Defining goals for molecular remission in Chronic Myeloid Leukemia.

SWAMI IYER, MDSWAMI IYER, MD
Houston, USAHouston, USA
• Associate Professor, Leader, early drugAssociate Professor, Leader, early drug
development in Oncology, the Methodist Cancerdevelopment in Oncology, the Methodist Cancer
CenterCenter
• Dr Iyer is the Leader for Early Drug DevelopmentDr Iyer is the Leader for Early Drug Development
Program in Hematology and Oncology at the MethodistProgram in Hematology and Oncology at the Methodist
Cancer Center, Houston, Texas. He recently served asCancer 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 theand as an Assistant Professor of Medicine at the
University of Texas Health Science CenterUniversity 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 extensiveinterests 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, MDSwami Padmanabhan Iyer, MD
Leader Early Drug Development Program andLeader Early Drug Development Program and
Co-Director of the Malignant HematologyCo-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, TXHouston, 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

•TKI Intolerance
•Compliance
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

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
AP/BP
–Event-free survival 81%
–Transformation-free survival 92%
• If MMR at 12 mo: 100%
–Survival 85% (93% CML-related)
• Annual rate of transformation: 1.5%, 2.8%,
1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4%

Event-Free Survival by
Molecular Response at 18 Months
Baccarani et al. Blood, 108 (11): Abstract 2138
EFS(%)
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 randomization
0 12 24 36 48 60 72

Let us look at the Milestones

Decreasing residual
leukemia
Numberofleukemiacells(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
Logreductionfrombaseline
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

NumberofLeukaemiccellsNumberofLeukaemiccells
10101212
10101111
10101010
101099
101088
101077
101066
101055
101044
101033
CCyRCCyR
residual disease
is assessed at
the molecular
level
Relationship between treatment responseRelationship between treatment response
level and number of leukaemic cellslevel and number of leukaemic cells
MMRMMR
DiagnosisDiagnosis

Unlike other measurementUnlike other measurement
parameters it is difficult toparameters it is difficult to
define a complete moleculardefine a complete molecular
responseresponse
undetectable BCR-undetectable BCR-
ABLABL
CMRCMR
CCyCCy
RRMMRMMR
10101212
10101111
10101010
101099
101088
101077
101066
101055
101044
101033
Limit of detection willLimit of detection will
vary for each samplevary for each sample
Relationship between treatment responseRelationship between treatment response
level and number of leukaemic cellslevel and number of leukaemic cells
For the IRIS trial CMR was defined asFor the IRIS trial CMR was defined as
undetectable BCR-ABL with a sensitivity of atundetectable 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.
??
NumberofLeukaemiccellsNumberofLeukaemiccells

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 CHR
Loss of CCgR
Mutation
CE
Loss of MMR
Mutation
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
Any
Stable or
improving
MMR
Baccarani. JCO 2009; 27: 6041-51

Gold Standard- CCyR
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=0.20CCyR
PCyR
No MCyR
%withoutAP/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 th s s in c e r a n d o m iz a tio n
0 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%)

%withoutAP/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 th s s in c e ra n d o m iz a tio 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
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
Proportionalive
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
ProportionPFS
1.0
0.8
0.6
0.4
0.2
0
0 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
BCR-ABL%BCR-ABL%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
00 ~~101066
leukaemic cellsleukaemic cells
major molecular responsemajor 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

CMRCMR
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
PBBCR-ABL%PBBCR-ABL%
ISIS
00
Months on standard dose imatinibMonths on standard dose imatinib
48482424 36361212 6060 727266

CMRCMR
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 additionalWhat is the additional
benefit of a further 1 logbenefit of a further 1 log
reduction of BCR-ABL forreduction of BCR-ABL for
patients with CCyRpatients with CCyR??
CCyR 6 moCCyR 6 mo
MMR 15 moMMR 15 mo
00
Months 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
PBBCR-ABL%PBBCR-ABL%
ISIS

EFS: 6-Month Landmark Analysis
Events : 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%
%WithoutEvent
0
10
20
30
40
50
60
70
80
90
100
Months Since Start of Treatment
0 12 24 36 48 60 72 84

92%
91%
64%
53%
P = .25
BCR-ABL % (IS)
<=0.1%
>0.1-1%
>1-10%
>10%
%WithoutEvent
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84

86%
95%
62%
58%
P = .01
BCR-ABL % (IS)
<=0.1%
>0.1-1%
>1-10%
>10%
%WithoutEvent
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84

