1. Michael J. Mauro MD
Updates from ASH 2010: Second and Third Generation TKIs for CML Compound-Specific Toxicities of TKIs in CML

2. IRIS 8-Year Update – 37%* Unacceptable Outcome
Main Causes of Treatment Failure With Imatinib
Primary resistance
Secondary resistance
Progression to AP/BC
Toxicities/chronic AEs
Deininger M et al. Blood. 2009;114(22):462. Abstract # 1126. 2

3. Annual Event Rates: Imatinib Arm
Loss of CHR
Loss of MCyR
AP/BC
Death during treatment
AP/BC
Estimated EFS at 8 years = 81%
1 progression to AP/BC and 2 non–CML-related deaths occurred in year 8
Deininger M et al. ASH 2009, Poster 1126.

4. Study Design and Endpoints in ENESTnd
Randomized*
N=846
217 centers
35 countries
Nilotinib 300 mg BID, n=282
Nilotinib 400 mg BID, n=281
Imatinib 400 mg QD, n=283
Follow-up 5 years
The results reported here are for 846 patients with at least 12 months of follow-up
The hypothesis was that nilotinib (300 or 400 mg BID) has a significantly greater MMR rate at 12 months compared to imatinib 400 mg QD
Rationale for 300mg BID arm:
Similar AUC and Cmin between 300 mg BID and 400 mg BID
If taken with food, 300 mg BID and 400 mg BID
Predicted to have a lower Cmax
Reduced risk of QTcF prolongation
Molecular response was assessed by RQ-PCR at baseline, monthly for 3 mos and every 3 mos thereafter. Samples were analyzed at a central PCR laboratory and in duplicate.
The assumed MMR rates were 40% vs 55% (90% power to detect this difference) and required 771 patients
Enrollment ended 30-Sep-08. Due to overwhelming response, overenrollment occurred and 846 pts were randomized (100 pts recruited in last 15 days in Sep08)
Study not designed for formal comparisons between nilotinib arms
Randomization was startified by Sokal risk group
ECG and echocardiograms were followed prospectively in all patients in all treatment arms on study
Primary endpoint: MMR at 12 months
Key secondary endpoint: durable MMR at 24 months
Other endpoints: CCyR by 12 months, time to MMR and CCyR, EFS, PFS, time to AP/BC on study treatment, OS including follow-up
*Stratification by Sokal risk score.
Hughes T et al. ASH 2010, Abstract #207.

5. Patient Disposition in ENESTnd
Nilotinib 300 mg BID
n=282
Nilotinib 400 mg BID
n=281
Imatinib 400 mg QD
n=283
Still on treatment, % 74 78 67
Discontinued, % 26 22 33
Disease progression*
<1 1 4
Suboptimal response/treatment failure*† 9 2 13
Adverse events 6 10
Abnormal laboratory values 3
Death
Protocol violation
Other reason
Overall, 80% and 81% of patients remained on study in the nilotinib 300 mg BID and 400 mg BID arms, while 75% of patients remained on the imatinib arm
Thus, more patients discontinued imatinib (25%) compared with nilotinib 300 mg BID (20%) or 400 mg BID (19%)
Importantly, more patients discontinued imatinib due to disease progression to AP/BC, and suboptimal response or treatment failure as defined by the ELN
Discontinuation due to adverse events or laboratory abnormalities was lowest for nilotinib 300 mg BID
*Investigator assessment of criteria.
†Patients with suboptimal response were required to discontinue nilotinib 300 mg BID, while those receiving nilotinib 400 mg BID could remain on study
Data cut-off: 20Aug2010.
Hughes T et al. ASH 2010, Abstract #207. 5

6. Cumulative Incidence of MMR* in ENESTnd
% With MMR 3 6 9 12 15 18 21 24 27 30 33 n
Nilotinib 300 mg BID 282
Nilotinib 400 mg BID 281
Imatinib 400 mg QD 283
By 12 months
55%, P<0.0001
By 24 months
71%, P<0.0001
67%, P<0.0001
44%
27%
51%, P<0.0001
Δ 24%-28%
Δ 23%-27%
Time Since Randomization (Months)
Data cut-off: 20Aug2010.
*ITT population.
Hughes T et al. ASH 2010, Abstract #207.
100 90 80 70 60 50 40 20 10

7. CCyR Rates* by 24 Months in ENESTnd
P=0.0018
P=0.016
n=282
n=281
n=283
Data cut-off: 20Aug2010.
*ITT population.
Hughes T et al. ASH 2010, Abstract #207.

