Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge. Review a downloadable slide deck by Michael W. N. Deininger, MD, PhD, covering the most clinically relevant new data reported from Community Oncology Clinical Debates: Chronic Myelogenous Leukemia. Target Audience This educational activity has been designed to meet the unique learning needs of hematologists, medical oncologists, oncology fellows, and pathologists involved in the treatment of patients with chronic myelogenous leukemia (CML). This program is designed to provide hematologists/oncologists with the latest clinical updates on the treatment of patients with CML in the frontline and relapsed settings. Key elements of this program will highlight many of the clinical challenges faced by physicians as they select appropriate therapeutic regimens for their patients. Assisting clinicians in gaining further perspective regarding the importance of response criteria, clinical monitoring of treatment failure/suboptimal response/disease resistance, timing for switching therapy to obtain maximum therapeutic benefit, the significance of BCR-ABL mutational analysis in patients and how this can assist in selecting therapy and designing individualized approaches to managing CML will be important discussion points throughout the symposium.

2. DISCLAIMER
This slide deck in its original and unaltered format is for educational purposes and is
current as of April 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
Food and Drug Administration and off-label uses of approved products. Readers
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
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.

5. Learning Objectives
L
Upon completion of this activity,
participants should be better able to:
 Assess patient and disease characteristics for selecting
optimal frontline therapies for patients with CML
 Identify the characteristics that define a relapsed patient
with CML
 Evaluate the role of mutational analysis for
individualizing therapy choices for patients with CML
 Identify investigational agents in clinical development for
patients with CML

6. Activity Agenda
 Activity Overview (5 mins)
 Interactive Clinical Debates (50 mins)
– Clinical Debate 1: How Do You Choose the Optimal
Frontline Therapy for Patients With CML?
– Clinical Debate 2: How Should the
Relapsed/Refractory CML Patient Be Treated?
 Questions & Answers (5 mins)

7. Interactive Clinical Debates

8. Clinical Debate 1:
How Do You Choose the Optimal
Frontline Therapy for Patients With CML?

9. CML: Epidemiology and Etiology
 In the US, there were 4,870 cases in 2010 and an
expected 5,430 cases in 2012
 15% of all adult leukemias
 Incidence increases significantly with age
– Median age: ~ 67 years
– Prevalence increasing due to current therapy
– Most patients present in CP
• Majority of CML-related deaths due to progression to AP/BC
– 50% of CML patients are asymptomatic at diagnosis
 Risk factors
– Radiation exposure
CML = chronic myeloid leukemia; CP = chronic phase; AP = accelerated phase; BC = blast crisis.
NCCN, 2012; Jemal et al, 2010; ACS, 2012; Richardson et al, 2009; Bacarrani, Cortes, et al, 2009.

10. Most CML Patients Are Diagnosed
in the Chronic Phase
Chronic Phase Blast Phase

11. Ph Is the Result of t(9;22)(q34;q11)
BCR
{
q11 BCR ABL
Ph
22
{
ABL
q34 ABL
BCR
9 9q+
Ph = Philadelphia.

12. The Cytogenetic Hallmark of CML
Is the Philadelphia Chromosome
9q+
Ph 9
22
22q- = Ph chromosome
Courtesy of Christl Müller, Leipzig.

13. RT-PCR for BCR-ABL
Target
sequence
RT-PCR for BCR-ABL in CML 1 Denaturation:
Heat briefly to
1) Qualitative RT-PCR allows for separate DNA
strands
the diagnosis of CML 2 Annealing: Cool
to allow primers
Cycle 1
2) Quantitative RT-PCR is used yields 2
molecules
to form hydrogen
bond with ends Primers
of target
to quantify the amount of sequence
disease 3 Extension: DNA
polymerase adds New
nucleotides to the nucleo-
3) Allows for the identification of 3” end of each
primer
tides
cryptic BCR-ABL
translocations Cycle 2
yields 4
molecules
4) Does not require a bone Cycle 3 yields
marrow aspirate for optimal 8 molecules;
2 molecules
results
(in white
boxes)
match target
sequence
RT-PCR = real time polymerase chain reaction.
Suh et al, 2000; Menif et al, 2009; Adapted from Rollins et al, 2000.

