SWAMI IYER, MD SWAMI IYER, MD Houston, USA Houston, USA • Associate Professor, Leader, early drug Associate Professor, Leader, early drug development in Oncology, the Methodist Cancer development in Oncology, the Methodist Cancer Center Center • Dr Iyer is the Leader for Early Drug Development Dr Iyer is the Leader for Early Drug Development Program in Hematology and Oncology at the Methodist Program in Hematology and Oncology at the Methodist Cancer Center, Houston, Texas. He recently served as Cancer Center, Houston, Texas. He recently served as the Director of Hematological Malignancies at CTRC, the Director of Hematological Malignancies at CTRC, and as an Assistant Professor of Medicine at the and as an Assistant Professor of Medicine at the University of Texas Health Science Center University of Texas Health Science Center (UTHSCSA). He is a physician scientist with laboratory (UTHSCSA). He is a physician scientist with laboratory interests in Heat shock proteins and has extensive interests in Heat shock proteins and has extensive expertise in clinical studies. expertise in clinical studies.
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Defining goals for molecular remission in Chronic Myeloid Leukemia.
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SWAMI IYER, MDSWAMI IYER, MDHouston, USAHouston, USA
• Associate Professor, Leader, early drug Associate Professor, Leader, early drug development in Oncology, the Methodist Cancer development in Oncology, the Methodist Cancer CenterCenter
• Dr Iyer is the Leader for Early Drug Development Dr Iyer is the Leader for Early Drug Development Program in Hematology and Oncology at the Methodist Program in Hematology and Oncology at the Methodist Cancer Center, Houston, Texas. He recently served as Cancer Center, Houston, Texas. He recently served as the Director of Hematological Malignancies at CTRC, the Director of Hematological Malignancies at CTRC, and as an Assistant Professor of Medicine at the and as an Assistant Professor of Medicine at the University of Texas Health Science Center University of Texas Health Science Center (UTHSCSA). He is a physician scientist with laboratory (UTHSCSA). He is a physician scientist with laboratory interests in Heat shock proteins and has extensive interests in Heat shock proteins and has extensive expertise in clinical studies.expertise in clinical studies.
Monitoring Responses in CMLMonitoring Responses in CML
Swami Padmanabhan Iyer, MD Swami Padmanabhan Iyer, MD Leader Early Drug Development Program and Leader Early Drug Development Program and
Co-Director of the Malignant Hematology Co-Director of the Malignant Hematology Program, Associate Professor,Program, Associate Professor,
Houston Methodist Cancer Center, Houston Methodist Cancer Center, Weill Cornell Medical College,Weill Cornell Medical College,
Houston, TX Houston, TX
CML Survival 1965 -Present (n=1884)
MDACC 2009
4
• The remarkable progress made in the treatment of CML over the past decade has been accompanied by steady improvements in our capacity to accurately and sensitively monitor response to therapy.
• After the initial target of therapy, complete cytogenetic response (CCR), is achieved, peripheral blood BCR-ABL transcript levels measured by real-time quantitative reverse transcriptase PCR (RQ-PCR) define the subsequent response targets, major and complete molecular response (MMR and CMR).
• The main purpose of monitoring response with cytogenetics and RQ-PCR is to identify patients likely to achieve better long-term outcome if they are switched early to second-line therapy, either another TKI or an allograft.
Rationale for monitoring Responses in CML
Considerations for TKI Rx in CML
Goals of Rx- achieving CCyR and CMR through Milestones in a predictable timely fashion
Reasons for not reaching the milestones•Clonal evolution- Transformation•TKI Intolerance•TKI Resistance- Mutations•Compliance
Deininger et al; Blood 2009; 114: Abst# 1126
Goals of Rx- achieving CCyR and CMR through Milestones in a predictable timely fashion
Reasons for not reaching the milestones•Clonal evolution- Transformation•TKI Intolerance•TKI Resistance- Mutations•Compliance
Deininger et al; Blood 2009; 114: Abst# 1126
Considerations for TKI Rx in CML
Clinical Value of molecular monitoring in CML
• Early detection of relapse
• Monitoring response of patients treated for relapse
• Evaluation of leukemia cell contamination in stem cell collections
• Monitoring response in complete cytogenetic responders
IRIS 8-Year Update
37%Unacceptable
Outcome
Deininger et al; Blood 2009; 114: Abst# 1126
Results with Imatinib in Early CP CML – The IRIS Trial at 8-Years
• 304 (55%) patients on imatinib on study• Projected results at 8 years:
–CCyR 83%• 82 (18%) lost CCyR, 15 (3%) progressed to
Event-Free Survival by Molecular Response at 18 Months
Baccarani et al. Blood, 108 (11): Abstract 2138
EF
S (
%)
Response at 18 months
CCyR with >3 log reduction
CCyR with <3 log reduction
No CCyR
0
10
20
30
40
50
60
70
80
90
100
Months since randomization0 12 24 36 48 60 72
Deininger et al; Blood 2009; 114: Abst# 1126
Let us look at the Milestones
Decreasing residual leukemia N
umbe r of le ukem
i a cells (log10 )
0
1
2
3
4
5
6
7
8
9
10
11
12
13
0
6.0
5.0
4.0
3.0
1.0
0
Lo
g r
edu
ctio
n f
rom
bas
eli
ne Leukocytosis
Ph-chromosome pos
RQ-PCR <3 log
Cure ?
