1. METHOD OF PARTICIPATION CME-certified Oncology
Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials:
Pre-activity Survey
Located at the front of your syllabus
CME Evaluation with Post-activity Survey
Located at the back of your syllabus
METHOD OF PARTICIPATION A
CME-certified Oncology
Exchange
Activity

3. Off-label Discussion Disclosure
Disclosures
All relevant financial relationships with commercial interests reported by faculty speakers, steering committee members, non-faculty content contributors and/or reviewers, or their spouses/partners have been listed on page 5 of your program syllabus.
Off-label Discussion Disclosure
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

4. Educational Objectives
At the conclusion of this activity, participants should be able to demonstrate the ability to:
Identify changes in therapeutic indications and clinical practice guideline for CML
Understand practical aspects of monitoring responses in patients with CML
Identify the role of BCR-ABL mutations in making treatment decisions in CML
Review emerging data from ongoing studies of novel treatment regimens and evaluate ongoing clinical trials of investigational agents

5. Pre-activity Survey
Please remove the Pre-activity Survey from the front of your packet
Your answers are vital to our understanding of the effectiveness of this CME program, and will help shape future educational activities and topics
Please fill in the most appropriate answer(s) for the questions below:
Degree:  MD/DO  Nursing Professional  PharmD  Other: _____________________________
Specialty:  Oncology/Hematology  Transplant specialist  Internal Medicine  Other: ___________

6. Pre-activity Survey Question 1
Please rate your level of confidence in treating and managing patients with chronic myelogenous leukemia (CML): Not confident Expert

7. Pre-activity Survey Question 2
Please rate your level of competence in individualizing treatment options for patients with CML based on patient and disease characteristics: Not competent Expert

8. Pre-activity Survey Question 3
Six years after starting imatinib, a 53-year-old patient’s BCR-ABL/ABL has increased to 27.3%. After performing a bone marrow biopsy, the patient is still in chronic phase, has 75% Ph+ metaphases and an F317L mutation. The patient receives nilotinib at 400 mg for 12 months after which there is no cytogenetic response. The most suitable option for this patient would be to:
Continue therapy unchanged
Consider ponatinib, omacetaxine, or SCT
Consider bosutinib or dasatinib
None of the above, enroll in a clinical trial
Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

9. Pre-activity Survey Question 4
A 37-year-old male was diagnosed with CML and treated with imatinib 400 mg for 12 months. He was re-evaluated and found to be in hematologic and partial cytogenetic response. Which of the following options would NOT be appropriate at this point:
Repeat mutational analysis
Switch therapy
Check patient’s compliance with medications
Continue treatment
None of the above
Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

10. Pre-activity Survey Question 5
Cytogenetic analysis at 6 months of a 45-year-old female patient, who received prior imatinib, shows Philadelphia chromosome in 45% of metaphases and a BCR-ABL/ABL of According to the European LeukemiaNet recommendations for the management of CML, how would you characterize this response.
Failure
Warning
Suboptimal response
Optimal response
Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

11. Pre-activity Survey Question 6
Which of the following treatment options can be considered for a patient who has failed imatinib and dasatinib or nilotinib:
Omacetaxine
Bosutinib
Ponatinib
Any of the above
Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

12. Evolution of CML Therapy

13. Signal Transduction Inhibition in CML The Beginning
All seven individuals showed a similar minute chromosome.
The findings suggest a causal relationship between the chromosome abnormality observed and chronic granulocytic leukemia.
Nowell PC & Hungerford DA. Science 1960, 132: 1497

14. The Evolution of CML Therapy
Chemotherapy 
SCT 
IFN 
TKI

15. History Lesson #1: SCT is Curative (For Some)
Overall Survival
Leukemia-Free Survival
58%
50%
Reprinted with permission. © (2013) American Society of Clinical Oncology. All rights reserved.  Arora, M et al: J Clin Oncol 27(10):

16. History Lesson #2: CCyR Correlates with Improved Survival
Kantarjian et al. Cancer 2003; 97: 1033

17. History Lesson #3: SCT is NOT the Only Curative Treatment for CML
Kantarjian et al. Cancer 2003; 97: 1033

18. Survival in Early Chronic Phase CML
TKI
Interferon
Chemotherapy
Kantarjian et al. Blood 2012; 119: Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY.

19. Is The Outcome Really That Good?
MDACC event: progression to AP/ BP; loss of MCyR; loss of CHR; no response (ELN criteria); intolerance; or death (any cause, any time)
Kantarjian et al. ASH 2010; Abstract 672.