8. Progression to AP/BC* in ENESTnd
0.7%
1.1%
4.2%
n=282
n=281
n=283
Progression-free survival: 98.0% with nilotinib 300 mg BID, 97.7% with nilotinib 400 mg BID, and 95.2% with imatinib 400 mg QD (NS)
Data cut-off: 20Aug2010.
*ITT population.
Hughes T et al. ASH 2010, Abstract #207. 8

9. Overall Grade 3/4 Myelosuppression Any Time on Study in ENESTnd
Overall, grade 3/4 myelosuppression was low across all arms
Grade 3/4 neutropenia and anemia were higher for imatinib, whereas thrombocytopenia was higher for nilotinib
All newly occurring grade 3/4 hematologic laboratory abnormalities occurred within the first 2 months of therapy for all arms
Overall, grade 3/4 laboratory abnormalities were uncommon for all arms
Data cut-off: 20Aug2010.
Hughes T et al. ASH 2010, Abstract #207.

10. Study Drug-Related Nonhematologic Adverse Events (≥10% in Any Group) in ENESTnd
% of Patients Treated
Nilotinib 300 mg BID
n=279
Nilotinib 400 mg BID
n=277
Imatinib 400 mg QD
n=280
All Grades
Grade 3/4
Nausea 14
<1 21 1 34
Diarrhea 8 7 26
Vomiting 5 9 18
Peripheral edema 6 15
Facial edema 2 11
Eyelid edema 16
Periorbital edema
Muscle spasms 27
Rash 32 37 3 13
Headache 22
Pruritus
Alopecia
Myalgia 10
Fatigue
Data cut-off: 20Aug2010.
Hughes T et al. ASH 2010, Abstract #207. 10

11. QTcF Changes in ENESTnd
% of Patients
Nilotinib 300 mg BID
n=279
Nilotinib 400 mg BID
n=277
Imatinib 400 mg QD
n=280
QT >500 msec
QTcF increase from baseline
>60 msec
<1*
Maximum QTcF increase from baseline, msec
10.4
12.4
7.3
All maximum changes occurred within 6 months of therapy initiation
3 drug-related events of syncope: 1 patient in each arm; not attributed to QT prolongation
No episode of torsades de pointes or sudden death
At the 24-month data cut-off, 1 patient in the imatinib arm had a QTcF >500 msec, but no patient in any of the nilotinib arms had QTcF >500 msec
No patient had a decrease in LVEF <45%
WARNING: QT PROLONGATION AND SUDDEN DEATHS
TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving TASIGNA. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, as well as following any dose adjustments.
*Not associated with clinical signs or symptoms of arrhythmia.
Larson RA et al. ASH 2010, Abstract 2291.
Hughes T et al. ASH 2010, Abstract 207.
TASIGNA PI 2010. 11 11 11

12. GIMEMA* (CML0307): Study Design
Open-label, multicenter, phase 2
Nilotinib 400 mg twice daily
Endpoints
Primary
CCyR rate at 1 year
Secondary
Molecular response
Rosti G et al. ASH 2010, Abstract 359.

13. GIMEMA* 3-Year Update: Complete Cytogenetic Response Rates
Only 1 patient had a confirmed loss of CCyR
N=73 (ITT)
Months
Rosti G et al. ASH 2010, Abstract 359.

