This slide deck, intended for educational purposes, provides information about chronic myeloid leukemia (CML) therapies, diagnostic approaches, and management strategies, reflecting views of various medical faculty. Key learning objectives include optimal therapy selection based on patient characteristics, understanding laboratory tests for diagnosis and monitoring, and addressing relapses and second-line treatment options. Disclaimers emphasize that the content does not substitute professional medical advice and may discuss unapproved drug uses.

2. DISCLAIMER
This slide deck in its original and unaltered format is for educational purposes and is
current as of March 2012. All materials contained herein reflect the views of the
faculty, and not those of IMER, the CME provider, or the commercial supporter. These
materials may discuss therapeutic products that have not been approved by the US
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should not rely on this information as a substitute for professional medical advice,
diagnosis, or treatment. The use of any information provided is solely at your own risk,
and readers should verify the prescribing information and all data before treating
patients or employing any therapeutic products described in this educational activity.
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3. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USE
This activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. PIM and IMER do not recommend the
use of any agent outside of the labeled indications.
The opinions expressed in the activity are those of the faculty and do not
necessarily represent the views of PIM and IMER. Please refer to the official
prescribing information for each product for discussion of approved indications,
contraindications, and warnings.

4. Disclosure of Conflicts of Interest
 Jorge E. Cortes, MD, has no real or apparent conflicts of
interest to report.
 Michael W.N. Deininger, MD, PhD, reported a financial
interest/relationship or affiliation in the form of: Consultant,
Ariad Pharmaceuticals, Inc., Bristol-Myers Squibb
Company, Novartis Pharmaceuticals Corporation;
Contracted Research, Bristol-Myers Squibb Company,
Celgene Corporation, Genzyme, Inc.
 Jerald P. Radich, MD, reported a financial
interest/relationship or affiliation in the form of: Consultant,
Ariad Pharmaceuticals, Inc., Bristol-Myers Squibb
Company, Incyte Corporation, Novartis Pharmaceuticals
Corporation, Pfizer, Inc.; Contracted Research, Novartis
Pharmaceuticals Corporation.

5. Learning Objectives
L
Upon completion of this activity, participants
should be better able to:
 Describe the laboratory tests needed to accurately
diagnose/monitor CML
 Employ strategies for selecting optimal frontline
therapies based on individual patient characteristics
 Explain how to define and identify a relapse
 Describe the role of mutational analysis in individualizing
second-line treatment
 List investigational agents in clinical development for
patients with relapsed/refractory disease
 Provide accurate and appropriate counsel as part of the
treatment team

6. Introduction to Faculty Panel
 Jorge E. Cortes, MD
– Professor, Leukemia
– The University of Texas M. D. Anderson Cancer Center
 Michael W. N. Deininger, MD, PhD
– Chief – Division of Hematology and Hematologic Malignancies
– Huntsman Cancer Institute University of Utah
 Jerald P. Radich, MD
– Professor
– Fred Hutchinson Cancer Research Center

7. Activity Agenda
 Roundtable Expert Discussions on CML Clinical Debates: A
Collaborative Video Viewpoint Series with Medscape
 Pre-Assessment
 Panel Introduction
 Clinical Debate 1: What Is the Optimal Frontline Therapy for
Patients With CML? (30 mins)
 Case study
– What laboratory tests should be ordered and how should the results be
interpreted to make an accurate diagnosis? If CML is confirmed, how
should first-line therapy be chosen based on patient characteristics?
How should patients be monitored?
– Avoiding diagnosis pitfalls: RT-PCR vs. FISH vs. bone marrow
biopsyInterpreting PCR resultsHow do patient comorbidities influence
choice of first-line therapy?The latest trial data on alternatives to
frontline imatinib: Second-generation TKIs

8. Activity Agenda (cont.)
 Clinical Debate 2: What Constitutes a Relapse and How Should the
Relapsed/Refractory Patient Be Treated? (30 mins)
 Case study:
– How can a relapse be confirmed? What is the role of mutational
analysis in choosing between an imatinib dose increase, second-line
TKI, novel agent in a clinical trial, or stem cell transplant?
– Defining hematologic, cytogenetic, and molecular response: What
constitutes an optimal response? A relapse?
– When should first-line therapy with imatinib be stopped and a new agent
administered?
– What is the role of cytogenetic testing in treatment choice for the
relapsed/refractory patient?
– What are the investigational novel agents in clinical development
available to patients with T315I mutations and/or relapsed/refractory
disease?
 Post-Assessment

9. Roundtable Expert Discussions
on CML Clinical Debates:
A Collaborative Video Viewpoint
Series With Medscape

10. Clinical Debate 1:
What Is the Optimal Frontline
Therapy for Patients With CML?

11. Case Study 1:
Newly Diagnosed CML
 47-yr-old teacher found to have elevated
WBC (53 x 109/L) on routine blood work
while trying to purchase life insurance policy
 Initial work-up
– WBC (53 x 109/L), platelets (583 x 109/L),
peripheral blood blasts (6%), basophils (2%)
– Spleen palpable 7 cm below costal margin
 PMH includes diabetes mellitus well
controlled with insulin
CML = chronic myeloid leukemia; WBC = white blood count; PMH = past medical history.

12. Case Study 1
Laboratory Testing
 You suspect a diagnosis of CML
 What is your recommendation for initial work-up of this
patient?
– Bone marrow aspiration with differential
– Cytogenetic analysis
– Peripheral blood FISH
– Real-time PCR in peripheral blood
– Mutations analysis
– Leukocyte alkaline phosphatase
– Vitamin B12 levels
FISH = fluorescent in situ hybridization; PCR = polymerase chain reaction.

13. Case Study 1:
Diagnosis and Result Interpretation
 Bone marrow with 8% blasts, 3% basophils
 Cytogenetics: 46XY, t(9;22;11) in 20/20
metaphases
 FISH shows 98% interphases with a BCR-ABL
fusion signal and deletion of the derivative
9 gene
Ph = Philadelphia; ACA = additional chromosomal abnormalities.