20. Or Is It Really That Bad?
281 pts Rx with imatinib as initial therapy (73 SD, 208 HD)
CCyR 88%  75 stopped IM
41 events  23 received subsequent TKI  14 (67%) CCyR
CEFS at 7 yrs = 88%
EFS at 7 yrs = 81%
Probability (%)
0.2
0.4
0.6
0.8
1.0
0.0 12 24 36 48 60 72 84
Al-Kali et al. Cancer 2011; 117:
CEFS = Current event free survival; EFS = Event free survival

21. Good Outcome: Just in Clinical Trials?
65 pts treated off protocol & 71 on protocols
Imatinib 400 mg; Median f/u 51 mo
Median [range], or Percentage
On protocol
Off protocol
US Population
Age, y
49 [15-79]
49 [15-84]
High-risk Sokal 6 5
3-mo MCyR 71 69
12- mo CCyR 84 83
12-mo MMR 30 24
5-yr EFS 86
5-yr TFS 96 94
5-yr OS 90
Median income, $
45,735
44,606
42,148
Education HS or less 42 43 48
Uninsured 10 8 14
Yilmaz et al. ASH 2012; Abstract #1693

22. Clinical Case Discussions
Case 1: Frontline Therapy in Newly Diagnosed Setting

23. Case 1: History & Presentation
37 year old male, manufacturing employee at a mechanical shop. Married with two children.
Presented with noted weight loss of 22 pounds in the last 12 months, with simultaneous onset of night sweats and fullness in the left side of his abdomen.
This patient did not have a PCP and had not been seen by a physician since his childhood days for routine checkups.

24. Case 1: Work-up
The major clinical finding was splenomegaly at 14 cm below the costal margin.
Laboratory tests revealed:
WBC of 317,000/ml with 47% immature myeloid cells (meta myelocytes, myelocytes, promyelocytes)
3% blast cells and 7% basophils in the peripherial blood
Blood chemistries were abnormal with elevated lactated dehydrogenase of 842 u/L
Platelet count was 916,000
Hemoglobin was 9.3
Other blood chemistries were WNL.

25. Case 1 (continued)
CML is suspected and a test for bcr-abl revealed that the disease was bcr-abl positive leukemia with b3 a2 transcript consistent with CML.
A bone marrow test followed and revealed bone marrow with high cellularity of 100% with predominant but well matured myeloid series. The bone marrow had 4% myeloblasts
Bone marrow cytogenetic test revealed 20/20 cells with Ph+ and no evidence of additional chromosomal abnormalities was noted.
With the diagnosis of CML in the chronic phase the patient was placed on imatinib 400 mg daily.

26. Case 1: Question 1 Is this the correct treatment decision?
Imatinib is approved as first line treatment for CML and it is the correct choice
The patient has high risk CML and he would have benefited from starting nilotinib or dasatinib
With high-risk disease the patient should have been placed on ponatinib
All are correct
Only 1 & 2 are correct
Only 2 & 3 are correct

27. Case 1: Answer Is this the correct treatment decision?
Imatinib is approved as first line treatment for CML and it is the correct choice
The patient has high risk CML and he would have benefited from starting nilotinib or dasatinib
With high-risk disease the patient should have been placed on ponatinib
All are correct
Only 1 & 2 are correct
Only 2 & 3 are correct
Choices 1 and 2 are correct. Although imatinib, nilotinib, and dasatinib are all approved treatment options, the patient has a high risk CML by SOKAL criteria and responses to nilotinib 300 mgs x2 daily are superior to treatment with imatinib 400 mgs daily.

28. IRIS 8-Year Update At least 37% Unacceptable Outcome
EFS = 81%; Freedom from progression to AP/BC = 92%; OS = 85%
Deininger M, et al. Blood ;114(22): 1126.

29. Imatinib Toxicities Imatinib: Common or Frequent Complaints
Neutropenia
Musculoskeletal complaints
Thrombocytopenia – mainly during yr 1
Hypophosphatemia
GI disturbances / Diarrhea
Rash
Edema and fluid retention
Pediatrics: growth retardation
Occasional bone mineral metabolism problem
Long Term Toxicities of Imatinib
Liver, kidney, cardiac toxicity and immunosuppression.
CHF:
1276 patients at MDACC were studied with median follow up at 47 mos
22 patients, or 1.7% have CHF, however 13/22 had received cardio toxic drugs in the past.
Management of Acute Toxicities
Management of anemia and neutropenia includes use of erythropoietin and filgrastim
Atallah et al, Blood 2007; 110: 1233–1237; Gleevec prescribing information, 2013.; NCCN Guidelines v

30. ENESTnd 3-year update: OS and PFS
Nilotinib 300 mg BID
(n = 282)
Nilotinib 400 mg BID
(n = 281)
Imatinib 400 mg QD
(n = 283)
3-yr OS, %
95.1
97.0
94.0
HR (95% CI) vs imatinib
0.75 ( )
0.46 ( ) --
P value vs imatinib
.4413
.0639
PFS
Nilotinib 300 mg BID
(n = 282)
Nilotinib 400 mg BID
(n = 281)
Imatinib 400 mg QD
(n = 283)
3-yr PFS, %
96.9
98.3
94.7
HR (95% CI) vs imatinib
0.44 (0.17–1.15)
0.30 (0.10–0.92) --
P value vs imatinib
0.0260
BID, twice daily; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; QD, once daily.
BID, twice daily; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; QD, once daily.
Larson RA, et al. Leukemia 2012; 26: ; Kantarjian et al , ASH 2012 Abstract 1676.

