DONG WOOK KIM, MD Seoul, S. Korea • Professor, Seoul ST. Mary Hospital, Seoul, S. Korea • Dr. Kim the Head of Cancer Research Institute at the Catholi c University of Korea, a chairman of Asia CML Study Allian ce (ACSA) that is an Asian hematologist network and the pu rpose is to improve the quality and standardization of CML t herapy and research in Asian countries on the basis of unders tanding the current situation. And also ACSA seeks collabor ation in CML studies and sharing information for new medic al discoveries in CML and ELN (European Leukemia Net) P anel for CML recommendation 2013.
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Imatinib vs. 2nd gen TKI in newly diagnosed Chronic Myelogenous Leukemia
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DONG WOOK KIM, MDSeoul, S. Korea
• Professor, Seoul ST. Mary Hospital, Seoul, S. Korea
• Dr. Kim the Head of Cancer Research Institute at the Catholi
c University of Korea, a chairman of Asia CML Study Allian
ce (ACSA) that is an Asian hematologist network and the pu
rpose is to improve the quality and standardization of CML t
herapy and research in Asian countries on the basis of unders
tanding the current situation. And also ACSA seeks collabor
ation in CML studies and sharing information for new medic
al discoveries in CML and ELN (European Leukemia Net) P
anel for CML recommendation 2013.
Imatinib vs. 2G TKI
in newly diagnosed CP-CML
Prof. Dong-Wook Kim MD, PhD
Seoul St. Mary’s Hospital
The Catholic University of Korea
• ENESTnd: MMR, Nil vs IM, approved
• DASISION: cCCyR, Das vs IM, approved
• BELA: cCCyR, Bos vs IM, fail to achieve primary endpoint
• EPIC: MMR, Pon vs IM, suspended due to serious VEs
• RE-RISE: MMR, Rad vs IM, ongoing in Asian countries
• BFORE: MMR, Bos vs IM, ongoing in Global
Clinical trials with IM vs 2 or 3 G TKI
in new CML patients
Treatment strategy recommendation,
chronic phase, firstline
Baseline (firstline treatment)
- Imatinib 400 mg once daily, or
- Nilotinib 300 mg twice daily, or
- Dasatinib 100 mg once daily
In case of intolerance, switch to another TKI
In case of failure, switch to another TKI
In case of warning, do not switch, until the warning is confirmed or
becomes a failure
Baccarani M., et al. Blood 2013, 122(6):872-884
Characteristics of registered patients (n=3,717)
- Type of 1st TKI -
by 1-DEC-2014 7th ACSA-ASH 2014 in San Francisco
Asia Collaboration of CML Research
IM3420 (92%)
Nil92 (3%)
Das120 (3%)
Bos20 (1%)
Rad54 (1%)
Pon11 (0%)
Asia CML Registry (ACR)
- 10 Asian countries
- 17 major hospitals
DASISION (CA180-056) Study Design
Primary end point: confirmed CCyR by 12 months
– 77% dasatinib vs. 66% imatinib (P=0.007)1
Database lock of 24-Mar-2014
5-year
final resultsRandomizeda
Imatinib 400 mg QD (n=260)
Dasatinib 100 mg QD (n=259)
Treatment-naïve
CML-CP patients
(N=519)
108 centers
26 countries
Enrollment:
September 2007–
December 2008
aStratified by EURO (Hasford) risk score.1. Kantarjian H et al. N Engl J Med 2010;362:2260–70.
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
KR1401170300
ENESTnd Study Design
N = 846
217 centers
35 countries
Imatinib 400 mg QD (n = 283)
Nilotinib 300 mg BID (n = 282)
RANDOMIZE
Nilotinib 400 mg BID (n = 281)
Follow-up: 5 years; extended to 10 years
after protocol amendment
Primary end point: MMR at 12 months
Patients were stratified according to Sokal risk score at diagnosis
BID, twice daily; QD, once daily. Saglio G, et al. Blood. 2013:[abstract 92].
Patient Disposition at 5 Years
At 5 years (study end), 61% and 63% in dasatinib and imatinib are still on
initial therapy
Treated Patients, n (%)
Dasatinib 100 mg QD
(n=258)
Imatinib 400 mg QD
(n=258)
On initial therapy at study end 158 (61) 162 (63)
Discontinued
Progression or treatment failure 28 (11) 36 (14)
AE related to study treatmenta 42 (16) 17 (7)
AE unrelated to study treatmenta 12 (5) 4 (2)
Poor/nonadherence 1 (<1) 7 (3)
Other 17 (7)b 31 (12)c
aAEs defined by investigator.
bIncludes withdrawal of consent and patient request (4 each), insufficient molecular response (3), pregnancy (2), and lost to follow-up, loss of CCyR, increased BCR-ABL, and relocation to the US (1 each).
cIncludes patient request (10), no molecular response/loss of molecular response (4), withdrawal of consent and suboptimal response (3 each), lost to follow-up, insufficient cytogenetic response, and investigator request (2 each), and pregnancy, recurrence of blasts in bone marrow,no CMR, no MMR, and appearance of mutation (1 each).