14. Monitoring Response:
Sensitivity of Strategies
100% Diagnosis: 1012 Leukemia Cells
Complete
Hematologic
Blood Counts Response
10%
Complete
Cytogenetic
Cytogenetics Response
1%
Major
PCR Molecular
Response
0.1%
4.5 log = 0.0032%
Complete
Undetectable Range Molecular
Response

15. BCR-ABL Kinase Activity Is
Essential for CML Pathogenesis
L
BABL Imatinib (µM)
R-A -
R
BCBC 0.1 0.5 1.0 5.0 10
00
121 BCR-ABL-
22
5 32 p 2
566 2DD 232p
KK 3 3
BCR-ABL
NALM-1 cells (Ph+)
Deininger et al, 1997.

16. Imatinib Greatly Improved Survival
in CML-CP (MDACC data)
MDACC = The University of Texas M. D. Anderson Cancer Center.
Quintas-Cardama & Cortes, 2006.

17. Case Study 1
 A 60-year-old man presents to his PCP with a
history of left-sided abdominal pain, poor
appetite, and loss of 10 kg of body weight
 PMH is significant for interstitial lung disease
with right heart failure and recurrent pleural
effusions. A recent EKG shows a QTc interval of
433 ms.
 Physical exam reveals splenomegaly (14 cm
under left rib cage)
PCP = primary care physician; PMH = past medical history; EKG = electrocardiogram.

18. Laboratory Findings
 HGB 10.1 g/dL, WBC 321/nL, platelets 810/nL
 Diff: 25% segs, 23% bands, 17% myelocytes,
10% promyelocytes, 8% basophils,
6% monocytes, 4% lymphocytes, 9% blasts
 Bone marrow: 7% blasts, 5% basophils
 Cytogenetics: 46XY,t(9;22)[20]
HGB = hemoglobin; WBC = white blood count; Diff = differentials; segs = segmented neutrophils.

19. Case Study 1: Question 1
Which diagnostic tests would you add?
1) FISH for BCR-ABL
2) BCR-ABL mutation screening
3) CT abdomen/pelvis ± contrast
4) None of the above
5) All of the above
FISH = fluorescent in situ hybridization; CT = computed tomography.

20. Case Study 1: Question 2
Which information is not important for decision-
making?
1) Spleen 14 cm
2) WBC 321/nL
3) PLTs 810/nL
4) Peripheral blood blasts 9%
5) History of pleural effusions
PLTs = platelets.

21. Case Study 1: Question 3
Which of the following are acceptable therapeutic
choices?
1) Imatinib 400 mg QD
2) Imatinib 400 mg BID
3) Nilotinib 300 mg BID
4) Dasatinib 100 mg QD
5) Only 1, 2, and 3
6) Only 1, 3
7) Only 1, 3, and 4
NCCN, 2012; Sprycel® prescribing information, 2010; Tasigna® prescribing information, 2011;
Gleevec® prescribing information, 2010.

22. Case Study 1: Question 4
The patient is started on nilotinib 300 mg BID.
Which two statements about monitoring this patient
are incorrect?
1) Blood counts should be monitored weekly until stable
2) Monitoring transaminases and lipase is unnecessary
3) A BMB and karyotyping at 3 months are standard of care
4) Once a complete cytogenetic response has been documented
monitoring continues with qPCR only
5) Annual BMB should continue indefinitely
BMB = bone marrow biopsy.

23. Getting Things Right at Diagnosis
The Bare Minimum
 History and physical exam: Record spleen size in cm below costal margin
 Complete blood count
 Bone marrow aspirate with marrow differential
 Conventional cytogenetics
 Do not treat leukocytosis with imatinib!
Optional
 Bone marrow trephine
 FISH for BCR-ABL Mandatory in case of Ph-
 Diagnostic PCR for BCR-ABL negative karyotype
 Flow cytometry
NCCN, 2012.

24. Getting Things Right at Diagnosis
(cont.)
Establish Disease Phase
 PLT < 100
 Blood or marrow blasts > 15%
 Basophils > 20%
 Blasts and promyelocytes > 30%
 Blasts > 30%
Establish Sokal Risk Score
= Exp [0.0116 (Age – 4.34)] Low risk < 0.8
+ 0.0345 (Spleen – 7.51)
+ 0.188 [(PLT/700)2 – 0.563] Intermediate risk 0.8–1.2
+ 0.0887 (PB blasts – 2.1) High risk > 1.2
NCCN, 2012.

25. New CML Risk Score (Eutos Score) for
Patients Treated With Imatinib
PFS
Requires Confirmation
High risk: > 87
Low risk: ≤ 87
Eutos Score = (7 x basophils) + (4 x spleen size)
PFS = progression-free survival.
Hasford et al, 2011.