31. ENESTnd 3-yr Update Nilotinib 300 mg BID (n = 282)
(Larson et al 2012, Leukemia )
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
Response by 3 yrs, %
MMR
73; P < .0001
70; P < .0001 53
MR4
50; P < .0001
44; P < .0001 26
MR4.5
32; P < .0001
28; P = .0003 15
3-mo landmark analysis: BCR-ABL transcript levels*, % MMR by 1 yr/2 yrs, %
≤ 1% (n = 120, 123, 41)
76/89
72/91
71/78
> 1 to ≤ 10% (n = 89, 95, 133)
40/67
38/54
31/52
> 10% (n = 24, 28, 88)
4/29
14/29
2/20
Freedom from progression to AP/BC, %
Estimated 3-yr rate on core treatment
99.3; P = .0059
98.7; P = .0185
95.2
Including events after discontinuation
96.7; P = .0496
98.1; P = .0076
93.5
OS, %
Estimated 3-yr OS rate
95.1; P = .4413
97.0; P = .0639
94.0
Only CML-related deaths
98.1; P = .0356
98.5; P = .0159
Patients with BCR-ABL mutation, n
Any mutation 11 21
T315I 3 2
* Patients with unevaluable/missing PCR assessments at 3 mo, atypical transcripts, or MMR by 3 mo were excluded.

32. ENESTnd 3-Yr Update Hematologic AEs and Biochemical Abnormalities
Grade 3/4 AEs, %
Nilotinib 300 mg BID
(n = 279)
Nilotinib 400 mg BID (n = 277)
Imatinib 400 mg QD (n = 280)
Neutropenia
11.8
10.8
21.4
Thrombocytopenia
10.4
12.3
8.9
Anemia
3.9
4.7
5.7
Lipase increase
7.5
7.9
ALT increase
4.3
9.4
2.5
Total bilirubin increase
0.4
Hyperglycemia
6.1
5.4
AEs, adverse events; ALT, alanine aminotransferase; BID, twice daily; QD, once daily.
Nilotinib Toxicities
Prolongation of QTC and vascular adverse events
Coronary events
Peripheral Arterial Occlusive Disease – PAOD
Larson RA, et al. Leukemia 2012;26; Tasigna prescribing information, 2013; NCCN Guidelines v 32

33. DASISION 3-Yr Update Cumulative Molecular Responses
Outcome, %
Dasatinib 100 mg QD (n = 259)
Imatinib 400 mg QD (n = 260)
Cumulative MMR
1 yr
46* 23
2 yrs
64* 46
3 yrs
68* 55
Cumulative MR4
35† 22
Cumulative MR4.5
22‡ 12
*P < vs imatinib. †P = vs imatinib. ‡P = vs imatinib.
OS and PFS
3-Yr Survival Outcome
Dasatinib (n = 259)
Imatinib (n = 260)
HR (95% CI)
PFS, %
91.0
90.9
1.00 ( )
OS, %
93.7
93.2
0.86 ( )
Deaths, n 17 20 -
Hochhaus A, et al. ASCO Abstract 6504.

34. DASISION 3-Yr Update Hematologic AEs and Biochemical Abnormalities
Toxicities
Grade 3/4 AEs, %
Dasatinib 100 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
Neutropenia
24.0
20.9
Thrombocytopenia
19.4
11.2
Anemia
11.6
8.5
Decreased phosphorus
7.0
28.3
Decreased calcium
3.1
1.9
Elevated creatinine
1.2
0.8
Elevated total bilirubin
Elevated ALT
0.4
1.6
Elevated AST
Decreased potassium
2.3
Impaired platelet aggregation and bleeding
Pleural effusion (up to 29% of pts)
Reversible pulmonary arterial HTN
Dose interruption in 83% of pts
Dose reduction in 71% of pts
AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; QD, once daily.
Hochhaus A, et al. ASCO Abstract 6504; Sprycel Prescribing information 2013; NCCN Guidelines v 34

35. Case 1 (continued)
The patient responded rapidly to imatinib with resolution of his symptoms: weight gain and splenomegaly.
The WBC returned to normal as did the platelet count, and the anemia resolved.
Repeat quantitative bcr-abl test after 3 months of treatment revealed bcr-abl/abl ratio by international scale of 11%.
A FISH test for bcr-abl was 22% positive.
With these improved results the physician elected to continue imatinib at 400 mg daily.
NCCN Guidelines v4.2013