14. Case Study 1:
Diagnosis and Result Interpretation (cont.)
 How would you interpret these results?
– Classic Ph chromosome
– Varian Ph chromosome
– Clonal evolution
– ACA
– Blast phase
– An error in reporting
Ph = Philadelphia; ACA = additional chromosomal abnormalities.

15. What Is Clonal Evolution
Clonal evolution
Xx
Xx
9 22
x
Xx
Diploid
Xx Xx
x
ACA
x (Clonal “selection”)
Variant Ph

16. Case Study 1:
Diagnosis
 Basedon these results what phase do you
consider this patient to be in?
– Chronic phase
– Late chronic phase
– Second chronic phase
– Accelerated phase
– Blast phase

17. CML Phases
Chronic Accelerated Blastic
Past 3-5 years 12-18 months 3-9 months
Present 25+ years 4-5 years 6-12 months
• Asymptomatic • Blasts ≥ 15% • Blasts ≥ 30%
(if treated) • Bl + pros ≥ 30%
• Basophils ≥ 20% • Extramedullary
• None of criteria for
accelerated or blast • Plts < 100,000/mcl disease with localized
blast phase • Clonal evolution immature blasts
17

18. Choosing First-Line Therapy
 If the patient has a healthy brother and sister,
what are the options for first-line treatment?
– Imatinib 400 mg
– Imatinib 800 mg
– Dasatinib 100 mg daily
– Nilotinib 300 mg bid
– Nilotinib 400 mg bid
– SCT
bid = twice daily; SCT = stem cell transplant.

19. Patient Characteristics:
Influencing Therapy
 How do patient comorbidities influence
choice of first-line therapy?
bid = twice daily; SCT = stem cell transplant.

20. Improving Frontline Therapy in
CML
 Standard-dose imatinib
 High-dose imatinib
 Imatinib-based combinations
 Second generation TKI
– Dasatinib
– Nilotinib
– Bosutinib
TKI = tyrosine-kinase inhibitor.
NCCN, 2011.

21. Results With Imatinib in Early
CP-CML: IRIS Trial at 8 Yrs
 304 (55%) patients on imatinib on study
 Projected results at 8 yrs
– CCyR: 83%
• 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP
– EFS: 81%
– TFS: 92%
• If MMR at 12 mos: 100%
– Survival: 85% (93% CML-related)
 Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%,
0.5%, 0%, 0%, 0.4%
CP-CML = chronic-phase CML; CCyR = complete cytogenic response; AP = accelerated phase; BP = blast phase; EFS
= event-free survival; TFS = transformation-free survival; MMR = major molecular response; IRIS = International
Randomized Study of Interferon and STI571.
Deininger et al, 2009.

22. Survival in Early CP-CML
Kantarjian et al, 2011.

23. Long-Term Outcome With Imatinib
in Early CP-CML (ITT)
1.0
0.9
0.8
Probability (%)
0.7
0.6
0.5 Survival 63%
PFS
0.4
CHR
0.3 EFS
Loss of MCyR
0.2
0.1
0 6 12 18 24 30 36 42 48 54 60
Time From Start of Imatinib Therapy (mos)
de Lavallade et al, 2008.

24. TOPS: Rate of MMR Over Time
by Imatinib Dose (ITT)
476 patients with early CP-CML randomized to imatinib 400 mg
daily vs. 800 mg daily
Percent (%)
Outcome at 24 mos
400 mg 800 mg
CCyR 76 76
MMR 54 51
EFS 95 95
PFS 97 98
 Significant impact of dose intensity/treatment interruptions on MMR rate
TOPS = tyrosine kinase inhibitor optimization and selectivity: ITT = intent-to-treat; PFS = progression-free survival.
Baccarani, Druker, et al, 2009.

25. High-Dose Imatinib as Initial Therapy in CML
 281 patients Rx’d with imatinib 400 mg (n = 73) or 800 mg (n = 208)
Overall Response (%) 400 mg 800 mg p Value
CCyR 87 91 .49
MMR 78 87 .06
CMR 39 49 .21
Time to CMR EFS
1
1.0
Total CMR
800 mg 206 100 p = 0.04
0.8 400 mg 71 28 0.8
0.6
0.6
0.4 0.4
Total No.event
400mg 73 15 p = 0.01
800mg 208 22
0.2 0.2
0 0.0
0 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120
CMR = complete molecular response.
Pemmaraju et al, 2010.

26. Significance of OCT-1 Activity
in Response to Imatinib
 Transporter responsible for imatinib cell influx
 Not required for second generation TKI
Percent (%)
Outcome Dose p Value
Low OCT-1 High OCT-1
MMR < 600 mg 27 92 .021
600 mg 72 87 .093
EFS < 600 mg 27 67 .018
600 mg 61 80 .241
TFS < 600 mg 73 100 .048
600 mg 100 100 NS
OCT-1 = organic cation transporter-1; NS = not significant.
White, Dang, et al, 2010.

27. Imatinib + IFN as Frontline
Therapy for CML
 CML-IV
– 1,014 patients randomized to IM 400 mg, IM 800 mg, or IM 400 mg +
IFN-α (median dose: 1.7 MU/d)
– No improvement in response rate of 5-yr PFS with IFN
 SPIRIT
– 636 patients randomized to IM 400 mg, IM 600 mg, IM + ara-C, and
IM 400 mg + Peg-IFNα-2a
– Higher rate of MMR, SMRa, and CMR at 24 mos
– No difference in 4-yr EFS
 MDACC
– 91 patients randomized to IM 800 mg ± Peg-IFN-2b
– No difference in response, EFS, PFS
a
≤ 0.01%.
IM = intramuscular prospective randomized trial; SPIRIT = STI571; ara-C = cytarabine; SMR = superior molecular response;
MDACC = The University of Texas M. D. Anderson Cancer Center.
Hehlmann et al, 2011; Preudhomme et al, 2010; Cortes et al, 2011.