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
KR1401170300
Patient Disposition at 5 Years
Few patients have discontinued treatment since the 4-year data cutoff
• 3.5% (n = 10) on nilotinib 300 mg BID; 4.3% (n = 12) on nilotinib 400 mg BID; 6.0% (n = 17) on imatinib
– Of 17 imatinib discontinuations, 5 (vs 0 nilotinib discontinuations) were due to suboptimal response/treatment failure
Median time on core treatment comparable and median dose intensity close to intended dose for all
treatment armsa Patients are either on study drug or in post-treatment follow-up after discontinuation of study drug.b Patients with suboptimal response or treatment failure on nilotinib 300 mg BID or imatinib core treatment were eligible to
discontinue the core study and enter an extension study to receive nilotinib 400 mg BID.
MMR rates have significantly increased in dasatinib arm
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
KR1401170300
Cumulative Incidence of MMR
MMR, major molecular response (BCR-ABLIS ≤ 0.1%).a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.
By 1 Yeara By 5 Yearsa
55%, P < .0001
51%, P < .0001
27%
Δ 24% to 28%
60%
77%, P < .0001
77%, P < .0001
Δ 17%
By 4 Yearsa
76%, P < .0001
73%, P < .0001
56%
Δ 17% to 20%
100
0 2 6
90
80
70
60
50
40
30
20
10
0
Pati
en
ts W
ith
MM
R,
%
Time Since Randomization, Calendar Years31
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
4 5
Saglio G, et al. Blood. 2013:[abstract 92].
MMR rates were also significantly higher in both nilotinib arms
0 6 12 18 24 30 36 42 48 54 60
100
90
80
70
60
50
40
30
20
10
0
Cumulative MR4.5 Rates Over Time
By 1 year
By 2 years
By 3 years
By 4 years
By 5 years
3%
8%
13%
23%
33%
5%
19%
24%
34%
42%
p=0.0251
Months Since Randomization
% W
ith
MR
4.5
Dasatinib 100 mg QD
N
Imatinib 400 mg QD 260259
MR4.5, BCR-ABL (IS) ≤0.0032% (for subjects with B2a2 and B3A2 transcripts).
Cumulative rate of MR4.5 was also significantly higher in dasatinib arm
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
KR1401170300
Cumulative Incidence of MR4.5
MR4.5, molecular response ≥ 4.5-logs (BCR-ABLIS ≤ 0.0032%).a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.
By 5 Yearsa
11%, P < .0001
7%, P < .0001
1%
Δ 6% to 10%
31%
52%, P < .0001
54%, P < .0001
Δ 21% to 23%
By 4 Yearsa
40%, P < .0001
37%, P = .0002
23%
Δ 14% to 17%
100
0 2 6
90
80
70
60
50
40
30
20
10
0
Pati
en
ts W
ith
MR
4.5
, %
Time Since Randomization, Calendar Years
31
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
4 5
By 1 Yeara
Saglio G, et al. Blood. 2013:[abstract 92].
By 5 yrs, more than half of nilotinib-treated patients had achieved MR4.5
Dasatinib 100 mg QD
(n=259)
Imatinib 400 mg QD
(n=260)
BCR-ABL at 3 Monthsa≤10%
n=198
>10%
n=37
≤10%
n=154
>10%
n=85
Transformation to AP/BPb, n (%) 6 (3) 5 (14) 5 (3) 13 (15)
0
5
10
15
20
Pati
en
ts,
n12
(4.6%)
19
(7.3%)
Dasatinib
n=259
Imatinib
n=260
On study During follow-up beyond discontinuation
Transformation to AP/BP CML by 5 Years
One imatinib patient and no dasatinib patients transformed between 4 and 5 yearsaOne dasatinib and one imatinib patient transformed but did not have 3-month molecular assessments.
bIncluding follow-up beyond discontinuation (intent to treat).
4.6% (12 pts) progressed to AP/BC in dasatinib arm comparing with 7.3% in IM arm
An achievement of EMR at 3 mos was able to decrease dis. progression by 5 yrs.
ENESTnd 5-Year Update
Data cutoff: May 22, 2013
KR1401170300
20
10
0
5
10
15
20
25
Progressions on Study
Pati
en
ts,
nProgression to AP/BC on Studya
(Including After Treatment Discontinuation)
a Includes progression to AP/BC (excluding clonal evolution) or deaths in patients with advanced CML occurring on study (on
core or extension treatment or during follow-up after treatment discontinuation).
a Includes events occurring on core or extension treatment or during follow-up after treatment discontinuation.b Patients for whom the principle cause of death was either “study indication” or “unknown” or not reported but occurred
subsequent to a documented progression to AP/BC.
Imatinib
400 mg QD
(n = 283)
Nilotinib
300 mg BID
(n = 282)
Nilotinib
400 mg BID
(n = 281)
Estimated 5-year PFS, % 91.1 92.0 95.3
Progressions and deaths, n 23 22 11
Hazard ratio (95% CI) — 0.92 (0.51-1.65) 0.46 (0.23-0.95)
P value .77 .03
Estimated 5-year OS, % 91.6 93.6 96.0
Total deaths, n 21 18 10
Deaths in patients with
advanced CML, nb 15 6 4
Hazard ratio (95% CI) — 0.84 (0.45-1.58) 0.46 (0.22-0.98)
P value — .58 .04
At 5 yrs of FU, PFS and OS were higher in patients treated with nilotinib 400mg BID than with IM
There were 6 newly reported deaths in year 5
Imatinib (n = 2): both due to study indication
Nilotinib 300 mg BID (n = 3): study indication, rectal cancer, and pneumonia