36. Case 1: Question 2 Is continuation of imatinib an appropriate option?
No, the patient failed to achieve a bcr-abl/abl ratio of <10% and should be a candidate for allogeneic bone marrow transplant.
It is the correct treatment. The patient has achieved a hematologic response and a partial cytogenetic response
The response is inadequate and the patient should have been switched to a 2nd generation TKI inhibitor, either nilotinib or dasatinib
A mutation analysis should have been performed first and if there was no bcr-abl mutation, then the decision to continue with the same treatment could have been made
NCCN Guidelines v4.2013

37. Case 1: Answer Is continuation of imatinib an appropriate option?
No, the patient failed to achieve a bcr-abl/abl ratio of <10% and should be a candidate for allogeneic bone marrow transplant.
It is the correct treatment. The patient has achieved a hematologic response and a partial cytogenetic response
The response is inadequate and the patient should have been switched to a 2nd generation TKI inhibitor, either nilotinib or dasatinib
A mutation analysis should have been performed first and if there was no bcr-abl mutation, then the decision to continue with the same treatment could have been made
Patients with more than 10% bcr-abl/abl ratio are at a higher risk of progression and have a lower chance to achieve MMR at 12 months. NCCN Guidelines suggest treatment switch which involves 2nd generation TKI’s or dose escalation of imatinib. Bcr-abl mutation analysis can be performed at that stage and if mutations are detected this can served as a guide for treatment choices.
NCCN Guidelines v4.2013

38. Case 1 (continued)
After six months of therapy the patient started to complain of worsening diarrhea – up to 6x daily, poorly controlled with Imodium.
The patient states that it has been embarrassing at times because of an inability to control it and that it is interfering with his work and social activities.
At this juncture the hematologist lowered the imatinib to 200 mg daily

39. Adverse Event Management: Diarrhea
Imatinib’s most frequently reported drug-related adverse events were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash
Important to listen to patients and acknowledge that diarrhea can be debilitating and may seriously affect their daily activities.
Physicians should discuss diet and explain to patients that certain foods, like spicy ones, can worsen diarrhea.
Patients should be prescribed anti-diarrheal medications as needed.
TKI dosage should be adjusted accordingly.
Gleevec prescribing information 2013; DeAngelo, 2012; Kurtin, 2010.

40. NCCN Guidelines for CML Treatment Continuation or Change
Time
Response
Recommendation
3 mo.
Bcr/abl: ≤ 10 %
Continue treatment
Bcr/abl: > 10%
Evaluate compliance ; Mutation Analysis; Change Therapy
12 mo.
CCYR
Continue Treatment
≤ PCYR
Evaluate compliance ; Mutation Analysis; Change Therapy /Evaluate for HSCT
18 mo.
NCCN Guidelines v4.2013

41. Case 1: Outcome
The patient continued on imatinib 200 mg daily for an additional 9 months.
At 12 months was found to be in hematologic response and partial cytogenetic response.
Overall, he tolerated this change in treatment reasonably well and his diarrhea was moderately well controlled.

42. Clinical Case Discussions
Case 2: Relapsed/Refractory Setting

43. Case Study 2
A 54-year old man has been receiving therapy with imatinib 400 mg daily for 6 months. Cytogenetic analysis shows Philadelphia chromosome in 25% of metaphases.
Question 1
How would you label this response:
Failure
Secondary resistance
Suboptimal response
Optimal response
Warning
None of the above

44. Case Study 2: Answer How would you label this response: Failure
Secondary resistance
Suboptimal response
Optimal response [ELN 2009 criteria]
Warning [ELN 2013 criteria]
None of the above
Answer = 4; Optimal Response
[per ELN 2009 criteria for failure and suboptimal response]
Answer = 5; Warning
[per ELN 2013 criteria for failure and suboptimal response]

45. Criteria for Failure and Suboptimal Response to Imatinib – ELN 2009
Time (mo)
Response
Failure
Suboptimal
Optimal 3
No CHR
No CgR
>95% Ph+
≤65% Ph+ 6
>35% Ph+
≤35% Ph+ 12
1-35% Ph+
CCgR
0% Ph+ 18
≥5% Ph+
No MMR
MMR
Any
Loss of CHR;
Loss of CCgR;
Mutation;
CCA/Ph+
Loss of MMR;
Mutation
Stable or improving MMR
Acronyms: Ph = Philadelphia chromosome; CHR = complete hematologic response; CgR = cytogenetic response; MMR = major molecular response; CCgR = complete cytogenetic response; CCA = clonal chromosome abnormalities.
Baccarani et al. JCO 2009; 27:

46. Criteria for Failure and Suboptimal Response to Imatinib – ELN 2013
Time (mo)
Response
Failure
Warning
Optimal 3
No CHR,
and/or
Ph+ >95%
BCR-ABL1 >10%,
Ph %
BCR-ABL ≤10%,
Ph+ ≤35% 6
BCR-ABL1 >10%
Ph+ >35%
BCR-ABL1 1-10%,
Ph+ 1-35%
BCR-ABL <1%,
Ph+ 0% 12
BCR-ABL1 >1%
Ph+ >0%
BCR-ABL1
>0.1-1%
≤0.1%
Any
Loss of CHR
Loss of CCgR
Confirmed loss of MMR
Mutations
CCA/Ph+
CCA/Ph-
(-7, or 7q-)
BCR-ABL1 ≤0.1%
Acronyms: Ph = Philadelphia chromosome; CHR = complete hematologic response; CgR = cytogenetic response; MMR = major molecular response; CCgR = complete cytogenetic response; CCA = clonal chromosome abnormalities.
Baccarani et al. Blood 2013; 122: Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY.