2.0CCyR
MMR
RQ-PCR negative(undetectable)
RQ-PCR >3 log
Ph chromosome and BCR-ABL transcript numbers as measures of ‘residual’ leukemia during treatment
Nu
mb
er o
f L
euka
emic
cel
lsN
um
ber
of
Leu
kaem
ic c
ells
10101212
10101111
10101010
101099
101088
101077
101066
101055
101044
101033
CCyRCCyR
residual disease is assessed at the molecular
level
Relationship between treatment response Relationship between treatment response level and number of leukaemic cellslevel and number of leukaemic cells
MMRMMR
DiagnosisDiagnosis
Unlike other measurement Unlike other measurement parameters it is difficult to parameters it is difficult to
define a complete molecular define a complete molecular responseresponse
undetectable BCR-undetectable BCR-ABLABL
CMRCMR
CCyCCyRRMMR MMR
10101212
10101111
10101010
101099
101088
101077
101066
101055
101044
101033
Limit of detection will Limit of detection will vary for each samplevary for each sample
Relationship between treatment response Relationship between treatment response level and number of leukaemic cellslevel and number of leukaemic cells
For the IRIS trial CMR was defined as For the IRIS trial CMR was defined as undetectable BCR-ABL with a sensitivity of at undetectable BCR-ABL with a sensitivity of at least 4.5 log below the standardised baselineleast 4.5 log below the standardised baseline
Hughes et al. N Eng J Med. 2003;349(15):1423-32.Hughes et al. N Eng J Med. 2003;349(15):1423-32.
??
Nu
mb
er o
f L
euka
emic
cel
lsN
um
ber
of
Leu
kaem
ic c
ells
Criteria for Failure and Suboptimal Response to Imatinib
Time (mo)
Response
Failure Suboptimal Optimal
3 No CHR No CG Response < 65% Ph+
6 No CHR>95% Ph+ ≥35% Ph+ ≤35% Ph+
12 ≥35% Ph+ 1-35% Ph+ 0% Ph+
18 ≥5% Ph+ No MMR MMR
Any
Loss of CHRLoss of CCgR
MutationCE
Loss of MMRMutation
Stable or improving
MMR
Baccarani. JCO 2009; 27: 6041-51
Criteria for Optimal Response to Imatinib
Time (mo)
Response
Optimal
3 < 65% Ph+
6 ≤35% Ph+ MCyR
12 0% Ph+ CCyR
18 MMR
AnyStable or improving
MMR
Baccarani. JCO 2009; 27: 6041-51
Gold Standard- CCyR
Deininger et al; Blood 2009; 114: Abst# 1126
Let us look at the Milestones
19
IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos
Estimated rate at 60 months
n= 86 93%n= 73 81%
n= 350 97% } p<0.001} p=0.20CCyRPCyRNo MCyR
Response at 12 months
% w
ithou
t AP
/BC
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
M o n t h s s i n c e r a n d o m iz a t i o n0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6
Rx aim: major CG response (Ph ≤ 35%)
% w
ithou
t AP
/BC
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
M o n t h s s i n c e r a n d o m i z a t i o n
0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6
IRIS. Survival Without AP/BC Worse If No CGCR In Year 2 But Not Related To MMR
n= 139 100%n= 54 98%n= 89 87%
Estimated rate at 60 months
p<0.001 p=0.11
Response at 18 months
CCyR with >=3 log red.CCyR with <3 log red.No CCyR
Rx aim: CGCR in Year 2+; no need for MMR
MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS
Patients with MCyR have better OS than patients that do not
Landmark analysis at 6 mos
0 12 24 36 48 60 72
Cytogenetic response at 6 mos Total Dead P-value
Complete 201 5
Partial 39 1
Minor 10 3
Othersa 9 3
0.85
0.01
0.62
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n a
live
Months
Kantarjian H. Cancer. 2008;112:837–845.
MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS
Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos.
Landmark analysis at 12 mos
Pro
po
rtio
n P
FS
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72
Months
Cytogenetic response at 12 mos Total Failure P-value
Complete 214 7
Partial 19 3
Minor 5 2
Others 8 5
0.02
0.2
0.22
Kantarjian H. Cancer. 2008;112:837–845.
EFS and Survival by 12-month Response-CCyR vs Others with TKI Frontline Rx
Jabbour E et al. Blood. 2011.
EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx
Jabbour E et al. Blood. 2011.
100
BC
R-A
BL%
BC
R-A
BL%
ISIS
0.010.01
1.01.0
1010
0.0010.001
BCR-ABL International Scale (IS)BCR-ABL International Scale (IS) Absolute valuesAbsolute values
Undetectable by PCRUndetectable by PCR 0 0 ~~101066 leukaemic cells leukaemic cells
major molecular response major molecular response ≤0.10% (MMR)≤0.10% (MMR)
-1 log-1 log
-2 log-2 log
-4 log-4 log
-5 log-5 log
MCRMCR
CCRCCR
-3 log-3 log0.10.1
BaselineBaseline
CMR CMR 66 mo66 mo
CMRCMR
Achieving an MMR may be associated with the most favourable event free survivalAchieving an MMR may be associated with the most favourable event free survival
CCyR 6 moCCyR 6 mo
MMR 15 moMMR 15 mo
1.01.0
0.100.10
0.010.01
1010
Base-Base-lineline
PB
BC
R-A
BL
%
PB
BC
R-A
BL
%
ISIS
00Months on standard dose imatinibMonths on standard dose imatinib
48482424 36361212 6060 727266
CMR CMR 66 mo66 mo
CMRCMR
Achieving an MMR may be associated with the most favourable event free survivalAchieving an MMR may be associated with the most favourable event free survivalWhat is the additional What is the additional benefit of a further 1 log benefit of a further 1 log
reduction of BCR-ABL for reduction of BCR-ABL for patients with CCyRpatients with CCyR? ?
CCyR 6 moCCyR 6 mo
MMR 15 moMMR 15 mo
00Months on standard dose imatinibMonths on standard dose imatinib
48482424 36361212 6060 727266
1.01.0
0.100.10
0.010.01
1010
Base-Base-lineline
PB
BC
R-A
BL
%
PB
BC
R-A
BL
%
ISIS
EFS: 6-Month Landmark AnalysisEvents : loss of CHR, MCR, AP/BC or deathEvents : loss of CHR, MCR, AP/BC or death
93%85%85%
56%
P = .25
BCR-ABL % (IS)
<=0.1%>0.1-1%>1-10%>10%
% W
ith
ou
t E
ven
t
0
10
20
30
40
50
60
70
80
90
100
Months Since Start of Treatment0 12 24 36 48 60 72 84
EFS: 12-Month Landmark Analysis
92%91%
64%
53%
P = .25
BCR-ABL % (IS)
<=0.1%>0.1-1%>1-10%>10%
% W
ith
ou
t E
ven
t
0
10
20
30
40
50
60
70
80
90
100
Months Since Start of Treatment0 12 24 36 48 60 72 84
EFS: 18-Month Landmark Analysis
86%
95%
62%58%
P = .01
BCR-ABL % (IS)
<=0.1%>0.1-1%>1-10%>10%
% W
ith
ou
t E
ven
t
0
10
20
30
40
50
60
70
80
90
100
Months Since Start of Treatment0 12 24 36 48 60 72 84
BUT MMR = Progression
rbloechlinger, 03/01/2011
Greater than MMR does not equal less than progression?