14. GIMEMA 3-Year Update: Survival Rates
Overall Survival
Progression-Free Survival
100 80 60 40 20 12 24 36
100 80 60 40 20 12 24 36
97%
97%
Total, n 73
Progressions, n 1
Unrelated death
Total, n 73
Deaths, n 2
Failure-Free Survival
Event-Free Survival
100 80 60 40 20 12 24 36
100 80 60 40 20 12 24 36
97%
91%
Total, n 73
Failures, n 1
Unrelated death
Total, n 73
Events, n 6
Failures: 2009 ELN criteria.
Events: failure, or treatment discontinuation for any reason.
Rosti G et al. ASH 2010, Abstract 359. 14

15. Summary of GIMEMA 3-Year Update
Only 1 patient with a progression at 3 years
Molecular responses are stable after a median follow-up of 3 years
CMR (≤0.01%) by 36 months is 57%
Nilotinib (400 mg BID) safety profile unchanged with longer follow-up
Tolerability with nilotinib 400 mg BID improves over time; 92% of patients remain on nilotinib
Supports importance of maintaining planned starting dose
Nilotinib continued to have significant activity in the frontline treatment of patients with CML-CP, with a CCyR rate of 92%, an MMR rate of 82%, and a CMR rate of 12% at 24 months
Only one patient failed nilotinib and progressed to lymphoid blast crisis (in the first 6 months of therapy)
No patients progressed in the second year of follow-up
All but 5 patients remain on nilotinib, two-thirds on 400 mg twice daily (scheduled dose)
Overall, AEs decreased from month 6 onward
Hematologic toxicity was negligible (very low rates of grade 3/4 events)
Nonhematologic toxicity of grade ≥ 3 was uncommon
Between months 13 and 24, there were no grade 3/4 nonhematologic AEs
There were no grade 4 nonhematologic AEs with nilotinib therapy
Laboratory abrnormalities led to discontinuation in only 3 patients (increased lipase and/or amylase, at 9, 15, and 27 months)
No significant QT prolongation was observed up to 24 months
Nilotinib at 400 mg BID continues to be feasible, safe, and effective in patients with CML in early chronic phase
Reference
Rosti G, et al. Haematologica. 2010;95(s2):459 [abstract 1114] (oral).
Rosti G et al. Haematologica. 2010;95(s2):459 [abstract 1114] (oral). 15

16. Dasatinib Clinical Updates: DASISION 18 month and SWOG-S032516

17. DASISION Study Dasatinib 100 mg QD, n=259
Treatment-naïve Ph+ CML* (N=519)
108 centers
26 countries
Dasatinib 100 mg QD, n=259
Randomize
1:1
Imatinib 400 mg QD, n=260
*Stratified by Hasford score.
Follow-up 5 years
Primary endpoint: confirmed CCyR by 12 months
Secondary endpoints: MMR at any time, time to confirmed CCyR, time to MMR, rates of CCyR (observed at least once in at least 20 metaphase cells) and MMR by 12 months, progression-free survival, and overall survival
Shah et al. ASH 2010, Abstract 206.

18. DASISION Differences Endpoint was confirmed CCyR
Stratified by Hasford score
Exclusion criteria included pleural effusions at baseline
Progression if any of the following occurred:
A doubling of the white-cell count to more than 20×109 per liter in the absence of complete hematologic response (CHR)
A loss of CHR
An increase in Ph-positive bone marrow metaphase cells to more than 35%
Progression to accelerated phase or blastic-phase CML, OR
Death from any cause
Dose reductions or escalations allowed on both treatment arms
Routine chest x-ray at 6 month
Definition of EFS in ENESTnd: The time between randomization and the earliest of the following events on study treatment in the core phase of the study: death due to any cause, progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR.
Kantarjian H et al. N Engl J Med. 2010;362:

19. Patient Disposition and Treatment Discontinuations in DASISION
Treated Patients, n (%)
Dasatinib 100 mg QD
N=259
Imatinib 400 mg QD
N=260
Still on treatment
210 (81)
206 (80)
Discontinued
48 (19)
52 (20)
Progression*
9 (3)
13 (5)
Treatment failure
6 (2)
11 (4)
Adverse event (AE)
16 (6)
Nonhematologic
8 (3)
Hematologic
7 (3)
3 (1)
Unrelated AE
4 (2)
1 (<1)
Death
Other
15 (6)
*Increasing WBC count; loss of CHR; loss of MCyR including 30% rise in Ph+ metaphase cells and additional chromosomal abnormalities; progression to AP/BC.
PFS rates at 18 months were 94.9% and 93.7% for dasatinib and imatinib, respectively
OS rates were 96.0% for dasatinib and 97.9% for imatinib
Shah et al. ASH 2010, Abstract 206. 19