47. Case Study 2: Question 2
The patient has occasional muscle cramps, and no other toxicity. Your treatment recommendation:
Continue therapy unchanged
Increase the dose of imatinib to 400mg BID
Change therapy to nilotinib 400mg BID
Change therapy to dasatinib 100mg QD
SCT

48. Case Study 2: Answer
The patient has occasional muscle cramps, and no other toxicity. Your treatment recommendation:
Continue therapy unchanged
Increase the dose of imatinib to 400mg BID
Change therapy to nilotinib 400mg BID
Change therapy to dasatinib 100mg QD
SCT
Answer = 1; Continue therapy unchanged

49. Treatment Discontinuation for Frontline TKIs in CML
Percentage
F/U
(mo)
IM400
IM800
Nilotinib
Dasatinib
Bosutinib
ENESTnd*¥
>36 38 29
DASISION 31 30
BELA
>24 37
MDACC 24 18 8
We also compared the incidence of treatment discontinuation among the different therapies. In the large randomized studies, 20-25% of patients have been reported to have discontinued therapy by approximately 2 years. We analyzed the incidence of and reasons for treatment discontinuation for each arm within the first THREE years. We included treatment discontinuation due to any cause including: insurance issues, non-compliance, toxicity, or loss to follow up. Twenty-nine percent of patients had discontinued standard dose imatinib by 3 years, with failure being a prominent reason. Twenty-four percent had discontinued imatinib800 by 3 years; but there was no difference in the rate of discontinuation for toxicity in comparison to the lower standard dose of imatinib 400. Fewer of our patients discontinued dasatinib and nilotinib, even when considering the significant percentage that discontinued because of insurance and personal reasons. Personal reasons included the fear that these options were too experimental back in 2005.
* Nilotinib 300mg BID shown.
¥ Includes patients who discontinued into extension study; rates are 26% imatinib and 22% nilotinib if all excluded
Alattar et al. ASH 2011; Abstract #745; Saglio et al. ASH 2011; Abstract #452; Kantarjian et al. ASCO 2011; Abstract #6510; Cortes et al. ASH 2011; Abstract #455

50. Factors Influencing Early Discontinuation of 2nd Generation TKI
Adverse events
Lack of efficacy
Availability of alternative options
Decrease tolerance to adverse events
Unreasonable expectations regarding toxicity
Suboptimal management of AEs
Lack of familiarity
Baccarani et al. Blood 2013; 122:

51. Case Study 2: Question 3 Question 3
The patient has been on imatinib therapy now for 48 months. He had achieved an MMR (BCR-ABL/ABL <0.1% IS) that had been sustained for the last 18 months, most recently at 0.05 at 36 months and 0.03 at 42 months. A routine follow up assessment shows a normal CBS with a BCR-ABL/ABL of 0.09.
Question 3
What additional tests would you request:
Obtain FISH
Repeat PCR in 3 months
Assess for mutations
Repeat cytogenetic analysis
Perform a bone marrow aspiration
All of the above
1 & 3
3 & 5

52. Case Study 2: Answer What additional tests would you request:
Obtain FISH
Repeat PCR in 3 months
Assess for mutations
Repeat cytogenetic analysis
Perform a bone marrow aspiration
All of the above
1 & 3
3 & 5

53. Significance of KD Mutations in Patients Responding to Imatinib
PFS by Mutation at 2 Yrs
10 of 214 (5%) pts who achieved CCyR had mutation
4 before CCyR
Median time from mutation to loss CCyR 20.7 months
Median time from detection of mutation to 2-fold  PCR 12 mo
KD mutation predictive of loss of CCyR
Reprinted with permission. © (2013) American Society of Clinical Oncology.  All rights reserved.  Khorashad, JS et al: J Clin Oncol 26(29):

54. When to Look For Mutations?
Mutation analysis in 1301 pts receiving imatinib or 2nd generation TKI (GIMEMA)
Clinical condition
% Positive
Failure 27
No 3 mo 19
No 6 mo 11
No 12 mo 17
No 18 mo
Loss CCyR 31
Loss CHR 50
Suboptimal 5
No 3 mo 7
No 6 mo
No 12 mo 8
No 18 mo
Loss MMR 4
Soverini et al. ASH 2011; Abstract #112