28. EFS by Treatment in Early CP-CML
1.0
0.8
Probability EFS (%)
0.6
0.4 Total Events
Imatinib 400 mg 73 15
Imatinib 800 mg 208 22
Dasatinib 76 2
0.2 Nilotinib 1 p = 0.01
78
0.0
0 12 24 36 48 60 72 84 96 108 120
Time (mos)
Cortes, O’Brien, et al, 2009.

29. Nilotinib Vs. Imatinib in Newly
Diagnosed CML (ENESTnd)
R
A Nilotinib 300 mg bid (n = 282)
N
D
 N = 846 O
 217 centers M Nilotinib 400 mg bid (n = 281)
I
 35 countries Z
E
D
a Imatinib 400 mg QD (n = 283)
Follow-Up
5 yrs
 Primary end point: MMR at 12 mos
 Key secondary end point: Durable MMR at 24 mos
 Other end points: CCyR by 12 mos, time to MMR and CCyR, EFS,
PFS, time to AP/BC on study treatment, OS including follow-up
a
Stratification by Sokal risk score.
ENESTnd = evaluating nilotinib efficacy and safety in clinical trials - newly diagnosed patients; OS = overall survival.
Larson et al, 2010.

30. Nilotinib Vs. Imatinib in
Newly Diagnosed CP-CML
846 patients randomized to nilotinib 300 mg bid (n = 282), nilotinib 400 mg
bid (n = 281), or imatinib 400 mg QD (n = 283)
Minimum follow-up: 24 mos
Outcome Nil 300 Nil 400 IM 400
% CCyRa 87 85 77
% MMRa 71 67 44
% BCR-ABL ≤ 0.0032%a 26 21 10
% Discontinued Treatment 18 21 22
New Mutation (No.) 10 8 20
a
By 24 mos.
Larson et al, 2011; Kantarjian, Hochhaus, et al, 2011.

31. ENESTnd: Progression to AP/BC
Nilotinib 300 mg bid Nilotinib 400 mg bid Imatinib 400 mg QD
p = .0059 p = .0003
p = .0196 p = .0089
No. Patients
0.7% 1.1% 4.2% 0.7% 1.8% 6.0%
Including Clonal Evolution
 Progression events after discontinuation of treatment occurred in an additional 7, 2, and 6
patients (excluding clonal evolution) in nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib
arms, respectively; progression within 60 days of discontinuation occurred in 1, 1, and 2 of these
patients across respective arms
Larson et al, 2011; Kantarjian, Hochhaus, et al, 2011.

32. Dasatinib Vs. Imatinib Study in
Treatment-Naïve CML (DASISION)
Trial Design
Dasatinib 100 mg QD (n = 259)
 N = 519
Follow-Up
 108 centers Randomized a
5 yrs
 26 countries Imatinib 400 mg QD (n = 260)
 Primary end point: Confirmed CCyR by 12 mos
 Secondary/other end points: Rates of CCyR and MMR;
times to confirmed CCyR, CCyR and MMR; time in
confirmed CCyR and CCyR; PFS; OS
Stratified by Hasford risk score.
a
DASISION = dasatinib vs. imatinib study in treatment-naive CML patients.
Kantarjian, Shah, et al, 2011.

33. Dasatinib Vs. Imatinib in Newly
Diagnosed CP-CML
519 patients randomized to dasatinib 100 mg QD (n = 259) or imatinib
400 mg QD (n = 260)
Median follow-up: 24 mos
Outcome Das 100 IM 400
% CCyR 86 82
% MMR 64 46
% BCR-ABL ≤ 0.0032% 17 8
% Discontinued Therapy 23 25
New Mutations (No.) 10 10
Kantarjian, Shah, et al, 2011.

34. DASISION: Transformation
to AP/BP CML (ITT)
100 Dasatinib 100 mg QD Imatinib 400 mg QD
(%)
n/N 6/259 13/260 9/259 15/260
On Study Including Follow-Up
Beyond Discontinuation
Kantarjian, Shah, et al, 2011.

35. DASISION: Cumulative Incidence of MMR
100 Dasatinib 100 mg QD
Imatinib 400 mg QD
80 By 24 mos
64%
By 12 mos
60 46% p < .0001
MMR
(%)
40 46%
28%
20
0
0 10 20 30 40
Time (mos)
Kantarjian, Shah, et al, 2011.

36. DASISION: CMR4.5 Rates (ITT)
by Month of Treatment
100 Dasatinib 100 mg QD Imatinib 400 mg QD
(%)
6 mos 12 mos 18 mos 24 mos
Kantarjian, Shah, et al, 2011.

37. Bosutinib Efficacy and Safely in Newly
Diagnosed CML (BELA): Study Design
Phase III Open-Label Trial R Bosutinib
in Newly Diagnosed A 500 mg/day 5-yr follow-up
CP-CML N (n = 250)
D
N = 502 O
M
139 Sites, 31 Countries I Imatinib
Stratification Factors: Z 5-yr follow-up
400 mg/day
Geographical Region E
(3 regions), Sokal score (n = 252)
1-yr analysis
 Eligibility criteria: Cytogenetic diagnosis of Ph+ CP-CML
≤ 6 mos prior; No prior therapy other than hydroxyurea or anagrelide
 Primary end point: CCyR rate at 12 mos
 Secondary end points:
– MMR rate at 12 mos
– Time to CCyR and MMR
– Time to and rate of transformation to AP/BP CML, survival
– Safety and tolerability
BELA = bosutinib efficacy and safety in CML.
Gambacorti-Passerini et al, 2011.

