CML-A Functionally Curable Disease Hagop Kantarjian, MD

CML-A Functionally
Curable Disease
Hagop Kantarjian, MD
The University of Texas
M. D. Anderson Cancer Center
Houston, Texas, United States
Middle East Forum on
Hematologic Malignancies
Dubai
April 2013
CML. Historical vs. Modern Perspective
Parameter
•Course
•Prognosis
•10-yr survival
•Frontline Rx
•Second line Rx
Historical
Fatal
Modern
Indolent
Poor
Excellent
10%
84 - 90%
Allo SCT;
IFN-
Imatinib;
nilotinib;
dasatinib
New TKIs;
2
allo SCT
?
Survival in Early Chronic Phase CML
TKI
Interferon
Chemotherapy
Kantarjian . Blood 119:1981; 2012.
Population-Based CML Outcome in
Sweden
• 3173 patients diagnosed between 1973-2008
- Median age 62 yrs
80%
54%
37%
23%
21%
Bjorkholm. JCO. 29 2514, 2011
Therapy
of
CML
in
2013
•Frontline
- imatinib 400 mg daily
- nilotinib 300 mg BID
- dasatinib 100 mg daily
•Second / third line
- nilotinib, dasatinib, bosutinib, ponatinib,
omacetaxine
- allogeneic SCT
•Other
- decitabine, pegasys
- hydrea, cytarabine, combos of TKIs and
with TKIs
- investigational: hedgehog inhibitors,
JAK2 inhibitors, IL3-DT
Available TKIs in CML
TKI
Target
Imatinib
Bcr-Abl
Nilotinib
Bcr-Abl
post IFN;
frontline
400 BID post IM
CP,AP
frontline
Dasatinib
Src-Abl
100
Src-Abl
Bcr-Abl
T315I
Omacetaxine
--
500
45
Bosutinib
Ponatinib
Dose
(mg/D)
FDA
Approval in
CML
Unique AEs
400
post IM all
phases
frontline
salvage
salvage
pancreas;
LFT; rash
↓ PLT;
effusions
diarrhea; LFT
Pancreatitis
PLT↓
6
salvage
CML. The Next Questions
• Frontline CML Rx:
imatinib vs.
second TKIs
• Can we cure CML molecularly? Is
it necessary?
• Role and timing of allo SCT
• Monitoring of CML
• Others: prevalence, pregnancy CG
abn., Rx DC
7
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%
Deininger. Blood 114: abst 1126, 2009
Frontline Rx with Dasatinib or
Nilotinib at MDACC
• Parallel studies with nilotinib (400 mg BID) or dasatinib
(100 mg QD or 50 mg BID)
% Response
CGCR by 12 mos
MMR by 12 mos
3-yr Survival
3-yr TFS
3-yr EFS
3-yr FFS
Rx discontinuation
Nilotinib
N=100
93
73
100
97
91
78
11
Dasatinib
N=93
99
83
99
100
91
80
9
Quintas-Cardama. Blood 118: abst 454, 2011. Pemmaraju. Blood 118; abst 1700; 2011
TKI Frontline Therapy in CML
Long-Term Outcome By Response Time
Event-Free Survival
Transformation-Free Survival
p<0.001
Alattar et al. ASH 2011; Abstract #745
ENEST-nd. Study Design
Nilotinib 300 mg BID (n = 282)
• N = 846
• 217 centers
• 35 countries
R
A
N
D
O
M
I
Z
E
D
*
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
* Stratification by Sokal risk score.
10 years of follow-up are planned
Kantarjian. Blood 120:abst 1676;2012
Nilotinib vs Imatinib in Newly
Diagnosed Chronic Phase CML
• 846 pts randomized to nilotinib 300 mg BID (n=282),
nilotinib 400 mg BID (n=281), or imatinib 400 mg QD
(n=283)
• Minimum follow-up 48 mo
Outcome
% CCyR*
% MMR**
% BCR-ABL ≤0.0032%**
% Transformed AP/BP
% 4-yr EFS
% 4-yr OS
* by 24 months, ** by 48 months
Kantarjian. Blood 120;abst 1676: 2012
Nil 300 Nil 400 IM 400
87
85
77
76
73
56
40
37
23
3.2
2.1
6.7
95
97
93
94
97
93
ENEST-nd.Progression to AP/BC
Core Rx
P = .0009
25
P = .0059
P = .0085
P = .0185
Percentagen
Patients,
20
17
15
12
10
5
5
0
2
0.7%
3
1.1%
3
4.2%
1.1%
1.8%
6.0%
Including Clonal Evolution
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Kantarjian. Blood 120:abst 1676;2012
Imatinib 400 mg QD
ENEST-nd.Progression to AP/BC on Study
(Including After Treatment Discontinuation)
Nilotinib 300 mg BID
P = .0497
HR = 0.5 (0.2-1.0)
P = .0074
Patients, n
HR = 0.3 (0.1-0.8)
19
Nilotinib 400 mg BID
Imatinib 400 mg QD
9
6
3.2%
2.1%
6.7%
On Core or Extension Treatment or After Discontinuation
Kantarjian. Blood 120:abst 1676;2012
ENEST-nd. Cumulative Incidence of
MMR
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
100
Patients With MMR, %
n
282
281
283
90
By 4 Years
80
By 1 Year
76%, P < .0001
70
55%, P < .0001
73%, P < .0001
Δ 17%-20%
60
50
51%, P < .0001
40
Δ 24%-28%
56%
30
27%
20
10
0
0
6
12
18
24
30
36
42
Time Since Randomization, Months
Kantarjian. Blood 120:abst 1676;2012
48
54
60
ENEST-nd. Cumulative Incidence of
MR4.5
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
Patients With MR4.5, %
100
80
By 4 Years
By 1 Year
60
40%, P < .0001
40
37%, P = .0002
Δ 14%-17%
Δ 6%-10%
20
11%, P < .0001
23%
7%, P < .0001
1%
0
0
6
12
18
24
30
36
42
48
54
Time Since Randomization, Months
Kantarjian. Blood 120:abst 1676;2012
60
% With MR4.5
Nilotinib vs. Imatinib in CML (ENEST-nd).
