updated data of chronic myeloid leukemia treatment

1. Update on Current Monitoring
Recommendations in CML
Far Eastern Memorial Hospital
New Taipei City, Taiwan
Hsieh Pei-Ying

3. European Leukemia Net 2013:
Definitions of Response to TKIs first-line in 2013
References:
1. Baccarani M, et al. Presented at the 4th international Congress on Leukemia Lymphoma Myeloma. Istanbul, Turkey. May 22-25 2013.
Time Optimal Warning Failure
Diagnosis -
High risk
CCA in Ph+
-
3 months
PCgR
And/or < 10%
Minor CgR to 95%
Ph+
and/or > 10%
No CHR
and/or 95% Ph+
6 months
CCyR
And/or < 1%
< CCgR to minor
CgR
and/or > 1 – 10%
< minor CgR
and/or > 10%
12 months MMR
> 0.1 – 1%
(CCyR, no MMR)
> 1% Ph+
and/or > 1%
(No CCyR)

4. ENESTnd: Comparison of Nilotinib and
Imatinib in Newly Diagnosed CP CML
• Primary endpoint: MMR at 12 mos
• Secondary endpoint: durable MMR at 24 mos
Patients
diagnosed with
Ph+ CP CML
within 6 mos
(N = 846)
Nilotinib 300 mg BID
(n = 282)
Imatinib 400 mg QD
(n = 283)
Nilotinib 400 mg BID
(n = 281)
5-yr follow-up
Saglio G, et al. N Engl J Med. 2010;362:2251-2259. Larson RA, et al. Leukemia. 2012;26:2197-2203. Saglio G, et al.
ASH 2013. Abstract 92.
Stratified by Sokal risk
Extended to 10
yrs after
protocol
amendment

5. Patients newly
diagnosed with
CP CML
(N = 519)
Dasatinib 100 mg QD
(n = 259)
Imatinib 400 mg QD
(n = 260)
DASISION: Comparison of Dasatinib and
Imatinib in Newly Diagnosed CP CML
• Primary endpoint: confirmed CCyR at 12 mos
• Key secondary endpoints: MMR, time in confirmed
CCyR, time to confirmed CCyR and MMR, PFS, OS
Long-term
follow-up
Stratified by Hasford risk score
Jabbour E, et al. Blood. 2013;[E-pub ahead of print]. Cortes JE, et al. ASH 2013. Abstract 653.

6. What impacts on survival
after TKI treatment in CML?

7. Marin et al, J Clin Oncol 30:232-238, 2011
Impact 1:
Early molecular
response

8. ENESTnd trial: BCR-ABL Categories at 3 Months
0
20
40
60
80
100
Patients,%
BCR-ABL Level at 3 Months
n 176 234 88 24
BCR-ABL >10%
91
67
9
33>1- ≤10%
≤1%
Nilotinib 300 mg BID (n=258)
Imatinib (n=264)
• Reasons for unevaluable samples included:
• Atypical transcripts: 5 patients on nilotinib, 2 patients on imatinib
• Missing samples: 4 patients on nilotinib, 5 patients on imatinib
• Discontinuation: 15 patients (including 1 progression) on nilotinib, 12 patients (including 1 progression) on imatinib
*Calculated from total number of evaluable patients with PCR
assessments at 3 months.
BCR-ABL ≤10%
>1- ≤10%
≤1%
8 Saglio G, et al. Blood. 2013:[abstract 92].

9. • Failure to achieve BCR-ABL ≤ 10%IS at 3 months higher for dasatinib (84%) vs imatinib
(64%) independent of Sokal risk score.
DASISION Trial: ELN-Defined Optimal
Responses vs Treatment Failures
Cortes JE, et al. ASH 2013. Abstract 653.
ELN-Defined MR, % Dasatinib
(n = 259)
Imatinib
(n = 260)
At 3 mos
Optimal: BCR-ABL ≤ 10%IS
Warning: BCR-ABL > 10%IS
84
16
64
36
At 6 mos
Optimal: BCR-ABL ≤ 1%IS
Warning: BCR-ABL > 1% to 10%IS
Failure: BCR-ABL > 10%IS
69
19
11
49
34
17
At 12 mos
Optimal: BCR-ABL ≤ 0.1%IS
Warning: BCR-ABL > 0.1 to 1%IS
Failure: BCR-ABL > 1%IS
46
37
18
30
37
33