26. Is There A Role for Peripheral Blood
FISH for Monitoring Response?
 Good correlation between BM, FISH, and karyotyping
Distribution of I-FISH Data According to CBA Data
Cytogenetic response by I-FISH, n (%)
Cytogenetic response by CBA < 1% BCR-ABL+ 1%–5% BCR-ABL+ > 5% BCR-ABL +
nuclei nuclei nuclei
CCgR (n = 537), no Ph+ metaphases 444 (82.7) 71 (13.2) 22 (4.1)
PCgR (n = 77), 1%–35% Ph+ metaphases 7 (9.1) 32 (41.6) 38 (49.3)
p Value < .001 < .001 < .001
CBA = chromosome banding analysis; CCgR = complete cytogenetic response; I-FISH = interphase fluorescence in situ hybridization;
PCgR = partial cytogenetic response.
Testoni et al, 2009.

27. Is There A Role for Peripheral Blood
FISH for Monitoring Response? (cont.)
% Ph +
100
In Favor
80 r = 0.98
 Wide accessibility
 Excellent correlation with marrow 60
cytogenetics in patients on IFN-α
40
20
0
Against 0 20 40 60 80 100 % Ph +
 IFN-α results not validated in patients on imatinib
 Not validated prospectively with clinical end points
 Does not detect clonal evolution
 Limited sensitivity and dynamic range compared to qPCR
IFN = interferon.
Le Gouill et al, 2000.

28. Therapy Standards
Chronic Phase Advanced Phase
 Imatinib  Dasatinib
 Nilotinib  Nilotinib
 Dasatinib  Allotransplant
 (IFN-α)  (Imatinib)
 (Hydroxyurea)  (Hydroxyurea)
NCCN, 2012.

29. Choosing a TKI for First-Line Therapy
Study Comparison Patients / Major Author
Randomization End Points
IRIS IM 400 mg QD 1,106 / 1:1 PFS O’Brien et al, 2003
IFN / Ara-C
TOPS IM 400 mg QD 476 / 1:2 MMR at Cortes et al, 2010
12 months
IM 400 BID
ENESTnd IM 400 mg QD 846 / 1:1:1 MMR at Saglio et al, 2010
NIL 300 mg BID 12 months
NIL 400 mg BID
DASISION IM 400 mg QD 519 / 1:1 CCyR at Kantarjian et al, 2010
DAS 100 mg QD 12 months
TKI = tyrosine kinase inhibitor; IM = imatinib; NIL = nilotinib; DAS = dasatinib; MMR = major molecular response;
CCyR = complete cytogenetic response.

30. OS on First-Line Imatinib
(IRIS Study)
OS = overall survival.
Deininger et al, 2009.

31. IRIS Study: PFS by Molecular Response
at 12 Months on First-Line Imatinib
100
90
80
% w ith o u t p r o g r e s s io n
70
60
50
40 Estimated Rate at 54 Months
CCyR w it h >≥= 3 log reduction
C C y R with 3 lo g r e d u c t io n
30 95% } p = .068
20
10
CCyR w it h << 3 logereduction
C C y R with 3 lo g r d u c t io n
No CCyR
N o C C yR
89%
72%
} p < .001
0
0 6 12 18 24 30 36 42 48 54 60
M o n t h s s in c e r a n d o m iz a t io n
Deininger et al, 2009.

32. IRIS Study 7-Year Follow-Up: Prognostic Significance
of Molecular Response on First-Line Imatinib
p = .014 p = .0006
P=0.001
p = .019
Hughes et al, 2010.

33. Not All Data Are As Good As IRIS Data:
Hammersmith Hospital Experience
Event: 63%
Also off IM due to lack of
MCyR or toxicity
CHR = complete hematologic response; EFS = event-free survival; MCyR = major cytogenetic response.
de Lavallade et al, 2008.

34. The Community Experience: Only A Minority
of Patients Do Well Enough to Remain on IM
CCRe = complete cytogenetic response equivalence.
Lucas et al, 2008.

35. TOPS 24-Mos Update: Study Design
Imatinib 800 mg/day (400 mg BID; n = 319)
2:1
randomization
Imatinib 400 mg/day (n = 157)
N = 476
MMR* at 12 months PFS, OS
Total 5 years (planned)
 Patients enrolled at 103 sites in 19 countries, first patient first visit June 2005
 Cytogenetic analysis every 6 months until CCyR, then every 12 months
 Molecular analysis by PCR every month for Months 1–3, then every 3 months
Data cut-off of December 31, 2008.
*BCR-ABL/control gene ≤ 0.1% utilizing the International Scale.
TOPS = Tyrosine Kinase Inhibitor Optimization and Selectivity.
Cortes, Baccarani, et al, 2010.

