
6 (19)
9 (69)
5 (38)
55 (57)
2
3
4
Years
Fava et al, Blood 2007; 110: abst# 1944
Response to Dasatinib by BCR-ABL
Mutation in CML CP After Imatinib Failure
M244V
Cellular IC50 (nM)
Dasatinib Imatinib
N
1.3
2000
17
1500
9
L248V
G250E/V
1350–3900
23
Y253F/H/K 1.3–10
E255K/V
5.6–13
D276G
>10000
4400–8400
1500
14
10
3
T315I
>1000
>10000
3
F317L
7.4
1050
4
M351T
E355G
F359C/I/V
1.1
2.2
930
400
1200
15
6
8
L387M
2.0
1000
2
H396P/R
0.6–1.13
850–4200
Other
1.8
Complete CyR
Partial CyR
Complete HR
No response
17
30
Stone et al. Blood 2007; 110: abst# 734
Response to Nilotinib in CML CP
after Imatinib Failure by Mutation
Mutation
IC50
(nM)
No.
Percentage
MCyR CCyR MMR Progressed
No Mutation
83
60
42
25
23
IC50 ≤150 nM
45
62
40
29
31
700
8
13
0
0
38
E255K/V
548/791
8
38
0
14
75
F359C/V
258/161
10
10
0
0
90
33
58
42
20
39
IC50 >150 nM
Y253H
Others
Hughes et al. Blood 2007; 110: abst# 320
EFS by Mutations in CML CP Treated with
2nd Generation TKI after IM Failure
• 87/169 (51%) pts treated had mutation
• CP 31, AP 41, BP 15
• Mutations classified into high, intermediate, and low
sensitivity to dasatinib
or nilotinib based on IC50
EFS for Chr on ic Ph a s e
1 .0
Low IC50
.8
P = 0.43
No Mutation
.6
P = 0.0004
.4
Intermediate IC50
.2
0 .0
0
12
24
36
Mon t h s
• No significant difference in AP or BP
Jabbour et al, Blood 2007; 110: abst# 1941
Inducible Mutations in Mutagenesis
Studies with AMN and BMS
• Mutants induced by saturation, selection, or
induced (ENU)
• Mutations: imatinib 20, nilotinib 10, dasatinib 9
Drug
Concentration
Low
Intermediate
AMN
L248V, G250E, F359C,
L384M, L387F
Y253H, E255K/(V),
T315I
BMS
L248V, Q252H,
E255K/V, V299L
T315I, F317C/L/V
Bradeen et al. Blood. 2006; 108: 2332-8; Ray et al. Blood. 2007; epub ahead of print;
von Bubnoff et al. Blood. 2006; 108: 1328-33. Burgess et al. PNAS. 2005; 102: 3395-400.
Occurrence of Mutations Predicted
from In Vitro Models
NILOTINIB
DASATINIB
This series
N=10
In vitro
models*
This series
N=15
M244V (1)
Q252H (1)
Y253H (3)
G250E (1)
V299L (3)
+
F317L (5)
+
T495R (1)
Total match 80% patients
E255K (1)
In vitro
models*
+
+
+
D276G (1)
F311I/L (2)
F359V/C (3)
+
+
E453K (1)
H396P/R (2)
Total match
67% patients
Cortes et al. Blood 2007 [e-pub ahead of print]
*Burgess et al. PNAS 2005; 102: 3395-400; von Bubnoff et al. Blood 2006; 108: 34
1328-33;
Bradeen et al. Blood 2006; 108: 2332-8.
Impact of Clonal Evolution in Response
to Dasatinib or Nilotinib
• CE in 60/242 pts (25%) with CML AP treated with
nilotinib (30) or dasatinib (30) after IM failure
• Double Ph 28%, chr 8 (17%), chr 17 (17%), other 35%)
• Response: CHR 80%, CCyR 40%, PCyR 6%
1.0
0.9
0.8
p=0.04
0.7
0.6
0.5
0.4
p=0.01
0.3
0.2
No.