10. 10
Impact 2: Avoid progression to AP/BC

11. CML Survival After Allo-SCT:
Stage Is a Key Issue
*Includes both matched related and unrelated donors.
Pts receiving allo-SCT at FHCRC from 1995 to present. Figure is courtesy of Dr. Ted Gooley.
1.0
0.8
0.6
0.4
0.2
0
ProbabilityofSurvival
0 2 4 6 8 10 12 14 16
Yrs After Transplantation
CP (n = 576)
AP (n = 125)
BP/remission (n = 62)
BP (n = 44)
CP
AP
BP
11

12. Progression to AP/BC in ENESTnd Study
• Rates of progression to AP/BC were lower with nilotinib vs imatinib when including all
progressions occurring on study
• 2 new cases of progression to AP/BC after discontinuation of core treatment were observed
between the 4-yr analysis and the current analysis
• 1 in the imatinib arm and 1 in the nilotinib 300 mg BID arm
• BCR-ABL > 10%IS at 3 mos for both patients
Imatinib 400 mg BID
(n = 283)
Nilotinib 300 mg BID
(n = 282)
Nilotinib 400 mg BID
(n = 281)
Saglio G, et al. ASH 2013. Abstract 92.
Patients(n)
Progressions of Study
7.1% 3.5% 2.1%
P = .0588
P = .0047
25
20
15
10
5
0
20
10
6
New events in Yr 5

13. Progression to AP/BC in DASISION Study
n =
Patients(n)
On Study Including Follow-up Beyond
Discontinuation (ITT)*
14 (5.4%)
8(3.1%)
12
18
Dasatinib 100 mg QD Imatinib 400 mg QD
259 260 259 260
0
5
20
10
15
Cortes JE, et al. ASH 2013. Abstract 653.

14. What about MMR?

15. PFS (to AP/BP) for CCyR with/without
MMR@18m in IRIS trial 5 yrs F/U
Druker et al, N Engl J Med 2006;355:2408-17.
P<0.001 for whole group
P=0.11 for CCyR
with/without MMR
15

16. Difference for CCyR with/without MMR
16

17. CCyR with various MR@18m
• 差異無法反應在Transformation-free survival or OS
Falchi elt al, Am. J. Hematol. 88:1024–1029, 2013
Transformation-free survival Overall survival
17

18. Saglio G, et al. ASH 2013. Abstract 92.
ENESTnd 5-Yr Update:
Cumulative Incidence of MMR in CP CML
100
80
60
40
20
0 21 43 5 6
Yrs Since Randomization
PatientsWithMMR(%)
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
By 1 yr: By 4 yrs:
73% (P < .0001)
∆17% to 20%
56%
27%
By 5 yrs:
77% (P < .0001)
∆17%
60%
51% (P < .0001)
∆24% to 28%
0
55% (P < .0001)
76% (P < .0001)
77% (P < .0001)

19. ENESTnd 5-Yr Update:
Cumulative Incidence of MR4.5
• Significant benefit in cumulative MR4.5 over 5 yrs seen with nilotinib across all Sokal
risk groups
Saglio G, et al. ASH 2013. Abstract 92
100
80
60
40
20
0
0 21 43 5 6
Yrs Since Randomization
PatientsWithMR4.5(%)
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
By 1 yr:
∆6% to 10%
By 4 yrs:
23%
40% (P < .0001)
37% (P = .0002)
1%
7% (P < .0001)
By 5 yrs:
31%
52% (P < .0001)
∆21% to 23%
11% (P < .0001)
∆14% to 17%
54% (P < .0001)

20. MMR rates: DASISION 4-Year Update
MMR = major molecular
response, BCR-ABL ≤0.1%
MMR 4-year
cumulative rates
Hasford Risk Score
Low Intermediate High
Dasatinib 90% 70% 65%
Imatinib 69% 63% 52%
With faster and deeper responses, dasatinib maintained higher
MMR rates vs imatinib at year 4 across all risk groups
Dasatinib 100 mg QD Imatinib 400 mg QD
0 12
Months
24 36 48 60
0
20
40
60
80
100 P<0.0001
%WithMMR
46%
23%
64%
46%
69%
55%
74%
60%
76%
63%
1.6-fold higher
likelihood of
achieving
MMR with
dasatinib;
HR=1.55
(1.26-1.91)