55. Molecular Response in CML TFS and OS by MR at 24 months
Survival (%)
Response
Total
AP/BP
P-value (vs. UND) 66 1
n/a
113
.25 37
.38 72
.33 25
.56
Response
Total
Died
P-value (vs. UND) 66 3
n/a
113 4
.89 37 2
.94 72
.70 25
.22
Time (months)
Falchi et al. Am J Hematol 2013: (In press)

56. Criteria for Failure and Suboptimal Response to Imatinib – ELN 2013
Time (mo)
Response
Failure
Warning
Optimal 3
No CHR,
and/or
Ph+ >95%
BCR-ABL1 >10%,
Ph %
BCR-ABL ≤10%,
Ph+ ≤35% 6
BCR-ABL1 >10%
Ph+ >35%
BCR-ABL1 1-10%,
Ph+ 1-35%
BCR-ABL <1%,
Ph+ 0% 12
BCR-ABL1 >1%
Ph+ >0%
BCR-ABL1
>0.1-1%
≤0.1%
Any
Loss of CHR
Loss of CCgR
Confirmed loss of MMR
Mutations
CCA/Ph+
CCA/Ph-
(-7, or 7q-)
BCR-ABL1 ≤0.1%
Baccarani et al. Blood 2013; 122:

57. Criteria for Failure and Suboptimal Response to Imatinib – ELN 2013
Time (mo)
Response
Failure
Warning
Optimal 3
No CHR,
and/or
Ph+ >95%
BCR-ABL1 >10%,
Ph %
BCR-ABL ≤10%,
Ph+ ≤35% 6
BCR-ABL1 >10%
Ph+ >35%
BCR-ABL1 1-10%,
Ph+ 1-35%
BCR-ABL <1%,
Ph+ 0% 12
BCR-ABL1 >1%
Ph+ >0%
BCR-ABL1
>0.1-1%
≤0.1%
Any
Loss of CHR
Loss of CCgR
Confirmed loss of MMR
Mutations
CCA/Ph+
CCA/Ph-
(-7, or 7q-)
BCR-ABL1 ≤0.1%
Lack of MMR is not a criterion for failure; confirmed loss of MMR is
Baccarani et al. Blood 2013; 122:

58. Criteria for Failure and Suboptimal Response to Imatinib – ELN 2013
Time (mo)
Response
Failure
Warning
Optimal 3
No CHR,
and/or
Ph+ >95%
BCR-ABL1 >10%,
Ph %
BCR-ABL ≤10%,
Ph+ ≤35% 6
BCR-ABL1 >10%
Ph+ >35%
BCR-ABL1 1-10%,
Ph+ 1-35%
BCR-ABL <1%,
Ph+ 0% 12
BCR-ABL1 >1%
Ph+ >0%
BCR-ABL1
>0.1-1%
≤0.1%
Any
Loss of CHR
Loss of CCgR
Confirmed loss of MMR
Mutations
CCA/Ph+
CCA/Ph-
(-7, or 7q-)
BCR-ABL1 ≤0.1%
Lack of MMR represents warning; lack of CMR is neither loss nor warning
Baccarani et al. Blood 2013; 122:

59. Case Study 2: Question 4
Six years after the start of therapy, on a routine follow-up assessment you find the BCR-ABL/ABL has increased to 27.3% (IS). You perform a bone marrow and confirm that the patient is still in chronic phase but has 75% Ph+ metaphases. A mutation analysis shows a mutation F317L.
Question 4
Your choice now is:
Increase the dose of imatinib to 400mg BID
Change therapy to nilotinib 400mg BID
Change therapy to dasatinib 100mg QD
Change to bosutinib 500 mg BID
Change to ponatinib 45 mg daily
Proceed to SCT

60. Case Study 2: Answer Your choice now is:
Increase the dose of imatinib to 400mg BID
Change therapy to nilotinib 400mg BID
Change therapy to dasatinib 100mg QD
Change to bosutinib 500 mg BID
Change to ponatinib 45 mg daily
Proceed to SCT

61. 2nd Generation TKI in CML
Parameter
Dasatinib
Nilotinib
Bosutinib
Potency (fold vs IM)
325 30
20-50
Target
Src & Abl
Abl
Src & ABL
BCR-ABL binding
Active + Inactive
Inactive
Intermediate
Resistant mutations
T315I
Mutations with intermediate sensitivity
E255K/V, V299L, F317L
E255K/V, Y253F/H, Q252H, F359V
E255V/K,
V299L, F317L
Standard dose (CP)
100mg QD
400mg BID
500mg QD
Grade 3-4 neutropenia & thrombocytopenia
33% / 22%
31% / 33%
12% / 21%
Other notable toxicities
Pleural effusion, bleeding
Bilirubin, lipase elevation
Diarrhea, rash
C-kit inhibition (vs imatinib)
Increased
Similar
None
PDGFR inhibition (vs imatinib)
Clinical activity
Highly active
Sprycel®, Tasigna®, Bosulif® prescribing information (2013).