20. Confirmed CCyR in DASISION*
n= n=260
P=0.0086
P=0.0366
* ITT population
Shah et al. ASH 2010, Abstract 206. 20 20

21. MMR Rates (ITT) by Month of Treatment
n= n=260
P<0.0001
Molecular Response (%)
MMR, BCR-ABL <0.1%
Shah et al. ASH 2010, Abstract 206.

22. Transformation to Advanced-Phase CML in DASISION
5 patients who achieved CCyR transformed to AP/BP (2 dasatinib)
No patient who achieved MMR transformed to AP/BP to date
Patients were followed for transformation for up to 60 days after last dose of study drug; clonal evolution without additional criteria for AP was NOT counted as transformation to AP/BC
Shah et al. ASH 2010, Abstract 206. 22 22

23. Grade 3/4 Myelosuppression Any Time on Study: DASISION
Clinician 1
It is well appreciated that dasatinib is consistently associated with significantly more myelosuppression, with no increase in efficacy, when compared to nilotinib in the second and third line settings.
This relatively increased marrow toxicity may well reflect off target kinase inhibition, possibly of kit. Particularly in view of a greater number of deaths on dasatinib than imatinib on the DASISION study a comparison of the rates of myelosuppression between the two randomised studies is of major interest. The differences are quite marked.
At both doses nilotinib therapy was associated with significantly less neutropenia, thrombocytopenia, or anaemia than was seen in patients receiving imatinib therapy.
This situation was markedly different on the DASISION study where with all three cell lines, there was significantly more myelosuppression seen in patients receiving dasatinib. Whether this excess of myelosuppression was directly associated with the deaths seen in patients receiving dasatinib is a very important clinical issue.
The fact that nilotinib was associated with the achievement of highly statistically significant increased rates of major molecular responses but with less myelosuppression is a major clinical interest.
The fact that dasatinib was associated with what appear to be directly comparable rates of major molecular response and yet no significant protection from disease progression and a trend towards inferior survival when compared with imatinib is perhaps the most clinically important difference between these two prospective randomized studies conducted in patients with front-line disease.
Nearly 75% of cytopenia occurred during the first 4 months of treatment
Grade 3/4 bleeding occurred in 2 dasatinib-treated patients and 3 imatinib-treated patients
Shah et al. ASH 2010, Abstract 206.

24. Drug-Related Nonhematologic AEs (≥10%) in DASISION
% of Patients
Dasatinib
100 mg QD
N=259
Imatinib
400 mg QD
N=260
All Grades
Fluid retention 23 43
Superficial edema 10 36
Pleural effusion 12
Diarrhea 18 19
Rash 11 17
Nausea 9 21
Fatigue 8
Myalgia 22 38
Vomiting 5
Grade 3/4 AEs were infrequent (≤1%) with either treatment
Shah et al. ASH 2010, Abstract 206. 24 24

25. 2-Sided P Value for Evaluable
SWOG-S0325 Dasatinib vs Imatinib in Newly Diagnosed CML Patients: 12-Month Efficacy
% of Patients Treated
Derived ITT*†
Evaluable
Dasatinib 100 mg QD
n=123
Imatinib 400 mg QD
2-Sided P Value for Evaluable
CCyR BY 45 33 82 69
0.097
>3 log AT 47 32 59 43
0.042
>4 log AT 22 15 27 20
0.31
>4.5 log AT 17 11 21 14
0.26
OS AT 12 NA
100 99
0.65
PFS AT 12 96
0.20
*Derived ITT = responders/total patients randomized in each arm.
†Unclear duration of follow-up, missing cytogenetic samples in ~1/3 of patients.
Radich et al. ASH 2010, Abstract LBA-6.