38. Bosutinib Vs. Imatinib in
Newly Diagnosed CP-CML
 502 patients randomized to bosutinib 500 mg QD (n = 250) or imatinib
400 mg QD (n = 252)
 Minimum follow-up: 18 mos
Response at 12 mos Bos 500 IM 400
% CCyRa 79 79
% MMRa 55 45
% CMRa 18 10
% Discontinued Therapya 33 26
By 18 mos.
a
Gambacorti-Passerini et al, 2011.

39. Outcome by Frontline Therapy
in CP-CML: BELA
9 33 4 13 5 9
Gambacorti-Passerini et al, 2011.

40. Selective Dose Escalation and
Early Switch for CML Therapy
 105 patients, median follow-up: 21 mos (12–36 mos)
 Still on Rx: 88% (65% imatinib, 23% nilotinib)
Day 22 IM
IM < 1,000 ng/mL 800
IM
800
10%
IM
1% 800 Nilotinib
CCyR
IM
0.1%
800
IM600
MMR
1 3 6 9 12 15 18 21 24
Yeung et al, 2010.

41. TIDEL II Primary End Point: 12-mos MMR
101 103 103 105 76 59 48 33
80% 82%
80% 77%
71%
70% 67%
61%
60%
MMR
50% 48%
40%
30%
20% 18%
30%
10% 22% 21% CMR
13% 12% IS ≤ 0.0032%
0%
3 6 9 12 15 18 21 24
Time Points (mos)
 MMR after switch to nilotinib: For intolerance 91%, for suboptimal response 9%
TIDEL = trial of imatinib with dose escalation in CML.
Yeung et al, 2010.

42. Impact of OCT-1 Activity on Response to
Dose Increase or Change to Nilotinib
 63 patients with ≥ 12-mos follow-up and OCT-1 activity assessed
MMR
12-mos ⇑IM to Switched MMR
Mutations on IM
MMR 800 mg to Nil on Nil
800 mg
Low
OCT-1 37% 19% 23% 17% 42% 10%
(n = 26)
High
OCT-1 81% 0% 8% 100% 14% 100%
(n = 37)
White, Saunders, et al, 2010.

43. Probability of Resistance by
Molecular Response at 3 Mos
95
Probability of Resistance (%)
0–1 log (n = 10)
83%
> 1–2 log (n = 22) P <0.001
75 > 2 log (n = 20)
55
35
15
5%
0%
-5
0 5 10 15 20 25 30
Time on Imatinib (mos)
Hughes et al, 2006.

44. Probability of MMR and Progression by
Early Molecular Response to Imatinib
% Probability Outcome by Transcript Levels
BCR-ABL/ at Specified Mos
ABL
Transcript MMR (mos) Progression (mos)
Levels
3 6 12 3 6 12
≤ 0.1 100 96 97 4 1 3
> 0.1–1 84 69 61 3 7 2
> 1–10 53 44 20 11 9 8
> 10 33 15 7 13 23 50
p < .001 p < .001 p < .001 p < .001 p < .001 p < .001
Quintas-Cardama, Kantarjian, et al, 2009.

45. 7-Yr Outcome by Molecular Response:
All Patients
Percent (%)
Landmark
MMR No MMR
EFS 85 84
6 mos TFS 96 93
OS 90 89
EFS 91 79
12 mos TFS 99 90
OS 93 89
EFS 95 75
18 mos TFS 99 90
OS 95 90
Hughes et al, 2010.

46. 7-Yr Outcome by Molecular Response:
Only Patients With CCyR
Percent (%)
Landmark
MMR No MMR
EFS 85 93
6 mos TFS 96 98
OS 90 93
EFS 91 92
12 mos TFS 99 96
OS 93 97
EFS 95 86
18 mos TFS 99 96
OS 95 96
Hughes et al, 2010.

47. OS by 12-Mos Response
in CP-CML
 848 patients randomized to IM 400 mg, IM 800 mg, or
IM 400 mg + IFN
 Median follow-up: 40 mos
Hehlmann et al, 2011.

48. Time to Loss of CCyR by
Molecular Response at 18 Mos
Hughes et al, 2010.

49. Optimal Response to Second TKIs:
Frontline Response (N = 167)
 167 patients with CP-CML treated with frontline dasatinib or nilotinib
 Median follow-up: 33 mos (range: 3–66 mos)
Mos on Therapy Response Total (%)
Optimal 160 (100)
3 (N = 160) Sub-optimal 0
Failure 0
Optimal 152 (98)
6 (N = 155) Sub-optimal 3 (2)
Failure 0
Optimal 128 (99)
12 (N = 129) Sub-optimal 1 (1)
Failure 0
Optimal 99 (84)
18 (N = 119) Sub-optimal 14 (12)
Failure 5 (4)
Jabbour et al, 2011a.

50. Long-Term Outcome by Response
at 6 Mos From Start of Therapy
 435 CP-CML patients treated with frontline imatinib 400 (n = 73),
imatinib 800 (n = 208), dasatinib (n = 76), or nilotinib (n = 78)
EFS OS
Jabbour et al, 2011b.