MR 4.5 by 3 Years According to Sokal Risk
50
45
40
35
30
25
20
15
10
5
0
P = .0003
P = .0468
40
P = .0099
30
24
18
17
9
n=
103
Low
104
Nilotinib 300 mg BID
Saglio. Blood 118; abst 452, 2011
101
101
Intermediate
78
High
Imatinib 400 mg QD
78
Nilotinib vs. Imatinib in CML (ENEST-nd).
Survival After Progression to AP/BP
Progressed = 34
Died = 23
Alive = 11
100
90
80
Median survival
10.5 months
% Alive
70
60
50
40
30
20
10
0
0
6
12
18
24
Months Since Progression
Saglio. Blood 118; abst 452, 2011
30
36
42
Nilotinib vs. Imatinib in CML-CP. Adverse
Events and Grade 3/4 Myelosuppression
Rate difference (imatinib - nilotinib) with 95% CI
Favors imatinib
Favors nilotinib (300 mg BID)
Fluid retention
Diarrhea
Headache
Muscle cramps
Any grade
Nausea
Pruritus
Rash
Vomiting
Anemia
Grade 3/4
Neutropenia
Thrombocytopenia
-0.5
-0.4 -0.3 -0.2 -0.1 0
0.1
Hochhaus. Haematologica. 2010;95(s2):459 [abst 1113]
0.2
0.3
0.4
0.5
Dasatinib Versus Imatinib Study In Treatmentnaïve CML (DASISION). Trial Design
• N=519
• 108 centers
• 26 countries
Dasatinib 100 mg QD (n=259)
Randomized*
Follow-up
5 years
Imatinib 400 mg QD (n=260)
*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
Kantarjian. JCO. 29:abst 6510; 2011
Dasatinib vs Imatinib in Newly
Diagnosed Chronic Phase CML
• 519 pts randomized to dasatinib 100 mg QD
(n=259) or imatinib 400 mg QD (n=260)
• Minimum follow-up 36 mo
Outcome*
% CCyR
% MMR
% BCR-ABL ≤0.0032%
% Transformed AP/BP
% 3-yr PFS
% 3-yr OS
Das 100
86
68
22
4
91
94
IM 400
82
55
12
6
91
93
* by 24 months
Hochhaus. JCO 30: abst 6504; 2012.
DASISION. Cumulative Incidence of CCyR
100
By 12 months
85%
80
%
By 24 months
86%
82%
73%
60
Dasatinib 100 mg QD
Imatinib 400 mg QD
40
20
0
0
•
10
20
30
Months
cCCyR rate by 24 months for dasatinib vs
imatinib was 80% vs 74%
Kantarjian. JCO. 29:abst 6510; 2011
40
DASISION - Cumulative Incidence of MMR
and MR4.5
Dasatinib 100 mg QD
MR4.5
MMR
100
P<0.0001
40
P=0.00069
64%
60
68%
46%
55%
40
46%
20
% with MR4.5
80
% with MMR
Imatinib 400 mg QD
30
22%
17%
20
3%
10
12%
23%
9%
0
0
0
12
24
Months
36
2%
0
12
24
36
Months
MMR = BCR-ABL ≤0.1%
MR4.5 = BCR-ABL ≤0.0032%
Hochhaus, JCO 30: abst 6504; 2012
DASISION. Transformation to AP/BP
CML by 3 Years
Dasatinib 100 mg QD
Imatinib 400 mg QD
Number of patients, n
16
13
11
8
N
259
260
On study
Hochhaus. JCO 30: abst 6505;2012
259
260
Including follow-up beyond
discontinuation (ITT)
DASISION. Forest Plot Comparing Differences
in AE Rates for Dasatinib and Imatinib
Any grade
Grade 3/4
Fluid retention
Superficial edema
Pleural effusion
Myalgia
Nausea
Vomiting
Diarrhea
Fatigue
Headache
Rash
Neutropenia
Thrombocytopenia
Anemia
–40
l
l
l
l
l
l
l
l
l
l
l
l
l
–20
0
20
40
Rate Difference (dasatinib-imatinib) with 95% CI
Favors dasatinib Favors imatinib
Kantarjian. JCO. 29:abst 6510; 2011
CML Frontline Rx. Toxicities of TKIs
• Bothersome chronic side-effects
less frequent with nilotinib than with
imatinib: nausea, cramps, aches,
weight gain, fluid retention,
periorbital edema
• Rashes, headaches more frequent
with nilotinib
• Pleural effusions, cytopenias more
frequent with dasatinib
Frontline TKI for CML AP
• 58 pts with ≥15% blasts (n=8), ≥20%
•
•
basophils (n=22), platelets <100 x109/L
(n=3), or CE (n=22)
Rx: Imatinib 36, nilotinib 17, dasatinib 5.