26. SWOG-S0325 Dasatinib vs Imatinib in Newly Diagnosed CML Patients: 12-Month Safety
100 mg QD
n=123
Imatinib
400 mg QD
All grades thrombocytopenia (3/4), %
57 (18)
33 (8)
All grades pleural effusion* (3/4), %
14 (2)
2 (1)
Prolonged QT† (3/4), %
1 (0)
Deaths, n 3 4
CML-related deaths 1 2
Cardiac
Other
*Discontinuation due to pericardial effusion noted in at least 2 patients.
†Grade 3/4 = QTc prolongation >500 msec.
Radich et al. ASH 2010, Abstract LBA-6.

27. Phase 1 Study of Ponatinib: Best Response to Therapy
Median follow-up:
Best Response
Overall
T315I*
Non-T315I
Chronic
(n=38) %
Advanced
(n=17)
(n=9)
(n=5)
(n=29)
(n=12) %)
Hematologic
MHR 95 35
100 20 93 42
Cytogenetic
MCyR 66 24 55 25
CCyR 53 12 89 41 17
Molecular
MMR – 78
Acceptable safety profile at therapeutic dose levels
Pancreatic DLTs at 60 mg
*Includes only those with T315I status confirmed at study entry.
Cortes et al. ASH 2010, Abstract 210.

28. Bosutinib: Response Rates at 12 Months (ITT)
Newly Diagnosed Ph+ CML-CP Patients
CCyR, Primary Endpoint
P=0.601
P=0.002
Gambacorti-Passerini et al. ASH 2010, Abstract 208.

29. TIDEL-II: Selective Escalation of Imatinib Therapy and Early Switching to Nilotinib
67%
TIDEL -II PK
TIDEL-I
TIDEL -II
NIL ü ü
47%
Start Rx with imatinib 600 mg
TIDEL -I
Dose adjust to imatinib 800 mg for failing target ü ü
MMR rates at 12 months
Dose escalate if imatinib <1000 mg, D22 û ü û ü
Allow switch to nilotinib
Yeung DT et al. ASH 2010, Abstract #209.

30. Rates of CCyR and MMR From ENESTnd and DASISION
Nilotinib
300 mg BID
(n=282)
400 mg BID
(n=281)
Imatinib
400 mg QD
(n=283)
MMR, %
by 12 months
by 18 months 55 66 51 62 27 40
CCyR, % 80 84 78 82 65 74
Dasatinib
100 mg QD
(n=259)
Imatinib
400 mg QD
(n=260) 46
n/a 28 77 78 66 70
These data are from separate studies
ENESTnd (18 months)
24% of imatinib patients were dose escalated
Dose escalation was not permitted in nilotinib arms
DASISION (18 months)
15% of imatinib patients were dose escalated
6% of dasatinib patients were dose escalated
Larson RA et al. ASH 2010, Abstract 2291
Kantarjian et al. NEJM. 2010:362;2260. 30

31. Rates of Progression From ENESTnd and DASISION
Nilotinib
300 mg BID
(n=282)
400 mg BID
(n=281)
Imatinib
400 mg QD
(n=283)
AP/BC
n (%)
2 (0.7)
P = 0.006
1 (0.4)
P = 0.003
12 (4.2)
Dasatinib
100 mg QD
(n=259)
Imatinib
400 mg QD
(n=260)
6 (2.3)
P = NS
9 (3.5)
These data are from separate studies
ENESTnd (18 months)
No patient who achieved MMR progressed to AP/BC
4 patients who achieved CCyR on imatinib progressed to AP/BC
DASISION (18 months)
No patient who achieved MMR progressed to AP/BC
5 patients who achieved CCyR on imatinib/dasatinib progressed to AP/BC (2 dasatinib)
Larson RA et al. ASH 2010, Abstract 2291
Kantarjian et al. NEJM. 2010:362;2260. 31

32. generally accepted conclusions regarding CP CML therapy
Nilotinib and Dasatinib both engender more rapid and greater numbers of cytogenetic complete remissions; Bosutinib may as well with less conviction from available data
Molecular response (MMR, CMR) follows thereafter and is greater with 2G TKIs
Much more time is needed to understand ability to permit treatment interruption but optimism runs high
Each drug has a degree of ‘class effect toxicity’ as well as ‘specific toxicities’ of minimal morbidity; some related to response (lymphocytosis)?
Current modus operandi may be to ‘fit the TKI to the patient’- most potent TKI suitable for the patient based on comorbidities and risks, and then tolerable over at least the medium-term