51. CML Frontline Therapy – 2011
 Frontline therapy: New standard
– Imatinib is good
– Second generation TKI (dasatinib, nilotinib, bosutinib) are better
– Sequential therapy?
– Adequate monitoring and management of AEs
 Failure to therapy
– New definitions (no CCyR at 6 mos)?
– Prompt identification and action of suboptimal response if
imatinib therapy
 No need to change if responding to imatinib

52. How Should Patients Be
Monitored?
 Whichof the following tests would you use to
monitor your patient?
1) Cytogenetic analysis
2) FISH
3) PCR
4) Mutation analysis
5) Imatinib plasma levels
6) All of the above

53. Monitoring Procedures in CML
 CG: looks at all chromosomes; but: tedious;
needs metaphases; only 20 cells counted
(SD ± 15%); painful BM
 FISH: faster; 200 cells; PB; but: false + up to
5-10%; no information on other chromosomes
 PCR: most sensitive; PB; evaluable in CCyR;
predicts for relapse; but: not standardized; no
information on other chromosomes; variability up
to 0.5 log; use 1 source (PB) and 1 reliable lab
53

54. Monitoring Recommendations for
CML According to the ELN 2009
Objective Recommended frequency
Every 2 wk until CHR, then at least every 3 mo or as
Hematologic
required
At diagnosis, 3 mo, 6 mo and every 6 mo until confirmed
CCyR, then every 12 mo if molecular monitoring not
Cytogenetic assured
At failure or unexplained myelosuppression
Molecular Every 3 mo until MMR confirmed, then every 6 mo
In case of failure or suboptimal response, or before
Mutations
change to 2nd TKI
Baccarani et al. JCO 2009; 27: 6041-51

55. 7-Year Outcome by Molecular
Response – Patients with CCyR
Percentage
Landmark
MMR No MMR
EFS 85 93
6 mo TFS 96 98
OS 90 93
EFS 91 92
12 mo TFS 99 96
OS 93 97
EFS 95 86
18 mo TFS 99 96
OS 95 96
Hughes T, et al. 2010.

56. Clinical Debate 2:
What Constitutes a Relapse and
How Should the Relapsed/Refractory
Patient Be Treated?

57. Case Study 2: CML Post
Imatinib Therapy
A 52-yr-old woman with an HLA-identical
sibling started therapy with imatinib 400 mg
daily upon diagnosis of CP-CML.
 She has now received imatinib 400 mg daily
for 6 mos.
 CG at 12 mos shows Ph+ 50%.
HLA = human leukocyte antigen.

58. Confirming Relapse
 How can relapse be confirmed?
 Howcan you define hematologic, cytogenetic
and molecular response?
 What constitutes an optimal response?

59. Case Study 2: Response Post
Imatinib Therapy
 How would this response be labeled?
– Failure
– Secondary resistance
– Suboptimal response
– Optimal response

60. Criteria for Failure and Suboptimal
Response to Imatinib
Response
Time (mos)
Failure Suboptimal Optimal
3 No CHR No CG Response < 65% Ph+
No CHR
6 ≥ 35% Ph+ ≤ 35% Ph+
> 95% Ph+
12 ≥ 35% Ph+ 1%–35% Ph+ 0% Ph+
18 ≥ 5% Ph+ No MMR MMR
Loss of CHR
Loss of CCyR Loss of MMR Stable or
Any
Mutation Mutation Improving MMR
CE
Baccarani, Cortes, et al, 2009.

61. CML Post Imatinib Therapy:
Management
 How would you manage this patient now?
– Continue imatinib 400 mg QD
– Increase imatinib dose
– Change to dasatinib 100 mg QD
– Change to nilotinib 400 mg bid
– Allogeneic BMT
BMT = bone marrow transplant.

62. CML Post Imatinib Therapy (cont.)
 Thepatient has now received imatinib
400 mg daily for 12 mos with good tolerance.
You repeat a cytogenetic analysis and it
shows 10% Ph+ metaphases.
 How would you label this response now?
– Failure
– Secondary resistance
– Suboptimal response
– Optimal response

63. CML Post Imatinib Therapy:
Management (cont.)
 How would you manage this patient now:
– Continue imatinib 400 mg QD
– Increase imatinib dose
– Change to dasatinib 100 mg QD
– Change to nilotinib 400 mg bid
– Allogeneic BMT

64. Response Post Imatinib Therapy
(cont.)
 The patient has now received imatinib for
18 mos, the last 6 mos at 800 mg/d. The
patient has a sustained CCyR but has not
achieved an MMR.
 How would you label this response:
– Failure
– Secondary resistance
– Suboptimal response
– Optimal response

65. CML Post Imatinib Therapy
(cont.)
 How would you manage this patient now:
– Continue imatinib 400 mg bid
– Change to dasatinib 100 mg QD
– Change to nilotinib 400 mg bid
– Start an investigational option
– Allogeneic BMT

66. Cytogenetic Testing
 What is the role of cytogenetic testing in
treatment choice for the relapsed/refractory
patient?

67. Long-Term Outcome With Imatinib
in Early CP-CML (ITT)
1.0
0.9
0.8
Probability (%)
0.7
0.6
0.5 Survival 63%
PFS
0.4
CHR
0.3 EFS
Loss of MCyR
0.2
0.1
0 6 12 18 24 30 36 42 48 54 60
Time From Start of Imatinib Therapy (mos)
de Lavallade et al, 2008.

68. Frequency of Suboptimal Response
With Imatinib Therapy
Time on Rx % With Response
Response p Value
(mos) 400 mg 800 mg
Optimal 100 99
3 Suboptimal 0 0 NS
Failure 0 1
Optimal 83 96
6 Suboptimal 12 1 .002
Failure 6 3
Optimal 70 92
12 Suboptimal 17 4 < .001
Failure 13 3
Optimal 44 52
18 Suboptimal 33 43 .005
Failure 23 5
Alvarado et al, 2009.

69. EFS by Response to Imatinib at 18 Mos
Time (mos)
Alvarado et al, 2009.

70. Treatment Options for Imatinib
Resistant CML
 Higher doses of imatinib
 Second generation TKIs
 Allogeneic SCT
 Third generation TKIs (ie, T315I inhibitors)
 Others: Omacetaxine, decitabine, hedgehog
inhibitors
NCCN, 2011; Cortes, Khoury, Nicolini, et al, 2009; Kantarjian et al, 2003; Zhao et al, 2009.