62. 2nd Generation TKI in CML CP Post-Imatinib Resistance
Response
Percentage
Dasatinib
Nilotinib
Bosutinib
FU (mo)
>24
24*
CHR 89 77 86
MCyR 59 56 54
CCyR 44 41
24 mo PFS**
80%
64%
79%
24 mo OS**
91%
87%
92%
* Median
** All patients
Shah et al. Haematologica 2010; 95: ; Kantarjian et al. Blood 2011; 117: ; Cortes et al. Blood 2011; 118;

63. 2nd Generation TKI in CML CP Post-Imatinib Intolerance
Response
Percentage
Dasatinib
Nilotinib
Bosutinib
CHR
100 NR 85
MCyR 77 66 49
CCyR 67 51 41
Shah et al. Haematologica 2010; 95: ; Kantarjian et al. Blood 2011; 117: ; Cortes et al. Blood 2011; 118;

64. 2nd-Generation TKI in CML CP Post- Imatinib Failure
Toxicity
Dasatinib
Nilotinib
Bosutinib
Pleural effusion ++ -
Liver +
Transaminases
Bilirubin
Rash
Diarrhea
Lipase
- (+)
Glucose
Hypophosphatemia
Bleeding
QTc

65. 2nd-Generation TKI in CML CP Post- Imatinib Failure
Toxicity
Dasatinib
Nilotinib
Bosutinib
Anemia 13 11
Neutropenia 35 31 18
Thrombocytopenia 23 30 24
Shah et al. Haematologica 2010; 95: ; Kantarjian et al. Blood 2011; 117: ; Cortes et al. Blood 2011; 118;

66. Sensitivity of Mutations to TKI
IC50-fold increase (WT=1)
Imatinib
Bosutinib
Dasatinib
Nilotinib WT 1
L248V
3.54
2.97
5.11
2.80
G250E
6.86
4.31
4.45
4.56
Q252H
1.39
0.31
3.05
2.64
Y253F
3.58
0.96
1.58
3.23
E255K
6.02
9.47
5.61
6.69
E255V
16.99
5.53
3.44
10.31
D276G
2.18
0.60
1.44
2.00
E279K
3.55
0.95
1.64
2.05
V299L
1.54
26.10
8.65
1.34
T315I
17.50
45.42
75.03
39.41
F317L
2.60
2.42
4.46
2.22
M351T
1.76
0.70
0.88
0.44
F359V
2.86
0.93
1.49
5.16
L384M
1.28
0.47
2.21
2.33
H396P
2.43
0.43
1.07
2.41
H396R
3.91
0.81
1.63
3.10
G398R
0.35
1.16
0.69
0.49
F486S
8.10
2.31
3.04
1.85
Highly Resistant / Resistant / Sensitive
Redaelli et al. JCO 2009; 27:

67. CCyR by Mutations in CML Treated with 2nd Generation TKI after IM Failure
86/169 (51%) pts treated had mutation
CP 30/59 (51%), AP 41/71 (58%), BP 15/39 (38%)
IC50 for mutation with dasatinib, nilotinib predictive for response in CP and AP
Chronic Phase
Accelerated Phase
Jabbour et al, Blood 2009; 114: Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY.

68. Case Study 2: Question 5
The patient has received nilotinib for 12 months with no cytogenetic response. You elect now to:
Continue therapy unchanged
Change therapy to dasatinib 100mg QD
Change therapy to bosutinib 500 mg QD
Change therapy to ponatinib 45 mg QD
Change to omacetaxine
SCT

69. Case Study 2: Answer
The patient has received nilotinib for 12 months with no cytogenetic response. You elect now to:
Continue therapy unchanged
Change therapy to dasatinib 100mg QD
Change therapy to bosutinib 500 mg QD
Change therapy to ponatinib 45 mg QD
Change to omacetaxine
SCT
Answer = 4, 5, 6

70. Survival free from transformation
Are Responses Less Than CCyR Clinically Meaningful in 2nd Line Therapy for CML?
165 pts treated with ≥2nd line TKI after imatinib failure
Best response: CCyR 52%, PCyR 7%, mCyR 14%, CHR 14%, no response 17%
Overall responses
Survival
Survival free from transformation %
95% C.I.
CCyR 98
94-100 95
90-100
PCyR 89
71-100 73
47-100
MinCyR 85 84
69-100
CHR only 72
52-100 88
67-100
No response 67
45-100 NA
Responses inferior to CCyR still confer a long-term clinical benefit to patients treated with ≥2nd line TKI in CML CP compared to no response
Cortes et al. Clin Lymphoma Myeloma Leuk 2011; 11: 421-6