33. The toxicity spectrum of TKIs
Myelosupression
Transaminase 
Electrolyte Δ
QT prolongation
Imatinib:
Edema/fluid retention; myalgias, hypophosphatemia
Dasatinib:
Pleural/pericardial effusions
Bleeding risk
Bosutinib:
Diarrhea/Nausea/Emesis
Rash; ?Pleural effusion
Nilotinib:
Pancreatic enzyme elevation
Indirect hyperbilirubinemia

34. Selected Grade 3/4 Biochemical Abnormalities
ENESTnd:
Selected Grade 3/4 Biochemical Abnormalities
Additional events
between 12 and 24 months 9 8 8 7 6 5
% of Patients 4 4 3 3
< 1
Lipase ↑
ALT ↑
Total bilirubin ↑
Glucose ↑
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207]

35. Nilotinib in CML-CP 2nd line: Cmin and hyperbilirubinemia
Giles F et al, ASH 2010 Abstract #890
100
Median Nilotinib Cmin (ng/mL)
% With Grade 3/4 Bilirubin Elevation 60 40 20
TA(6)/TA(6) or TA(6)/TA(7) ( n = 18) 80
300
400
500
600
700
800
900
1000
TA(7)/TA(7) (n = 48)
Predicted probability at median baseline total bilirubin level 8.55 μmol/L
Higher nilotinib Cmin and Gilbert’s Syndrome ( TA[7]/TA[7] genotype) was associated with higher incidence of grade 3/4 total bilirubin
Hyperbilirubinemia typically occurred early in the course of therapy and was mild, transient, and easily managed with brief dose interruptions1
Only 1 patient (< 1%) discontinued the phase 2 registration study due to hyperbilirubinemia1
As has been observed previously,2 nilotinib-induced hyperbilirubinemia was associated with the TA(7)/TA(7) repeat polymorphism in the UGT1A1 gene
UGT1A1 encodes a key enzyme in bilirubin conjugation, and the TA repeat polymorphism in the promoter of this gene has been associated with hyperbilirubinemia
The association between nilotinib exposure and the TA(7)/TA(7) genotype suggests that nilotinib-induced hyperbilirubinemia is not indicative of liver damage
References
Kantarjian HM, Giles FJ, Bhalla KN, et al. Update on imatinib-resistant chronic myeloid leukemia patients in chronic phase (CML-CP) on nilotinib therapy at 24 months: Clinical response, safety, and long-term outcomes. Blood 2009;114:464.
Singer JB, Shou Y, Giles F, et al. UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia. Leukemia 2007;21:2311–2315.
NIL induced bili associated with the TA(7)/TA(7) repeat in the UGT1A1 gene
UGT1A1 gene TA promoter repeat polymorphism: ‘Gilbert’s (syndrome) gene’

36. Nilotinib in CML-CP 2nd line: Cmin and lipase elevation
Nilotinib Cmin Quartile (ng/mL)
% With Lipase Elevation
All grade incidence 33
Grade 3/4 incidence
100 80 60 40 20 34 50 53 30 10
< 451
39/119
(451,620)
40/118
(620,859)
59/118
≥ 859
63/119 13 14 15 23
16/119
17/119
18/119
27/119
n/N =
P = 0.001
P = 0.193
According to logistic regression analyses, the difference between Q1 and Q4 for all grade abnormalities was statistically significant, but the slope was nearly flat and not thought to be clinically significant
There was no statistically significant relationship between nilotinib Cmin and incidence of Grade 3/4 lipase elevations
Nilotinib-induced lipase elevation is typically asymptomatic and rarely (≤1%) associated with acute pancreatitis
Only 4 (1%) patients discontinued treatment due to lipase elevations or pancreatitis
This asymptomatic adverse event may have little to no clinical relevance
Reference
Kantarjian HM, Giles FJ, Bhalla KN, et al. Update on imatinib-resistant chronic myeloid leukemia patients in chronic phase (CML-CP) on nilotinib therapy at 24 months: Clinical response, safety, and long-term outcomes. Blood 2009;114:464.
Giles F et al, ASH 2010 Abstract #890