71. Treatment Recommendations
for CP-CML According to ELN
Status Recommendation
First-line
All Imatinib 400 mg
Second-line
IM Intolerant Dasatinib or nilotinib
Suboptimal Imatinib same dose, or ⇑ dose, or dasatinib or
niloitnib
Failure Dasatinib or nilotinib; SCT if AP/BP or T315I
Third-line
Second TKI Suboptimal Conitnue same; SCT if warnings and EBMT score
≤2
Second TKI Failure SCT
ELN = European LeukemiaNet; SCT = stem cell transplant; EBMT = European Group for Blood and Marrow Transplantation.
Baccarani, Cortes, et al, 2009.

72. Is There a Role for Imatinib
Dose Escalation?
 CCyR 50% if cytogenetic failure to imatinib
400 mg, 5% if hematologic failure
 Uses
– Suboptimal response: Long-term benefit unclear
– Failure
• Second generation TKI unavailable or impractical
• Loss of CyR
• Sensitive mutations
Breccia et al, 2011.

73. Dasatinib in CP-CML After Imatinib Failure
 60-mos follow-up of dose optimization study
 35% still on treatment: 46% still at 100 mg QD (35% < 100 mg QD)
Parameter (%) N = 167
MCyR (2-yr) 63
CCyR (2-yr) 50
5-yr MMR 44
5-yr PFS 57
5-yr OS 78
Pleural Effusion 24
Grade 3–4 4
 Mutations persisting or developing after dasatinib discontinuation for loss of response:
V299L, T315I, and F317L
Shah et al, 2011.

74. PFS With Dasatinib After Imatinib Failure
1.0
0.8
Not Progressed (%)
0.6
PFS rate (95% CI)
0.4 n 12 mos 24 mos 36 mos 48 mos 60 mos
100 mg QD 167 91% 81% 72% 63% 57% (48–67)
70 mg bid 168 87% 76% 68% 66% 61% (52–70)
0.2
140 mg QD 167 87% 75% 61% 56% 51% (40–62)
50 mg bid 168 86% 76% 73% 69% 67% (58–75)
0.0
0 6 12 18 24 30 36 42 48 54 60 66
Time (mos)
Progression was defined as increasing WBC count, loss of CHR or MCyR, ≥ 30% increase in Ph+
metaphases, confirmed AP/BP disease, or death
CI = confidence interval; CHR = complete hematologic response.
Shah et al, 2011.

75. OS With Dasatinib After Imatinib Failure
1.0
0.8
0.6
Alive (%)
OS rate (95% CI)
0.4 n 12 mos 24 mos 36 mos 48 mos 60 mos
100 mg QD 167 96% 91% 88% 82% 78% (72–85)
70 mg bid 168 94% 88% 81% 75% 73% (66–80)
0.2
140 mg QD 167 96% 94% 86% 83% 79% (72–86)
50 mg bid 168 96% 91% 85% 82% 75% (68–82)
0.0
0 6 12 18 24 30 36 42 48 54 60 66
Time (mos)
Shah et al, 2011.

76. Nilotinib in CP-CML Post Imatinib Failure
 321 patients with imatinib resistance (71%) or intolerance (29%)
 Median age – 58 yrs; median exposure – 19 mos
 Nilotinib 400 mg po bid ≥ 6 mos
Outcome Percent (%)
CHR 85
MCyR/CCyR 59/44
Resistant 56/41
Intolerant 66/51
24-mos OS/PFS 87/64
 Median dose intensity 789 mg/d
 Grade 3–4 ↓ platelets 31%, neutrophils 31%; lipase elevation 17%
(pancreatitis < 1%), bilirubin 8%
Kantarjian, Giles, et al, 2011.

77. EFS With Nilotinib After Imatinib
Failure in CP-CML
64% at 24 mos
Kantarjian, Giles, et al, 2011.

78. OS With Nilotinib After
Imatinib Failure in CP-CML
Kantarjian, Giles, et al, 2011.

79. Bosutinib (SKI–606) in CML and Ph+ ALL
 Src-Abl inhibitor 30x more potent than IM
– No inhibition of PDGFR, c-kit
 321 CP patients; median time from diagnosis 52 mos
 Bosutinib 400–600 mg/d; phase II 500 mg/d
 Median follow-up: 7 mos
Response (%) in CP, prior imatinib only (N = 102)
Resistant Intolerant
(n = 69) (n = 33)
CHR 81 82
MCyR 45 51
CCyR 32 40
MMR 42 39
CMR 22 32
 Grade 3–4 toxicity: Thrombocytopenia 21%, neutropenia 12%, diarrhea 8%, rash 7%
PDGFR = platelet-derived growth factor receptor; ALL = acute lymphocytic leukemia.
Cortes et al, 2008.

80. Better Outcome on Dasatinib
With Earlier Intervention
 Patients on dasatinib studies analyzed by failure status
on imatinib: loss of MCyR vs. loss of CHR
Percent (%)
Status at IM Failure No.
CCyR MMR
Loss of MCyR 151 72 60
Loss of CHR and MCyR 33 42 29
Loss of CHR (never MCyR) 109 26 26
Quintás-Cardama, Cortes, et al, 2009.

81. Dasatinib Early Intervention EFS and OS
EFS OS
Loss of MCyR
Loss of CHR
Loss of MCyR and CHR
Quintás-Cardama, Cortes, et al, 2009.

82. Mechanisms of Resistance to
Imatinib
 BCR-ABL dependent
– Mutations in ABL
– Amplification/overexpression
– Remigration of BCR-ABL to cytoplasm
 BCR-ABL independent
– Decreased hOCT1 expression
– Increased MDR expression
– Increased alpha-1 acid glycoprotein
– Overexpression of Src-related kinases
 Quiescent stem cells (persistence)
le Coutre et al, 2000; Weisberg et al, 2000; Mahon et al, 2000; Gamacorti-Passerini et al, 2000; Vigneri et al, 2001.