21. Cumulative Rate of MR4 and MR4.5:
DASISION 4-Year Update
%WithMR4.5
Months
P=0.030
0 12 24 36 48 60
Dasatinib 100 mg QD Imatinib 400 mg QD
MR4 = BCR-ABL ≤0.01%
MR4.5 = BCR-ABL ≤0.0032%
0
20
10
30
40
50
60
3%
2%
18%
9%
23%
12%
34%
21%
37%
30%
%WithMR4
Months
P=0.0021
0
20
10
30
40
50
60
12%
5%
28%
17%
35%
22%
47%
35%
0 12 24 36 48 60
53%
42%
MR4 MR4.5
More Dasatinib patients achieve the deepest levels of molecular response,
minimizing the risk of progression and allowing discontinuation study enrollment

22. 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
 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
 Nilotinib 400 mg BID (n = 1): sepsis
22 Saglio G, et al. Blood. 2013:[abstract 92].
PFS and OS in ENESTnd (5-year)

23. Like a Baseball Game…
• 王牌投手？ • 普通投手 救援投手？

24. Like a journey…

25. Try to stop TKI?

26. STIM Study: Stop IMatinib
N=100
STOPSustained CMR
for ≥ 2 years
Start
Imatinib
CMR
Q- RT-PCR from peripheral blood
every month in the first year and
every 2 months thereafter
Five BCR–ABL analyses by
Q- RT-PCR during these 2
years
Sixth datapoint checked
in centralized laboratory
Mahon FX et al. The Lancet Oncology, 2010;11(11): 1029-1035.
Molecular recurrence: positivity of
BCR–ABL transcript in Q-RT-PCR
confirmed by a second analysis point
indicating the increase of one log in
relation to the first analysis point, at
two successive assessments, or loss
of MMR at one point.

27. Treatment-free Ｓurvival of the STIM Ｓtudy
Median follow up: 55 months (range 9-72)
Mahon et al., ASH 2013 [abstract 255]

28. Which Patients will relapse?
Mahon et al., Lancet Oncol 2010]

29. STIM: Low Sokal Score and Previous Imatinib
≥5y Are Prognostic For Reduced Relapse Risk
Mahon FX, et al. Blood 2011;118:abstract 603.
Multivariate analysis (Cox model)
Hazard ratio (95% CI) P value
Sokal score 2.555 (1.278 -5.119) 0.008
IM duration (≥ 5 y vs < 5 y) 0.582 (0.340 -0.995) 0.047
At 24 Months:
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
SurvivalWithoutMolecularRelapse
0 3 6 9 12 15
Sokal Low + IM > 5 y:
Others
68% (95%Cl: 45–83)
33% (95%Cl: 22–42)
18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Months Since Discontinuation of Imatinib
P = .007

30. If your patient is a young woman who wants
to get pregnant…

31. Consideration about the
Side Effects

32. ENESTnd Trial:
Select All-Cause Cardiac and Vascular Events
by 5 Yrs (All Grades)
• Longer exposure to nilotinib compared with imatinib
• ~ 85% of patients with CV adverse event had ≥ 1 risk factor and suboptimal
management of hyperglycemia or hypercholesterolemia
• Preclinical data suggest nilotinib exerts proatherogenic (increased cytoadhesion
protein expression) and antiangiogenic (decreased proliferation and migration) effects
on vascular endothelial cells
Patients With Event, n
Nilotinib
300 mg BID
(n = 279)
Nilotinib
400 mg BID
(n = 277)
Imatinib
400 mg QD
(n = 280)
Total Yr 5 Total Yr 5 Total Yr 5
IHD 11 0 21 7 5 2
ICVE 4 1 8 3 1 0
PAD 4 0 6 1 0 0
Saglio G, et al. ASH 2013. Abstract 92. Emir H, et al. ASH 2013. Abstract 257.

33. DASISION Trial:
Arterial Occlusive Events (All Cause)
• Patients with cardiac ischemia generally had at least 1
baseline risk factor for CVD
• (eg. diabetes, HTN, hyperlipidemia, CAD)
• Dasatinib: 9 of 10 patients
• Imatinib: 2 of 3 patients
Cortes JE, et al. ASH 2013. Abstract 653.
Adverse event, n (%) Dasatinib (n = 259) Imatinib (n = 260)
All grades Grade 3/4 All grades Grade 3/4
Myocardial infarction 5 (1.9%) 2 2 (0.8%) 1
Angina 3 (1.2%) 1 1 (0.4%) 0
CAD, myocardial ischemia 2 (0.8%) 0 1 (0.4%) 0