37. Phase 1 Study of Ponatinib Dose Escalation
N Patients
Enrolled
Evaluable
w/DLT
DLT Event
2 mg capsules 3 -
4 mg capsules 6
8 mg capsules 7
15 mg capsules 8
30 mg capsules
45 mg capsules 13 12 1
Rash
45 mg tablets 9
Pancreatic
60 mg capsules 4
60 mg tablets 5 2
Fatigue;  ALT
All 74 patients are fully evaluable for DLT at the time of this report and this side shows the accrual of patients per cohort. The 4mg cohort was expanded because a patient experienced erythema nodosum, but this event was later deemed to be an idiosyncratic hypersensitivity reaction. The 8 mg cohort was expanded due to a patient with QT prolongation, although this was considered not related to study drug. No other patient developed any dose limiting toxicity until the 60mg cohort in which 4 patients developed DLT manifested as grade 3 or 4 elevation of lipase and/or amylase in 3 patients, 2 of them associated with grade 2 clinical pancreatitis. Two of the 5 patients treated at the same 60 mg dose with a tablet formulation experienced DLT, one each fatigue and elevation of transaminases. Only one pancreatic DLT event was seen among 25 patients treated with 45 mg capsules or tablets.
Cortes J, ASH 2010 Abstract #210 37

38. Nilotinib in CP-CML 2nd line:
Dose Interruption and time to response (n = 229)
Time to CCyR vs. dose interruption
Time to MMR vs. dose interruption
Cumulative dose interruption:
No interruption
<7 days
7-14 days
days
≥ 28 days
100 6 12 18 24 36 20 40 60 80
100
% Patients with MMR
Time (months)
P = *
P = * 80 60
% Patients with CCyR 40 20 6 12 18 24 36
Time (months)
*Log-rank test
Dose interruptions were 4% of total days of exposure1

39. ENESTnd Substudy: Adverse events in Patients with Type 2 Diabetes
None for ‘diabetes’
Ischemic heart disease (1)
Intestinal obstruction (1) and suicide (1)
Saglio G et al, ASH 2010 Abstract #3430

40. Changes in Parameters related to Glucose Metabolism in ENESTnd
Insulin levels increased in nilotinib arms more than imatinib control arm
No change in HGA1c values
Saglio G et al, ASH 2010 Abstract #3430

41. Hyperglycemia AEs, ENESTnd
Saglio G et al, ASH 2010 Abstract #3430
In Type II Diabetes population (n=57):
change in diabetic regimen on study: 14% in NIL 300 BID, 8% in NIL 400 BID, 4% in IM
no DKA/hyperosmolar events; one gr2 hyperglycemia->hospitalized in NIL 300 BID

42. CCyR by 12 mo: Type II DM versus overall, ENESTnd
Saglio G et al, ASH 2010 Abstract #3430

43. Lymphocytosis with Dasatinib Therapy
Schiffer C et al, ASH 2010 Abstract #358
Persistent expansion of clonal cytotoxic T cells or NK cells has been described in patients with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) receiving dasatinib1
Other small studies have also suggested a relationship between the development of T/NK lymphocytosis with both improved response and some toxicity
A recent analysis of ~1100 CML patients who were resistant to or intolerant of imatinib indicated that lymphocytosis occurred in ~30% of patients in all stages of CML after treatment with dasatinib2
In that analysis, lymphocytosis was associated with improved cytogenetic response and an increased incidence of pleural effusions
1. Porkka K, et al. Cancer 2010;116:377–86. Kruetzman A, et al. Blood 2010;116:
2. Schiffer C, et al ASCO abstract #6553.