71. Response to Bosutinib 3rd Line Therapy
114 pts who failed imatinib (600mg) & dasatinib or nilotinib
Minimum 24 mo F/U
Response, %
IM + D
resistant
(n = 37)
intolerant
(n = 49)
IM + NI
(n = 27)
CHR 62 80 76
MCyR 33 48 39
CCyR 19 43 27
PCyR 14 5 12
MMR 3 25 11
2-yr progression or death 21 49
IM, imatinib; D, dasatinib; NI, nilotinib.
Khoury et al. ASH 2012; Abstract #3785

72. Ponatinib Phase 2 Study - PACE Response Characteristics CP-CML
93% failed ≥2 TKI, 58% failed ≥3 TKI
Response Rate, n (%)
N=267
Any Cytogenetic Response
180 (67)
MCyR
149 (56)
CCyR
124 (46)
MMR
91 (34)
MR4.5
39 (15)
BCR-ABL ≤10% at 3 months, n/N(%)
142/240 (59)
1 prior approved TKI
14/16 (88)
Median Time to Response*, months [range]
2.8 [1.6 – 11.3]
5.5 [1.8 – 19.2]
91% MCyR sustained at 12 months (K-M)
Cortes et al. ASH 2012; Abstract #163

73. Omacetaxine for CML CP After Failure to ≥2 TKI
122 pts with CML CP (n=81) or AP (n=41) with ≥2 prior TKI
Omacetaxine 1.25 mg/m2 BID x14d, then x7d
Response, % CP
N=81 AP
N=41
Primary endpoint
MCyR 20%
MaHR 27%
CCyR 10%
CHR 24%
Median duration, mo
17.7 9
Median PFS, mo
9.6
4.7
Median OS, mo
33.9 16
11 pts (9 CP, 2 AP) ongoing response
Median 35 cycles over median 39 months
Median response duration: 14 mo CP, 24 mo AP
Cortes et al. Clin Lymphoma Myeloma Leuk 2013 [Epub ahead of print] 73

74. Management of Failure After TKI
Close monitoring per standard recommendations (ELN) required
Indication to change therapy when failure (not warning/suboptimal)
Mutation analysis when failure; informative in some patients
Avoid rapid succession of TKI
Manage adverse events effectively
Consider all your options

75. Participant Post-activity Survey
Please remove the Participant Post-survey & CME Evaluation from the end of your packet
By completing both the Pre- and Post-survey forms, you will help provide benchmarks and feedback that are vital to our understanding of the effectiveness of this CME program, and will help shape future educational activities and topics

76. Post-activity Survey
Please fill in the most appropriate answer(s) for the questions below:
Degree:  MD/DO  Nursing Professional  PharmD  Other: _____________________________
Specialty:  Oncology/Hematology  Transplant specialist  Internal Medicine  Other: ___________
Approximately, how many patients with CML do you treat/diagnose every month? _________

77. Post-activity Survey Question 1
As a result of attending the educational activity, please rate your level of confidence in treating and managing patients with CML: Not confident Expert

78. Post-activity Survey Question 2
As a result of attending the educational activity, please rate your level of competence in individualizing treatment options for patients with CML based on patient and disease characteristics: Not competent Expert

79. Post-activity Survey Question 3
Six years after starting imatinib, a 53-year-old patient’s BCR-ABL/ABL has increased to 27.3%. After performing a bone marrow biopsy, the patient is still in chronic phase, has 75% Ph+ metaphases and an F317L mutation. The patient receives nilotinib at 400mg for 12 months after which there is no cytogenetic response. The most suitable option for this patient would be to:
Continue therapy unchanged
Consider ponatinib, omacetaxine, or SCT
Consider bosutinib or dasatinib
None of the above, enroll in a clinical trial
Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

80. Post-activity Survey Question 4
A 37-year-old male was diagnosed with CML and treated with imatinib 400 mg for 12 months. He was re-evaluated and found to be in hematologic and partial cytogenetic response. Which of the following options would NOT be appropriate at this point:
Repeat mutational analysis
Switch therapy
Check patient’s compliance with medications
Continue treatment
None of the above
Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

81. Post-activity Survey Question 5
Cytogenetic analysis at 6 months of a 45-year-old female patient, who received prior imatinib, shows Philadelphia chromosome in 45% of metaphases and a BCR-ABL/ABL of According to the European LeukemiaNet recommendations for the management of CML, how would you characterize this response.
Failure
Warning
Suboptimal response
Optimal response
Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

82. Post-activity Survey Question 6
Which of the following treatment options can be considered for a patient who has failed imatinib and dasatinib or nilotinib:
Omacetaxine
Bosutinib
Ponatinib
Any of the above
Please do not discuss the answers at this point as we would like to analyze any improvements in learning from the pre-program survey to the post-program survey.

83. Thank you for joining us today!
Please remember to turn in your evaluation form.
Your participation will help shape future CME activities.