36. TOPS Trial: Imatinib 400 mg Vs. 800 mg:
MMR Rates Over Time (ITT)
ITT = intent to treat.
Cortes, Baccarani, et al, 2010.

37. Impact of Dose Intensity* on Cumulative
CCyR Rates, 800 mg Arm
p = .001 p = .510
100 91 94
90
% Patients Achieving CCyR
80
70
60
< 600 mg
≥ 600 mg
40
20
0
12 Months 24 Months
800 mg Arm
*Dose intensity (total amount of drug received divided by the number of days on treatment including days of zero dose)
in the first 12 months of treatment.
Cortes, Baccarani, et al, 2010.

38. Event-Free Survival* (ITT)
100
90
% Patients Without Event
80
70
60 EFS at 24 Months
50 95% for Both Arms
40
30
20 400 mg
10 800 mg
0
0 6 12 18 24 30 36 42
Months Since Randomization
*EFS; time between randomization and death, progression to AP/BC, loss of MCyR [Ph+ bone marrow cells > 35%] or loss of CHR.
Baccarani et al, 2009.

39. Nilotinib in CP1 First-Line:
3-Year Update of ENESTnd
Primary end point: MMR at 12 months
Saglio et al, 2011.

40. Patient Disposition
Few patients discontinued treatment since the 2-year follow-up
– 4% on nilotinib 300 mg BID; 5% on nilotinib 400 mg BID; 6% on imatinib
Saglio et al, 2011.

41. Cumulative Incidence of MMR
n
100 Nilotinib 300 mg bid 282
Nilotinib 400 mg bid 281
90 By 3 Years
Imatinib 400 mg qd 283
80 73%, p < .0001
By 1 Year
70
% With MMR
55%, p < .0001
70%, p < .0001
60
Δ 17%–20%
50
51%, p < .0001 53%
40 Δ 24%–28%
30
20 27%
10
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Months Since Randomization
Saglio et al, 2011.

42. Patients With High Sokal Risk Have the
Largest Improvement of MMR by 3 Years
p = .0264 p = .0020
p = .0004
80 77 75
70 67
63
60 54
% With MMR
50
39
40
30
Δ 14% Δ 21% Δ 28%
20
10
n = 103 104 101 101 78 78
0
Low Intermediate High
Nilotinib 300 mg BID Imatinib 400 mg QD
Saglio et al, 2011.

43. Cumulative Incidence of CMR
n
40 Nilotinib 300 mg bid 282
By 3 Years
Nilotinib 400 mg bid 281
32%, p < .0001
Imatinib 400 mg qd 283
% With MR4.5
By 2 Years
30
By 1 Year 26%
11%, p < .0001
28%, p = .0003
20
Δ 13%–17%
21%
15%
10 7%, p < .0001
Δ 6%–10% 10%
0 1%
0 3 6 9 12 15 18 21 24 27 30 33 36
Months Since Randomization
Saglio et al, 2011.

44. Progression to AP/BC: Including Events
After Discontinuation (ITT Analysis)
Number of Patients (n)
p = .0496
HR = 0.5 [0.2, 1.0] p = .0076 19
HR = 0.3 [0.1, 0.8]
9
6
3.2% 2.1% 6.7%
On Core Treatment and After Discontinuation
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
Off treatment progression information was prospectively collected for all patients
every 3 months after discontinuation
HR = hazard ratio.
Saglio et al, 2011.

45. Survival After Progression to AP/BC
100 Progressed = 34
Died = 23
90
Alive = 11
80
Median Survival
70
10.5 months
60
% Alive
50
40
30
20
10
0
0 6 12 18 24 30 36
Months Since Progression
Saglio et al, 2011.

46. Overall Survival
 Of 38 total deaths on study, 23 were following progression to AP/BC
CI = confidence interval.
Saglio et al, 2011.

47. Dasatinib in CP1 First-Line
2-Year Update of
DASISION
 Treatment-naïve
CML-CP Dasatinib 100 mg QD (N = 259)
patients Follow-up
(N = 519) Randomized*
5 years
 108 centers
Imatinib 400 mg QD (N = 260)
 26 countries
*Stratified by Hasford risk score
 Primary end point Confirmed CCyR by 12 months
 Other key end points Rates of CCyR and MMR, times to CCyR and
MMR, time in CCyR (measure of duration),
PFS, OS
Hochhaus et al, 2011.