Deeper molecular response and lower risk of transformation
Baseline
MMR
CMR5
Intrinsic biology of CML
Good AP/BCPoor
CMR4
Deeper molecular response and lower risk of transformation
MMR
CMR5
Depth of Molecular response
At 12 M
Intrinsic biology of CML
Good AP/BCPoor
High risk for transformation
CMR4
Deeper molecular response and lower risk of transformation
MMR
CMR5
High risk for transformationDepth of
Molecular response
At 12 M
Intrinsic biology of CML
Good AP/BCPoor
CMR4
IRIS trial: Overall estimated log reduction of BCR-ABL transcripts on IM
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
3 months 6 months 12 months 18 months 24 months
Months since start of treatment
4 log
3-<4 log
2-<3 log
<2 log
No CCyR
% o
f al
l pa
tie
nts
75% 50% 32% 26% 24%
19% 18% 29%
8%
20% 34%
25%
13%
Clinical Value of molecular monitoring in CML
• Early detection of relapse
• Monitoring response of patients treated for relapse
• Evaluation of leukemia cell contamination in stem cell collections
• Monitoring response in complete cytogenetic responders
Imatinib Failure or Suboptimal Response
38
CML. Criteria For Failure On Imatinib
• No major CG response at 6 mos (Ph 100%) (Ph > 35%)
• No major CG CR at 12 mos
• No CGCR in Year 2+
• CG relapse or hematologic relapse
• Not failure criteria
- suboptimal CG response
- QPCR ↑ in CGCR
Baccarani. Blood 108:1809-20, 2006
Results with Imatinib in Early CP CML – The IRIS Trial at 8-Years
Goals of Rx- achieving CCyR and CMR through Milestones in a predictable timely fashion
Reasons for not reaching the milestones•Clonal evolution- Transformation•TKI Intolerance•TKI Resistance- Mutations•Compliance
Deininger et al; Blood 2009; 114: Abst# 1126
IRIS 8-Year Results: Annual IRIS 8-Year Results: Annual Rate of Events on ImatinibRate of Events on Imatinib
• EFS = 81%• Freedom from progression to AP/BC = 92%
-1 progression to AP/BC and 2 non-CML related deaths in year 8
WithEvent,%
3.3
7.5
4.8
1.7
0.80.3
1.4 1.31.5
2.8
1.8
0.90.5
0 00.4
0
1
2
3
4
5
6
7
8
1 2 3 4 5 6 7 8
Year
EventLoss of CHR,Loss of MCyR,AP/BC,Death during treat
Deininger et al. ASH 2009. Abs # 1126
Phase III Study of Interferon vs Imatinib Mesylate Phase III Study of Interferon vs Imatinib Mesylate in Chronic Phase CML (IRIS): Transformation-Free in Chronic Phase CML (IRIS): Transformation-Free
Survival by Cytogenetic Response*Survival by Cytogenetic Response*%
*ITT population†Progression to AP/BC or death due to CML while on core treatment
1.1% 4.2% 1.8% 6.0%
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs imatinib in CML-CP
Hughes et al, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 207.
Primary endpoint Confirmed CCyR by 12 mos
Other key endpoints Rates of CCyR and MMR, times to CCyR and MMR, time in CCyR (measure of duration), progression-free survival, overall survival
DASISION (DASISION (CA180-056) study design ) study design (ongoing global phase 3 study)(ongoing global phase 3 study)
Follow-up
5 yearsRandomized*
Imatinib 400 mg QD (n=260)
Dasatinib 100 mg QD (n=259) Treatment-
naïve CML-CP patients (N=519)
108 centers
26 countries*Stratified by Hasford risk score
DASISION: First-line Dasatinib vs Imatinib in CML-CP
Shah et al, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 206.
ebednarek, 03/02/2011
added ref, please confirmremoved "confidential" from slides
8
27
3946
57
13
0.48
1828
41
7
0
20
40
60
80
100
BCR-ABL ≤0.0032%
MMR, BCR-ABL ≤0.1%
Based on time-to MMR analysis, likelihood of achieving a MMR was 1.8-fold higher with dasatinib vs imatinib (stratified log-rank P<0.0001; HR=1.8)
Among patients who achieved a MMR, median time to MMR was 8.3 mos for dasatinib and 11.8 mos for imatinib
P<0.0001
P=0.0002
MMR rates (ITT) by month of treatmentDasatinib 100 mg QD
Imatinib 400 mg QD
Mo 3 Mo 6 Mo 9 Mo 12 Any timeAny time
%
DASISION: First-line Dasatinib vs Imatinib in CML-CP
Shah et al, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 206.
5 patients who achieved a CCyR transformed to AP/BP CML (2 dasatinib, 3 imatinib) No patient who achieved a MMR transformed to AP/BP CML to date Patients were followed for transformation for up to 60 days after the last dose of
study drug; clonal evolution without additional criteria for AP CML was NOT counted as transformation
2.3
3.5
0
2
4
6
Transformation to Advanced Phase CML (ITT)Transformation to Advanced Phase CML (ITT)100
n/N 6/259 9/260
Dasatinib 100 mg QD
Imatinib 400 mg QD
%
DASISION: First-line Dasatinib vs Imatinib in CML-CP
Shah et al, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 206.
What is the best strategy to minimise progression AND maximise MMR?
Imatinib 400 mg/day for all Imatinib 400 mg/day for all NO
Imatinib at higher dose Imatinib at higher dose ????
Imatinib plus interferon Imatinib plus interferon ????
More potent TKI for all (nilotinib, dasatinib)More potent TKI for all (nilotinib, dasatinib)