CCyR 82%: imatinib 75%, nilotinib 95%
−
−
At 12 mo: imatinib 74%, nilotinib 83%
CE 91%, other 76%
−
4 pts transformed to BP (none had CyR @ 12
mo)
• MMR 68%: imatinib 66%, nilotinib 71%
• 24 mo EFS 90%, TFS 92%, OS 100%
Ohanian et al. ASH 2011; Abstract #3779
Risk Assessment for SCT in CML
Risk factor
Donor type
Stage
Age
Sex match
Time from Dx
Group
HLA-identical sibling
MUD
CP
AP
BP, ≥2nd CP
<20
20-40
>40
All other
M-rec/F-don
<12 mo
>12 mo
Score
0
1
0
1
2
0
1
2
0
1
0
1
Gratwohl. Lancet 1998; 352: 1087-92
Outcome After SCT by EBMT Score
% with
Score
score
0
2
1
18
2
28
3
28
4
15
5
7
6
2
LFS
62
61
44
34
28
37
15
% at 5 years
OS
TRM
76
21
73
21
59
35
49
47
38
53
39
45
19
81
RI
26
23
32
31
28
41
32
Gratwohl. Lancet 1998; 352: 1087-92
Overall Survival With TKI After
Imatinib Failure or With SCT
100
80
% alive
91%
60
40
~55%
20
Dasatinib
0
0
3
6
9
12
15
18
Months
21
24
27
30
100
90
80
% Alive
70
87%
60
50
40
30
20
Shah. Hematologica 2010 [E-pub ahead of print]
Kantarjian. Blood 2009; 114: Abs # 1129;
Gratwohl . Lancet 1998; 352: 1087-92
Nilotinib
10
0
0
3
6
9
12
15
18
21
24
27
Months Since Start of Treatment
30
33
36
CML. Role and Timing of allo SCT
Status
TKIs
Allo SCT
AP-BP
Interim Rx to MRD
ASAP
IM failure in CP,
T315I
Ponatinib interim
Rx to MRD
ASAP
IM failure in CP –
no CE, no
mutations, good
initial response
IM failure in CP –
CE, bad mutations,
no CG response
Older ≥65 – 70 post
IM failure
Long-term second
line TKIs
Third line post
second TKI failure
Interim Rx to MRD
Second line
Long-term
May forgo allo SCT
for many yrs of
32
QOL
CML in US. Incidence vs. Prevalence
The Changing Demographics of CML
•Incidence 5,000 cases/yr
•Prevalence plateaus when incidence
= annual mortality
2% Annual Mortality
X Incidence of 5000 cases = 100
Prevalence of 5000 X 100 ÷ 2 =
250,000 cases
Kantarjian. CML Chapter. Abeloff’s Clinical Oncology 4th Edition, 2279, 2008.
CML - Increasing Prevalence Over Time
Number of Cases
200000
180000
160000
140000
120000
100000
•
•
80000
60000
•
40000
20000
2000
2005
2010
2015
Incidence 4700 per year
Age-matched mortality ratio vs
normal population = 1.50
Accounts for increased US
population to 410 million in 2050
2020
2025
2030
2035
2040
2045
2050
Year
Huang. Cancer 118:3123;2012
CML Monitoring
• Establish confirmed CGCR in first year (BM
•
•
•
at 6-12 mo)
In CGCR
- FISH and QPCR every 6 mos
- If MMR (QPCR < 0.1%), may monitor with
QPCR only (watch for false results)
- If QPCR ↑ by 0.5 – 1 log and/or loss of MMR
(PCR> 0.1%) → monitor more frequently
Mutations studies if resistance / need to
change TKIs
Change TKI only for loss of CGCR, not
35
based on MMR/QPCR
Take Home Message – CML 2013
• Great therapy for CML
• Early response (3 months) predictive of response
• Should not change at 3 months
• Monitor at 6 months and decide
• Deeper molecular responses improve event-free
survival
• No impact on transformation or survival
• No clear benefit for CMR (except
discontinuation?)
• Few patients can discontinue safely
• New approaches: IFN, AZA, JAK2 inhibitors, etc
• Excellent new drugs: ponatinib, bosutinib,
omacetaxine
Leukemia Questions?
• Pager 713-404-3387
• hkantarj@mdanderson.org
Hagop Kantarjian, MD