161
34
23
24
CP
CP + CE
AP
AP + CE
0.1
Died (%)
13 (8)
8 (24)
7 (30)
16 (67)
p<0.0001
0.0
0
1
2
3
4
Years
Verma et al, Blood 2007; 110: abst# 2949
2nd Generation TKI in Newly Dx CML
Dasatinib
• 37 pts with previously untreated CML CP
• Dasatinib 100 mg SD or 50mg BID
• Median FU 18 mos
Nilotinib
• 32 pts with CML CP previously untreated
• Nilotinib 400 mg BID
• Median FU 6.5 mos
Cortes et al. Blood 2007; 110: abst# 29 & 30
TKI in Newly Diagnosed CML
Percent response
Parameter
IM400
IM800 Dasatinib Nilotinib
N = 50
N = 205
N = 39
N = 14
3 mo
37
62
72
96
6 mo
54
82
94
100
12 mo
MMR
(12 mos)
65
86
100
100
24
47
25
45
CG CR
37
Cortes et al. Blood 2007; 110: abst# 29 & 30
HHT in CML with Mutation T315 I
• 19 pts: 11 CP, 4 AP, 4 BP
• Failure on IM (19), dasatinib (10),
nilotinib (8), MK457 (3)
• HHT 1.25 mg SQ BIDx14 Q4 wks until
CHR → x 7 Q4 wks
• T315I undetectable in 4 CP and 1 AP
• Responses:
–CP: 5 CHR, 1 mCyR, 2 CCyR
–AP: 1 HI, 2 PHR, 1 mCyR
Khoury et al. Blood 2007; 110: abst# 1050
Case Study: Question 1
A 50-year old female presented with LUQ pain and
splenomegaly 10 cm/BCM. Her WBC was 105 x 109/L,
Plts 800 x 109/L. BM shows 5% blasts, 4% basophils.
CG show 100% Ph, no clonal evolution. She has a
perfect match brother. Your treatment plan is:
 Allogeneic BMT ASAP
 Imatinib 400 mg QD
 Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Case Study: Question 1
A 50-year old female presented with LUQ pain and
splenomegaly 10 cm/BCM. Her WBC was 105 x 109/L,
Plts 800 x 109/L. BM shows 5% blasts, 4% basophils.
CG show 100% Ph, no clonal evolution. She has a
perfect match brother. Your treatment plan is:
 Allogeneic BMT ASAP
 Imatinib 400 mg QD
 Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Recommended approach:
•
Imatinib 400 mg QD
Case Study: Question 2
Patient has now received imatinib 400 mg QD for 12
months. CG at 12 months shows Ph+ 10%. You
would now proceed to:
 Allogeneic BMT
 Continue Imatinib 400 mg QD
 Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Case Study: Question 2
Patient has now received imatinib 400 mg QD for 12
months. CG at 12 months shows Ph+ 10%. You
would now proceed to:
 Allogeneic BMT
 Continue Imatinib 400 mg QD
 Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Recommended approach:
•
Imatinib 400 mg BID
Case Study: Question 3
Patient has now received imatinib for two years, the
second year at imatinib 800 mg/D. Repeat CG show
Ph+ 0%, QPCR is .15%. You would now proceed with:
 Allogeneic BMT ASAP
 Send sample for mutation studies and
decide accordingly
 Continue Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Case Study: Question 3
Patient has now received imatinib for two years, the
second year at imatinib 800 mg/D. Repeat CG show
Ph+ 0%, QPCR is .15%. You would now proceed with:
 Allogeneic BMT ASAP
 Send sample for mutation studies and
decide accordingly
 Continue Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Recommended approach:
•
Continue imatinib 400 mg BID
Case Study: Question 4
Patient is now on imatinib 800 mg/D for the past 40
months. Repeat CG shows Ph+ 40%, and a mutation
screen identifies the T359C mutation. Your next
approach is:
 Allogeneic BMT ASAP
 Consider MK 0457
 Continue Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Case Study: Question 4
Patient is now on imatinib 800 mg/D for the past 40
months. Repeat CG shows Ph+ 40%, and a mutation
screen identifies the T359C mutation. Your next
approach is:
 Allogeneic BMT ASAP
 Consider MK 0457
 Continue Imatinib 400 mg BID
 Dasatinib 100 mg QD
 Nilotinib 400 mg BID
Recommended approach:
• Dasatinib 100 mg QD
Case Study: Question 5
The patient achieved a compete cytogenetic
response. One year later, cytogenetic analysis shows
50% Ph+ metaphases. A T315I mutation is detected.
Your approach now is:
 Allogeneic SCT
 Imatinib 400 mg BID
 Increase Dasatinib to 140 mg QD
 Change to Nilotinib 400 mg BID
 Consider Homoharringtonine
Case Study: Question 5
The patient achieved a compete cytogenetic
response. One year later, cytogenetic analysis shows
50% Ph+ metaphases. A T315I mutation is detected.
Your approach now is:
 Allogeneic SCT
 Imatinib 400 mg BID
 Increase Dasatinib to 140 mg QD
 Change to Nilotinib 400 mg BID
 Consider Homoharringtonine
Recommended approach:
• Allogeneic SCT or Homoharringtonine
Take Home Message – CML 2008
• Imatinib effective in most patients
– High-dose?
• Dose optimization and adequate monitoring
more important then ever
• Sub-optimal responses:
–  dose imatinib (400 mg → 800 mg)
– New TKI?
• Failure:
– Dasatinib, nilotinib
– Others (Bosutinib, INNO 406)
• Frontline use of new TKI?
• T315I: HHT, XL-228, PHA-739538