83. Sensitivity of Mutations to TKI
Ba/F3 cell proliferation IC50 (nM)
Imatinib Nilotinib Dasatinib
WT 260 13 0.8
M244V 2,000 38 1.3
G250E 1,350 48 1.8
Q252H 1,325 70 3.4
Y253F 3,475 125 1.4
Y253H > 6,400 450 1.3
E255K 5,200 200 5.6
E255V > 6,400 430 11
V299L 540 ND 18
T315A 971 61 125
T315I > 6,400 > 2,000 > 200
F317L 1,050 50 7.4
F31TV 350 ND 53
E355G 2,300 ND 1.8
F359V 1,825 175 2.2
V379I 1,630 51 0.8
H396P 850 41 0.6
H396R 1,750 41 1.3
Resistant / Moderately Sensitive / Sensitive
O’Hare et al, 2007.

84. CCyR by Mutations in CML Treated with
Second Generation TKI After IM Failure
 86/169 (51%) patients treated had mutation
– CP 30/59 (51%), AP 41/71 (58%), BP 15/39 (38%)
 Mutations classified into high, intermediate, and low sensitivity to dasatinib
or nilotinib based on IC50
Chronic Phase Accelerated Phase
Jabbour et al, 2009.

85. Spectrum and Frequency of BCR-ABL
KD Mutations Recovered After TKI
Therapy
 T315I and F359V recovered after treatment with SKI-606
Cortes et al, 2007.

86. Time to Response to Second Generation TKI
113 CP-CML patients receiving nilotinib (n = 43) or dasatinib
(n = 70) after imatinib failure
1
Response % AP/BP/Death/CHR
Probability of Resistance (%)
at 12 mos Loss Next Year
0.8
MCyR 3%
No MCyR 17%
0.6 No MCyR (27)
0.4 p = .003
0.2
MCyR (59)
0
0 12 24 36
Time (mos on imatinib)
CG Response at 3–6 mos Probability MCyR at 12 mos
None 3%–7%
≥ mCyR > 50%
Tam et al, 2008.

87. MSD and MUD SCT in CP-CML
 3,514 MDS and 1,052 URD SCT from CIBMTR from 1988–2003
 All in CP1; median age: 35–37
OS LFS
LFS = leukemia-free survival.
Arora et al, 2009.

88. Allo-SCT for CML in the Imatinib Era
Probablity of survival
n=84
Median age: 38 yrs (21–56 yrs)
Median time from Dx: 18 mo (5–54 mos)
HSCT in advanced phase, n= 28, 3 year survival 59%
HSCT after IM failure in 1st CP, n= 37, 3 year survival
94%
Elective HSCT, n=19, 3 year survival 88%
Months after transplantation
Saussele et al, 2010.

89. Allo-SCT After Imatinib Resistance
 47 patients with imatinib resistant CML
 34 CP, 9 AP, 4 BP
 19 (40%) with ABL1 mutations (4 with T315I)
 15/19 had AP, BP, or second CP
Jabbour, Cortes, et al, 2011.

90. Allo-SCT After Imatinib Resistance
EFS by Mutational Status
2-yr EFS, % 2-yr OS, %
Group No.
(95% CI) (95% CI)
All patients 47 49 (35–64) 63 (49-78)
ABL1 mutation 19 36 (14–58) 44 (20-67)
No mutation 28 58 (39-77) 76 (59-93)
p value .05 .02
Phase
CP 16 62 (39-86) 72 (49-96)
AP 31 44 (25-61) 59 (41-77)
p value .27 .30 OS by Mutational Status
CP only
ABL1 mutation 4 25 (0-67) 33 (0-87)
No mutation 12 75 (50-99) 81 (58-100)
p value .20 .13
AP/BP only
ABL1 mutation 15 40 (15-65) 46 (20-71)
No mutation 16 45 (18-72) 72 (48-96)
p value .20 .12
Jabbour, Cortes, et al, 2011.

91. SCT in CML According to ELN 2009
Searching for family donor
At diagnosis Patients in AP/BP
Patients < 20 yrs
Patients with warning factors
At imatinib failure All patients
Searching for unrelated donor
At diagnosis Patients in AP/BP
At imatinib failure Patients who progressed to AP/BP, or with T315I, or with
hematologic resistance
During/after second TKI Patients with TKI failure
Patients with a suboptimal response and EBMT risk 0–2
Performing allo-SCT
At diagnosis Patients in AP/BP (pretreatment with TKI recommended)
At imatinib failure Patients in AP/BP (pretreatment with second generation
TKI recommended), or with T315I
Failure to second TKI All patients
Baccarani, Cortes, et al, 2009.

92. Criteria for Failure to Second
Generation TKI (ELN)
Time (mos) Suboptimal Failure Warning
Baseline NA NA Imatinib Heme
Resistance
CE
Mutations
3 Ph+ 36%–65% Ph+ > 95% Ph+ 66%–95%
New mutation
6 Ph+ 1%–35% Ph+ 66%–95% Ph+ 36%–65%
New mutation
12 No MMR Ph+ > 35%
New mutation
Baccarani, Cortes, et al, 2009.

93. Dasatinib and Nilotinib in Advanced
Phase CML After Imatinib Failure
 Accelerated phase (dasatinib, nilotinib)
– MaHR: 50%–60%
– MCyR: 30%–40%
• CCyR: 19%–30%
– PFS: 40%–50% at 24 mos
 Blast phase (dasatinib)
– MaHR: 30%–40%
– MCyR: 30%–50%
– Median PFS: 3–5 mos
MaHR = major hematologic response.
Kantarjian et al, 2010; Kantarjian, Hochhaus, et al, 2011; Kantarjian, Giles, et al, 2011b.

94. Survival of Patients With T315I
CML AP (n=38, dead=16)
CML CP (n=82, dead=37)
Ph+ ALL (n=46, dead=32)
CML BP (n=56, dead=48)
Nicolini et al, 2009. Jabbour et al, 2008.