48. Cumulative Incidence of MMR
100 Dasatinib 100 mg QD
By 12 months By 24 months
Imatinib 400 mg QD
80
65%
% of Patients
60 47% Δ 18%
47%
40 Δ 19%
20 28%
0
0 3 6 9 12 15 18 21 24 27
Months
Response achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.
Hochhaus et al, 2011.

49. Cumulative Incidence of CMR
100 Dasatinib 100 mg QD
Imatinib 400 mg QD
80
% of Patients
60
40
By 24 months
20 17%
9%
0
0 3 6 9 12 15 18 21 24 27
Months
Response achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.
Hochhaus et al, 2011.

50. BCR-ABL Levels at 3 Months*
100
84% Dasatinib 100 mg QD
80
Imatinib 400 mg QD
64%
% of Patients
> 1–10%
60
40 36%
> 1–10%
≤ 1%
20 16%
≤ 1%
0
n/N 198/235 154/239 37/235 85/239
≤ 10% > 10%
BCR-ABL Level at 3 Months
*Calculated from total number of evaluable patients with PCR assessments at 3 months.
Hochhaus et al, 2011.

51. Cumulative Incidence of CCyR Within 24 Months
According to BCR-ABL Level at 3 Months
Dasatinib 100 mg QD Imatinib 400 mg QD
24 months 24 months
100 98% 100 100%
98% 94%
80 80
% CCyR
% CCyR
60 60 64%
40 38% 40
20 20
0 0
0 6 12 18 24 0 6 12 18 24
30 30
Months
Months
BCR-ABL at 3 months
≤ 1% > 1–10% > 10%
Hochhaus et al, 2011.

52. Transformation to AP/BP According to
BCR-ABL Level at 3 Months
10 9.4%
Dasatinib 100 mg QD
Imatinib 400 mg QD 8.1%
8
% Transformation
6
5.0%
4 3.3%
2.6%
2 1.8%
1.2%
0%
0
n/N 6/235 12/239 2/112 0/32 1/86 4/122 3/37 8/85
Total ≤ 1% > 1–10% > 10%
BCR-ABL Level at 3 Months
Hochhaus et al, 2011.

53. OS According to BCR-ABL Level
at 3 Months
Dasatinib 100 mg QD Imatinib 400 mg QD
100 100
80 80
% Alive
% Alive
60 60
40 BCR-ABL Level at 3 months 40 BCR-ABL Level at 3 months
≤ 1% ≤ 1%
20 > 1–10% 20 > 1–10%
> 10% > 10%
0 0
0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42
Months Months
For ≤ 10% vs. > 10% comparison: p = .0137 For ≤ 10% vs. > 10% comparison: p = .0081
Hochhaus et al, 2011.

54. Nilotinib and Dasatinib Are Better
Tolerated Than Imatinib
Nilotinib / Dasatinib Better
Nausea
IM NIL DAS IM
Saglio et al, 2011; Hochhaus et al, 2011.

55. ENESTnd Vs. DASISION
 Communalities
– Superiority of experimental arm in terms of primary end point
– Equal or better tolerability of experimental arm
– High drop out rates
– No difference in OS
Differences in Design
ENESTnd DASISION
Risk stratification Sokal Hasford
Dose escalation in
No Yes
experimental arm
Assessment of progression On therapy Up to 60 days post d/c of therapy
d/c = discontinuation.
Larson et al, 2011; Kantarjian et al, 2011.

56. ENESTnd Vs. DASISION
An Unallowed Comparison
ENESTnd DASISION
CCyR 24 months (%) 87/85a 86a
MMR 24 months (%) 62/59b 64a
PFS superior in experimental arm Yes No
Up to 60 days post d/c
Assessment of progression On therapy
of therapy
Response by time point.
Larson et al, 2011; Kantarjian et al, 2011.

57. SO325 Trial Design
 Randomization
– Imatinib 400 mg/d vs. dasatinib 100 mg/d
 Stratification
– Hasford risk category: Low vs. intermediate vs. high
 Number of patients
– N = 240 (120/arm)
 Assessment schedule
– Molecular and hematologic response: 3, 6, 9, 12 mos
– Cytogenetic response: 6, 12 mos
Radich et al, 2010.