Deeper molecular response
and lower risk of
transformation
Baseline
MMR
CMR5
Intrinsic biology of CML
Good AP/BCPoor
CMR4

and lower risk of
transformation
MMR
CMR5
Depth of
Molecular
response
At 12 M
Good AP/BCPoor
High risk for transformation
CMR4

and lower risk of
transformation
MMR
CMR5
High risk for transformation
Depth of
Molecular
response
At 12 M
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
%ofallpatients
75% 50% 32% 26% 24%
19% 18% 29%
8%
20% 34%
25%
13%

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
•TKI Intolerance
•Compliance

IRIS 8-Year Results: AnnualIRIS 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
0.8
0.3
1.4 1.31.5
2.8
1.8
0.9
0.5
0 0
0.4
0
1
2
3
4
5
6
7
8
1 2 3 4 5 6 7 8
Year
Event
Loss of CHR,
Loss of MCyR,
AP/BC,
Death during treat
Deininger et al. ASH 2009. Abs # 1126

Phase III Study of Interferon vs Imatinib MesylatePhase III Study of Interferon vs Imatinib Mesylate
in Chronic Phase CML (IRIS): Transformation-Freein Chronic Phase CML (IRIS): Transformation-Free
Survival by Cytogenetic Response*Survival by Cytogenetic Response*
%WithoutAP/BP
Months since randomization
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36 42 48 54 60 66
Cytogenetic
Response at 12 mo
Estimated Rate
at 60 mo
Complete (n=350) 97%
Partial (n=86) 93%
No MCR (n=73) 81%
P<0.001
P=0.20
*Population only includes patients who received first-line imatinib mesylate.

Criteria for Suboptimal Response to
Imatinib
Time
(mo)
Response
Suboptimal
3 No CG
Response
6 ≥35% Ph+
12 1-35% Ph+
18 No MMR
Any Loss of MMR
Mutation
Baccarani. JCO 2009; 27: 6041-51

Response
Evaluation
Time
Optimal Suboptimal Failure Warning
Baseline NA NA NA High risk;
CCA/Ph+
3 mos CHR and at
least minor
CgR
(Ph+ ≤ 65%)
No CgR
(Ph+ > 95%)
< CHR NA
6 mos At least
partial CgR
(Ph+ ≤ 35%)
< Partial CgR
(Ph+ > 35%)
No CgR
(Ph+ > 95%)
NA
12 mos CCgR Partial CgR
(Ph+ 1% to
35%)
< Partial CgR
(Ph+ > 35%)
< MMR
18 mos MMR < MMR < CCgR NA
Any time during
treatment
Stable or
improving
MMR
Loss of MMR;
mutations
Loss of CHR, loss of
CCgR, mutations,
CCA/Ph+
Increase in
transcript
levels,
CCA/Ph-
Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.
2009 ELN Recommendations for2009 ELN Recommendations for
Response AssessmentResponse Assessment
Lack or loss of molecular
response is not a
criterion for failure

Failure On Imatinib And Strategies
Imatinib Failure ↑ Imatinib
Second
Generation
TKI
• Ph 100% at 6 mos _ +
• Ph ≥ 35% at 12
mos
+ +
• No CGCR in yr 2 + +
• CG relapse + +
• Hematologic
relapse
_
+

PK
NIL
47%
67%
Comparison of MMR at 12 months
Yeung et al, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 209.

2nd
Generation TKI in CML
Parameter Dasatinib Nilotinib Bosutinib
Potency (fold vs IM) 325 30 20-50
Target Src & Abl Abl Src & ABL
BCR-ABL binding Active + Inactive Inactive Intermediate
Resistant mutations T315I T315I T315I
Mutations with
intermediate sensitivity
E255K/V, V299L,
F317L
E255K/V, Y253F/H,
Q252H, F359V
E255V/K,
V299L, F317L
Standard dose (CP) 100mg QD 400mg BID 500mg QD
Grade 3-4 neutropenia &
thrombocytopenia
33% / 22% 31% / 33% 12% / 21%
Other notable toxicities
Pleural effusion,
bleeding
Bilirubin, lipase
elevation
Diarrhea, rash
C-kit inhibition (vs
imatinib)
Increased Similar None
PDGFR inhibition (vs
imatinib)
Increased Similar None
Clinical activity Highly active Highly active Highly active

Conclusions
• MMR is a truly safe haven after 18 months
• Improving MMR response rate does not
equate to reducing progression rate
• More potent TKIs improve MMR and may
reduce progression
• Selective intensification is another promising
approach

Summary
• Both molecular and cytogenetic
evaluations should be used to
guide treatment decisions until
CCyR is achieved, with molecular
assessments measured thereafter
• MMR obtained at any time point
represents a “safe haven” for
patients