95. Use of Second Generation TKI as Third-Line Therapy
 37 patients treated with dasatinib (n = 29) or nilotinib (n = 8) after 2 TKI failure
 MCyR: CP 25%, AP 33%, BP 25%
Failure-Free Survival
1.0
0.9 Failure
No. No. Failure •Loss CHR
0.8 CP 16 10 •Loss MCyR
AP 9 9
BP 12 12
•Loss of CCyR
0.7 •Discontinuation for toxicity
•Transformation to AP/BP
0.6 •Death
0.5
0.4
0.3
0.2
0.1
0.0
0 6 12 18 24 30
T ime
Garg et al, 2009.

96. CML Resistance to Therapy
 Goal of therapy in CML: Improve long-term
outcome
 Current results could be improved
 Definition of resistance evolving
 Early end points critical for long-term benefit
 Early treatment intervention required for optimal
long-term benefit
 Good treatment options available
– Better treatment options needed

97. What Is The Role of Mutational
Analysis?
 When would you test for mutations on a
patient like this:
– At the time imatinib is started
– At the time suboptimal response is detected
– At the time resistance to imatinib is documented
– At regular intervals during therapy
– I would not check for mutations

98. Investigational Agents for
Relapsed/Refractory Disease
 What are the investigational novel agents in
clinical development available to patients with
T315I and/or relapsed/refractory disease?

99. Treatment Options for CML
With T315I or After ≥ 2 TKI
 Multi-kinase inhibitors
– MK-0457 (RIP)
– AP24534 (Ponatinib)
– DCC-2036
– PHA-739358
– XL-228
– KW-2449
 Omacetaxine (homoharringtonine)
 Other approaches (eg, HSP-90 inhibitors, histone
deacetylase inhibitors, etc.)
 Combination therapy
Xu et al, 2011; Eiring et al, 2011; King et al, 2011; Nguyen et al, 2011; Kim et al, 2011.

100. Ponatinib (AP24534) in
Refractory CML
 Orally administered multikinase inhibitor with
activity against all mutants including T315I
 At 40nM inhibits emergence of resistant clones
 Phase I study in 74 patients: 60 CML (44 CP, 7
AP, 9 BP), 4 Ph+ ALL, 6 AML FLT3 ITD, 4 Other
 Prior TKI (Ph+ diseases): 2 in 95%, 3 in 65%
 Mutations in 63%, T315I in 28%
 MTD 45 mg, DLT pancreatitis
MTD = maximum tolerated dose; DLT = dose-limiting toxicity; ITD = internal tandem duplication.
Cortes et al, 2010.

101. Phase I Study of Ponatinib (AP24534)
Best Response to Therapy CP-CML
N (%)
Best
Overall T315Ia Non-T315I
Response
(N = 38) (n = 9) (n = 29)
Hematologic
CHRb 36 (95) 9 (100) 27 (93)
Cytogenetic
MCyR 25 (66) 9 (100) 16 (55)
CCyR 20 (53) 8 (89) 12 (41)
Includes only those with T315I status confirmed at study entry.
a
Includes new CHRs and baseline CHRs.
b
Cortes et al, 2010.

102. Omacetaxine for CML With T315I
Response to Therapy
 81 patients with T315I CML
 Omacetaxine 1.25 mg/m2 bid x 14 days, then x 7 days
 Prior TKI: 1 in 21%, 2 in 53%, and 3 in 26%
No. (%)
Response CP AP BP
N = 49 N = 17 N = 15
Hematologic 42 (86) 6 (35) 7 (47)
CHR 42 (86) 5 (29) 3 (20)
HI NA 3 (18) 1 (7)
RCP NA 1 (6) 4 (27)
Cytogenetic 20 (41) 1 (6) –
MCyR 13 (27) 1 (6) –
CCyR 9 (18) 1 (6) –
Minimal 7 (14) – –
 Median survival: CP = NR (65% at 24 mos); AP = 19 mos; BP 2 mos
Cortes, Khoury, et al, 2009.

103. Response to Bosutinib Third-Line Therapy
 Dual Src and Abl inhibitor, no effect over c-kit or PDGFR
 114 patients who failed imatinib (600 mg) and dasatinib
or nilotinib
IM + D IM + D IM + NI
resistant intolerant resistant
Response (%) (n = 36) (n = 51) (n = 27)
CHR 61 80 78
MCyR 29 37 29
CCyR 9 34 17
PCyR 21 3 13
MMR 8 36 6
Khoury et al, 2010.

104. SCT for CML With T315I
 8 patients received 9 SCT
– 7 MUD, 2 CB
 Stage: 2 CP (in PCyR), 3 AP (active disease), 4 second CP from
LyBP (1 mCyR, 2 MMR, 1 CMR with extramedullary disease)
 Best response: 4 CMR (2 CP, 2 second CP), 3 CCyR (2 AP, 1 BP),
1 CHR (AP), 1 early death
 Median follow-up: 13 mos
– 3 died (5, 8, and 10 mos post SCT) with relapse
– 5 alive:
• 2 CP in CMR (14 and 42 mos post SCT)
• 1 AP in CCyR (26 mos) with persistent T315I
• 1 AP in CHR (39 mos) with persistent T315I
• 1 BP in CMR (10 mos post second SCT)
MUD = matched unrelated donor; CB = cord blood; LyBP = lymphoid blast phase; CMR = complete molecular response.
Velev et al, 2010.

105. Take Home Message – CML 2011
• Frontline therapy: new standard
– Imatinib is good
– 2nd generation TKI (dasatinib, nilotinib , bosutinib?)
are better
– Sequential therapy?
• Failure to therapy:
– New definitions (no CCyR at 6 months)?
– Change quickly if imatinib therapy
• No need to change if responding to imatinib
• Good (but not great) 2nd line therapy
• Future needs:
– 3rd line (Ponatinib ⇒ 2nd and 1st line?)
– Treatment discontinuation