58. BCR-ABL mRNA Level
Median BCR-ABL reduction: Dasatinib 3.3 log vs. imatinib 2.8 log, p = .048
Radich et al, 2010.

59. Clinical Debate 2:
How Should the Relapsed/Refractory
CML Patient Be Treated?

60. Case Study 2
 A 49-year-old man with CML has been on imatinib 400 mg
daily for 7 years
 He was diagnosed in chronic phase and achieved CCyR after
6 months
 His qPCR levels on the international scale have fluctuated
between 0.09% and 0.4%, but the most recent test showed an
increase to 5.6%
 Comorbidities include diabetes mellitus, polyarthritis, and
depression, for which he is managed by 3 additional
specialists
 He is asymptomatic and physical exam is negative

61. Case Study 2: Question 1
Which are the appropriate next steps?
1) Thorough ‘questioning’ for non-compliance
2) Thorough review of co-medications
3) Repeat qPCR
4) Bone marrow biopsy
5) Imatinib drug level testing
6) All of the above
7) Only 1, 2, and 3
8) Only 1, 2, 3, and 5

62. Case Study 2: Question 2
A thorough history reveals no evidence for non-compliance and there
was no recent change in medications. The repeat PCR test reveals a
level of 7.2IS.
What is your next step?
1) Bone marrow biopsy with cytogenetics
2) Screening for BCR-ABL kinase domain mutations on a
blood sample
3) Screening for BCR-ABL kinase domain mutations on a bone
marrow sample
4) Only 1, 2, and 3
5) Only 1 and 2

63. Case Study 2: Question 3
You receive the following results:
Normocellular marrow with micromegakaryocytes, 2% blasts
Mutation screening positive for F359V BCR-ABL mutation
Cytogenetics 46XY[15]/46XY,t(9;22),inv(3)[5]
What is your next step?
1) Increase imatinib to 800 mg BID
2) Switch to nilotinib 400 mg BID
3) Switch to dasatinib 140 mg QD
4) Evaluate for allotransplant
5) Only 2 and 4
6) Only 3 and 4

64. Resistance Work-Up
Failure to reach milestones or loss of response
No
Complete Diagnostic Work-Up
 Physical exam
 BMB
 Karyotyping
 BCR-ABL mutation screen
NCCN, 2012.

65. Therapeutic Milestones on Imatinib
Month Optimal Suboptimal Failure
3 <65% Ph+ >95%Ph+ No CHR
CCyR or 66-95%
6 1-35% Ph+
better Ph+
Less than
12 MMR or better >35% Ph+
MMR
18 CMR 0% Ph+ >0% Ph+
Baccarani et al, 2009.

66. Therapeutic Milestones on Imatinib
(cont.)
Month Optimal Suboptimal Failure
3 < 65% Ph+ > 95%Ph+ No CHR
6 CCyR or better 1%–35% Ph+ 66%–95% Ph+
12 MMR or better < MMR > 35% Ph+
18 CMR 0% Ph+ > 0% Ph+
Baccarani et al, 2009.

67. Therapeutic Milestones on Imatinib
(cont.)
Month Optimal Suboptimal Failure
3 < 65% Ph+ > 95%Ph+ No CHR
6 CCyR or better 1%–35% Ph+ 66%–95% Ph+
12 MMR or better < MMR > 35% Ph+
18 CMR 0% Ph+ > 0% Ph+
Baccarani et al, 2009.

68. Therapeutic Milestones on Imatinib
(cont.)
Month Optimal Suboptimal Failure
3 < 65% Ph+ > 95%Ph+ No CHR
6 CCyR or better 1%–35% Ph+ 66%–95% Ph+
12 MMR or better < MMR > 35% Ph+
18 CMR 0% Ph+ > 0% Ph+
Baccarani et al, 2009.

69. Therapeutic Milestones on Imatinib
(cont.)
Month Optimal Suboptimal Failure
3 < 65% Ph+ > 95%Ph+ No CHR
6 CCyR or better 1%–35% Ph+ 66%–95% Ph+
12 MMR or better < MMR > 35% Ph+
18 CMR 0% Ph+ > 0% Ph+
Baccarani et al, 2009.

70. Therapeutic Milestones on Imatinib
(cont.)
Month Optimal Suboptimal Failure
3
Favorable Favorable
6 Favorable outcome outcome
outcome likely: uncertain: unlikely:
12 Keep going! Consider Change
alternative! strategy!
18
Baccarani et al, 2009.

71. When Is BCR-ABL Mutation
Analysis Indicated?
Universally Accepted
 Failure to reach milestones
 Loss of response, progression
Controversial
 Routine at diagnosis in patients with AP/BC?
 Routine monitoring in high-risk patients?
 Which is the optimal technology?
 Which is the right qPCR trigger?
NCCN, 2012.