SummarySummary
o Dramatic responses are seen in patients treated with CML
with the TKIs
o Resistance to TKI is real and ABL kinase domain point
mutations are best studied mechanisms.
o Guidelines for bcr-abl mutation testing must be incorporated
to treatment strategies
o Predictable structure- Mutation- Response relationship for 2nd
Gen TKIs: P-loop for Nilotinib and Gatekeeper mutations for
Dasatinib
o Presence of T315I confers the highest resistance to all
approved TKIs and is associated with disease progression
and poor survival

谢谢
!!
Follow Blood Cancer Bytes on facebook and Twitter:
https://www.facebook.com/pages/Blood-Cancer-Bytes/119732178039292

ENESTnd: Nilotinib vs Imatinib in CML-CP
Study Design and Endpoints
• Primary endpoint: MMR at 12 months
• Key secondary endpoint: Durable MMR at 24 months
• Other endpoints: CCyR, time to MMR and CCyR, EFS, PFS,
time to AP/BC, OS
*Stratification by Sokal risk score
Imatinib 400 mg QD (n = 283)
Nilotinib 300 mg BID (n =
282)
R
A
N
D
O
M
I
Z
E
D
*
Nilotinib 400 mg BID (n = 281)
• N = 846
• 217 centers
• 35 countries
Follow-up
5 years
Hughes TP, et al. ASH Annual Meeting 2010: Oral Presentation 207.

71%, P < .0001
67%, P < .0001
44%
By 24 months
100
90
80
70
60
50
40
30
20
10
0
%withMMR
0 3 6 9 12 15 18 21 24 27 30 33
Time since randomization (Months)
55%, P < .0001
51%, P < .0001
27%
By 12 months
Δ 24%-28%
Δ 23%-27%
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
282
281
283
n
Data cut-off: 20Aug2010
Cumulative incidence of MMR*
*ITT population
Reference?
ENESTnd: Nilotinib vs imatinib in CML-CP
*ITT population

Kinetics of molecular response*Kinetics of molecular response*
Median BCR-ABLIS
% (range)
Time
(months)
Nilotinib
300 mg BID
n = 282
Nilotinib
400 mg BID
n = 281
Imatinib
400 mg QD
n = 283
0†
48.7 49.2 51.5
3 0.79 0.87 5.41
6 0.19 0.19 1.02
12 0.09 0.10 0.38
18 0.03 0.04 0.17
24 0.02 0.03 0.09
*Only typical BCR-ABL transcript considered
†
Baseline
Hughes et al, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 207.

BCR-ABL ≤ 0.01% (CMRBCR-ABL ≤ 0.01% (CMR44
) and BCR-ABL) and BCR-ABL
≤ 0.0032% (CMR≤ 0.0032% (CMR4.54.5
) at any time*) at any time*††
*ITT population
†
Most sensitive measure of leukemic burden available
%PatientsWithResponse
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
P < .0001
P = .0004
P < .0001
P < .0001
BCR-ABL (IS) ≤ 0.01%
(4-log reduction: CMR4
)
BCR-ABL (IS) ≤ 0.0032%
(4.5-log reduction: CMR4.5
)
n =
282
n = 281 n = 283 n =
282
n = 281 n = 283

Progression to AP/BC on core treatment*†
NumberofPatients
0.7% 0.7%
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
P = .0059
P = .0196
P = .0003
P = .0089
Including Clonal Evolution
*ITT population
†
Progression to AP/BC or death due to CML while on core treatment
1.1% 4.2% 1.8% 6.0%

 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 years
Randomized*
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.

8
27
39
46
57
13
0.4
8
18
28
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 treatment
Dasatinib 100 mg QD
Imatinib 400 mg QD
Mo 3 Mo 6 Mo 9 Mo 12 Any timeAny time
%

 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
%

What is the best strategy to minimise
progression AND maximise MMR?
 Imatinib 400 mg/day for allImatinib 400 mg/day for all NO
 Imatinib at higher doseImatinib at higher dose ????
 Imatinib plus interferonImatinib plus interferon ????
 More potent TKI for all (nilotinib, dasatinib)More potent TKI for all (nilotinib, dasatinib)
 Selective intensificationSelective intensification
 Individualised therapy based on biomarkersIndividualised therapy based on biomarkers

Deeper molecular response and lower
risk of transformation
Baseline
MMR
CMR5
Good AP/BCPoor
CMR4

Defining goals for molecular remission in Chronic Myeloid Leukemia.

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