34. Pleural Effusions with Dasatinib
Age Total patient
number
Pleural effusions-
any grade (%)
< 30 44 3 (7)
30-39 79 2 (3)
40-49 123 17 (14)
50-59 160 32 (20)
60-69 160 47 (29)
≦ 70 96 46 (48)
Porka et al., Cancer 2010]

35. Therapy on Progression

36. Ultradeep Sequencing of TKI-Resistant BCR-
ABL Mutations
• Low-level resistance mutations identified in patients who develop resistance
to second-generation TKIs following previous TKI failure
Soverini S, et al. ASH 2013. Abstract 380.
Sanger sequencing
Ultradeep sequencing
F317L
E255V
Y253H
T3151 T3151 T3151T3151 T3151
F317L
T3151
V299L
Y253H
Patient
Mutations(n) CP AP myBC lyBC Ph+ ALL
6
5
4
3
2
1
0

37. PACE Trial of Ponatinib in TKI-Resistant CML:
2-Yr Update
• Ponatinib: oral BCR-ABL TKI
• Active against multiple mutations including T315I
• Heavily pretreated study population
• CP CML pts: ≥ 2 TKIs: 93%; ≥ 3 TKIs: 60%
• Current follow-up: 2 yrs
Cortes JE, et al. ASH 2013. Abstract 650.
Pts with CML or Ph+ ALL
resistant or intolerant to
dasatinib or nilotinib or with
emergent T315I mutation
(N = 449)
Ponatinib 45 mg/day

38. PACE: Response in Heavily Pretreated Pts
With Ph+ Leukemias
• Estimated 89% of pts with CP CML to maintain MCyR ≥ 2 yrs
• Estimated 21% of pts with AP CML to maintain MaHR ≥ 2 yrs
Outcome CP CML AP CML BP CML Ph+ ALL
MCyR* CCyR* MMR* MaHR† MaHR MaHR
R/I, % 56 48 31 62 32 50
T315I, % 72 70 58 61 29 36
Total, % 60 54 38 61 31 41
Median TTR, mos 2.8 2.9 5.5 0.7 1.0 0.7
*At any time after initial ponatinib dose.
†14 AP CML pts with baseline MaHR and 1 AP CML pt with no baseline MaHR assessment counted as
nonresponders.

39. Most Common AEs With Ponatinib
*Combines the terms erythematous, macular, and papular rash.
Select Any Grade
AEs, %
CP CML (n = 270) Total Population (N = 449)
Any Grade Grade 3/4 Any Grade Grade 3/4
Nonhematologic
 Rash* 44 4 40 4
 Abdominal pain 43 9 40 9
 Headache 41 3 36 2
 Dry skin 41 3 36 2
 Hypertension 27 10 24 9
 Elevated lipase 25 12 21 12
Hematologic
 Thrombocytopenia 44 35 43 35
 Neutropenia 19 16 25 22
 Anemia 16 9 22 15

40. Most Common Serious AEs With Ponatinib
Serious AE, % CP CML
(n = 270)
Total Population
(N = 449)
Pancreatitis 7 6
Atrial fibrillation 4 3
Myocardial infarction 3 3
Coronary artery disease 3 2
Cerebrovascular accident 3 2
Cardiac failure 1 2
Hypertension 2 2
Anemia 2 3
Thrombocytopenia 2 3
Febrile neutropenia < 1 3

41. Most Common Vascular AEs With Ponatinib
AE, %
US Ponatinib Insert
(7/23/2012)
Median Follow-up: 12 Mos
(340 Pt-Yrs)
PACE Trial (9/3/2013)
Median Follow-up: 24 Mos
(578 Pt-Yrs)
Serious AE AE Serious AE AE
Cardiovascular 5 6 6 9
Cerebrovascular 2 3 4 6
Peripheral vascular 2 4 4 6
Venous
thromboembolism
2 3 3 5
Total vascular
occlusion
 By FDA criteria 9 14 14 20
 By trial criteria 10 18 15 24

42. Conclusion
• 2nd generation TKIs can provide faster and deeper response in CML,
CP; and a trend to better OS.
• 2nd generation TKIs provide higher rate of fitting new ELN guideline.
• 40% of patients with a durable CMR on imatinib therapy.
• Monitor the risk factors of arterial events is important when you
chose 2nd generation TKIs.