72. Which Increase of BCR-ABL Is the Right
Trigger for BCR-ABL Mutation Screening?
 NCCN guidelines: 10-fold
 ELN recommendations: 5-fold
 If you live in Australia: 2-fold
More than 2-fold rise Stable or decreasing
Mutations (%) 34/56 (61) 1/158 (0.6)
resistance (%) 31/34 (91) 1/1 (100)
No mutations (%) 22/56 (39) 157/158 (99)
resistance (%) 13/22 (59) 1/157 (0.6)
Brandford et al, 2004.

73. Receiver Operating Characteristic Analysis
to Define Optimal qPCR Trigger
100
90
Jmax (2.6-fold)
80
Sensitivity (%)
70
60
50
40
30
20
10
0
0 10 20 30 40 50 60 70 80 90 100
1 – Specificity (%)
Press et al, 2009.

74. What Are the Non-Transplant
Options for Patients With Relapse?
 (Imatinib dose escalation)
 Nilotinib
 Dasatinib
 Experimental agents
NCCN, 2012.

75. Dasatinib: PFS and OS in CML-CP
After IM Failure
100
80
% of Patients
60
OS
N 12 months 24 months
40 387 97% 94%
PFS
20 N 12 months 24 months
387 91% 80%
0
0 3 6 9 12 15 18 21 24 27 30 33
Months
Stone et al, 2007.

76. Nilotinib: PFS and OS in CML-CP
After IM Failure
% Alive
Months Since Start of Treatment
Adapted from Kantarjian et al, 2007.

77. Patients With Cytogenetic Response to
Second-Line TKIs at 3 Months Do Well
Proportions of patients
ultimately achieving 12 MMCyR
Proportion Alive (%)
Time point, response n 12 MMCyR, no. (%)
3 months
Minor cytogenetic 15 10 (67)
Complete hematologic 42 3 (7)
response or
hematologic failure
6 months
Minor cytogenetic 16 8 (50)
Complete hematologic 39 1 (3)
response or Months From 12-Month Landmark
hematologic failure
Tam et al, 2008.

78. Blast Crisis: PFS on Dasatinib
100
80 Myeloid Blast
% Not Progressed
Lymphoid Blast
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30
Months
Gambacorti et al, 2007.

79. Dasatinib for IM Failure in CP: Frequency of Baseline
BCR-ABL Mutations by In Vitro IC50 to Dasatinib
 Patients with resistance or suboptimal response to imatinib
Unknown IC50 to dasatinib (n = 74)
9% 38 different BCR-ABL mutations
IC50 ≤ 3 nM (n = 248)
M244V, G250E,
Y253F/H/K, F311L,
No BCR-ABL 31% M351T, E355G,
mutation F359C/I/V, V379I,
(n = 421) L387M, H396P/R
52%
< 1% V299L (n = 1)
1% Q252H (n = 6) IC50 > 3 nM
2% F317L (n = 13) (n = 42)
5%
3% E255K/V (n = 25)
2% T315I (n = 20) IC50 > 200 nM
Müller et al, 2008.

80. Response Rates by In Vitro IC50 to
Dasatinib (excluding T315I)
100 96 94 IC50 to dasatinib
Unknown (n=83)
82
80 ≤3 nM (n=254)
73
>3 nM (n=44)
58
60 54
47
%
43
40 34 34
25
18
20
0
CHR MCyR CCyR MMR
Müller et al, 2008.

81. Nilotinib Efficacy According to
Baseline BCR-ABL Mutations in CML-CP
Baseline Mutations in Imatinib-Resistant Patients (N = 202)
Others* No Mutation
T315I 15% IC50-based grouping
3% IC50 ≤ 150 nM
F359C/V
M244V, L248V, G250E,
5% 45%
Q252H, E275K, D276G,
E255K/V F317L, M351T, E355A,
4%
E355G, L387F, F486S
Y253H
4%
IC50 > 150 nM
24% Y253H, E255K/V,
F359C/V
IC50 ≤ 150 nM IC50 > 10,000 nM
T315I
*Mutations without available IC50 data.
Hughes et al, 2009.

82. The “Default” Mutant T315I Is Resistant to
All Currently Approved BCR-ABL TKIs
O’Hare et al, 2007.

83. NCCN Guidelines:
Treatment Options Based on BCR-ABL
Kinase Domain Mutation Status
BCR-ABL KD Mutation Treatment Recommendation
T315I HSCT or clinical trial
V299L, T315A, F317L/V/I/C Consider nilotinib rather than dasatinib
Y253H, E255K/V, F359V/C/ Consider dasatinib rather than nilotinib
I
Any other mutation Consider high dose imatinib or dasatinib
or nilotinib
NCCN, 2012.

84. Drug Therapy Options for Patients With
Failure on Second-Line TKI Treatment
 Third generation ABL kinase inhibitors
– Ponatinib
– Bosutinib
– DCC-2036
 Non-targeted agents
– Omacetaxine
 Inhibitors of other pathways
– Hedgehog/SMO inhibitors
– Beta-catenin inhibitors
National CML Society, 2011; Hu et al, 2009; Jagani et al, 2010; NCCN, 2012.

85. Ponatinib (AP24534): Binding to ABLT315I
T315I
N
H2N N
O
NH
O
Imatinib
AP24534 F3C N N
OH
AP24534
Cellular Proliferation – IC50 (nM)
BCR-ABL
AP24534 Imatinib Dasatinib Nilotinib
Native 0.5 224 0.8 13
T315I 11 > 3,125 > 200 > 2,000
O’Hare et al, 2009, 2011.

86. Phase I Study of Ponatinib: Safety
N (%; N = 74)
Treatment-Emergent AEs
(≥ 20% any grade) Any Grade ≥ Grade 3
Fatigue 26 (35) 0 (0)
Constipation 25 (34) 0 (0)
Rash 25 (34) 1 (1)
Headache 24 (32) 0 (0)
Arthralgia 23 (31) 2 (3)
Nausea 22 (30) 0 (0)
Abdominal pain DLT: Pancreatitis
20 (27) 3 (4)
Pyrexia 17 (23) 2 (3)
Muscle spasms 16 (22) 0 (0)
Vomiting 16 (22) 0 (0)
Thrombocytopenia 20 (27) 15 (20)
Neutropenia 10 (14) 6 (8)
Anemia 14 (19) 6 (8)
Data October 15, 2010
DLT = dose-limiting toxicity.
Cortes et al, 2010.

87. Response to Ponatinib
N (%; 55 evaluable)
Best Response Overall T315I* Non-T315I
to CML-CP (N = 38) (N = 9) (N = 29)
Hematologic
CHR** 36 (95) 9 (100) 27 (93)
Cytogenetic
MCyR 25 (66) 9 (100) 16 (55)
CCyR 20 (53) 8 (89) 12 (41)
N (%; 55 evaluable)
Best Response Overall T315I* Non-T315I
to CML-AP (N = 17) (N = 5) (N = 12)
Hematologic
MHR 6 (35) 1 (20) 5 (42)
Cytogenetic
MCyR 4 (24) 1 (20) 3 (25)
CCyR 2 (12) 0 (0) 2 (17)
Data October 15, 2010
*Includes only those with T315I status confirmed at study entry.
Cortes et al, 2010.

88. Treatment Approach for T315I Detection
and TKI Failure
T315I detection in the
context of TKI failure
Determine disease phase Evaluate for allograft
CP AP/BC
No Tx candidate Tx candidate
Chemotherapy or IA
Investigational agent
Allograft in
remission
NCCN, 2012.

89. Survival After Allogeneic Transplant
in Patients With Imatinib Failure
Saussele et al, 2010.

90. Key Takeaways
 Imatinib, nilotinib, and dasatinib are all approved options for
frontline therapy
 Nilotinib and dasatinib are superior to imatinib in newly
diagnosed CML-CP in surrogate end point (CCyR; MMR; CMR)
 Improved PFS (statistically significant for nilotinib)
 Longer follow-up required to ascertain positive effect on OS
 Good monitoring starts with complete staging at diagnosis
 Milestones define responses as optimal, suboptimal, or failure
and are dependent on the type of therapy (will be updated for
new TKIs)

91. Key Takeaways (cont.)
 Treatment recommendations are outlined in the NCCN
guidelines for specific BCR-ABL kinase domain mutations
(eg, dasatinib for F359V/C/I mutations). However:
– Ponatinib is the most promising salvage therapy option for
patients who failed second-line TKIs, including those with the
T315I mutation
 Allotransplant remains an important salvage option and is a
mandatory consideration in case of progression to AP/BC
 The following targeted agents are options for patients who
fail second-line TKIs: Ponatinib, bosutinib, DCC-2036