44. Lymphocytosis with Dasatinib Therapy
Schiffer C et al, ASH 2010 Abstract #358
Patients enrolled in the DASISION study were retrospectively evaluated for lymphocytosis (N=516)
Lymphocytosis was defined as lymphocytes >3.6 x 109/L on ≥2 occasions after 28 days of treatment
The interval between blood counts was usually between 1-3 months
Immunophenotyping was not done as part of these studies
Rates of complete cytogenetic response (CCyR), major molecular response (MMR), progression-free survival (PFS), and adverse events (AEs) were measured in those with and without lymphocytosis
Statistical comparisons were retrospective and not adjusted for multiple comparisons
Median follow-up was 18 months (Range 0−30)

45. Cumulative Incidence of Lymphocytosis, DAS vs IM
Schiffer C et al, ASH 2010 Abstract #358
100
Dasatinib
26% (68/258)
Imatinib
6% (15/258)
P<0.0001 90 80 70 60
Lymphocytosis (%) 50 40 30 20 10 3 6 9 12 15 18 21 24 27 30 33
Months
SUBJECTS AT RISK DASATINIB IMATINIB
258
229
210
201
195
194
192
190
190
190
190
258
254
248
246
244
243
243
243
243
243
243

46. Cumulative response rates according to presence of lymphocytosis (minimum follow-up 15 months)
Schiffer C et al, ASH 2010 Abstract #358
Lymphocytosis
CCyR
cCCyR
MMR
Dasatinib
Yes
93%
85%
68%
(n=258) No
76%
54%
Imatinib
53%
27%
83%
72%
42%
CCyR=complete cytogenetic response; cCCyR=confirmed CCyR; MMR=major molecular response

47. Landmark analysis of response at 12 months
by presence of lymphocytosis
Schiffer C et al, ASH 2010 Abstract #358
Lymphocytosis by 12 months
cCCyR in
patients on
treatment at 12 months
MMR in
Dasatinib
Yes
26%
86%
56%
(n=225) No
74%
83%
41%
P=0.546
P=0.0496
Imatinib 5%
67%
25%
(n=228)
95%
69%
29%
P=1.0
cCCyR=confirmed complete cytogenetic response; MMR=major molecular response

48. Fluid-related adverse events* *
* 22% vs 9 %, 95% CI 4-24%
No significant difference in other AEs
In dasatinib-treated patients, the incidence of grade 3-4 pleural effusion was 1.5% with lymphocytosis and 0% without

49. QTc prolongation with 2G TKIs in front-line Nilotinib phase II data
ENESTnd DASISION
Nilotinib
300 mg BID
Nilotinib
400 mg BID
Imatinib
400 mg QD
Imatinib
400 mg QD
Dasatinib
100 mg QD
No patients with QTc >500ms
<1% QTc >60ms
No patients with QTc >500ms
<1% QTc >60ms
No patients with QTc >500ms
No patients with QTc >60ms
QTc >500ms in 0.4%
5% QTc >60ms
QTc >500ms in 0.4%
5% QTc >60ms
Nilotinib phase II data

50. QTc and relationship to nilotinib trough concentration
Larson R et al, ASH 2010 Abstract #2291
Nilotinib in CML-CP 2nd Line: Cmin (steady state)
by disease phases
Nilotinib Cmin (ng/mL)*
5000
4000
3000
2000
1000
1165
1190
998.5 CP
n = 200 AP
n = 81 BP
n = 88
Disease Phase
Giles F et al, ASH 2010 Abstract #890

51. Adherence to therapy is step one along the ‘path in CML’
Adherence to prescribed therapy, irrespective of intensity, significantly affects outcome (Ibrahim A et at ASH 2010 Abstract #3414)

52. Toxicity Conclusions I
Elevated bilirubin and pancreatic enzyme elevation with nilotinib appear related to dose/exposure and the former associated with conjugation enzyme polymorphism
Pancreatic enzyme elevation appears to be a class effect
3% in IM treated patients in ENESTnd; never studied with DAS; DLT with ponatinib
Type II DM patients with hyperglycemia but little/no morbidity/SAEs, need for change in glycemic control therapy
QTc prolongation is a class effect seen in a very limited fashion in front-line use of 2G TKIs and is related to dose/exposure of nilotinib

53. Toxicity Conclusions II
Dasatinib associated lymphocytosis appears very common, is associated with pleural effusion and increased MMR
Other phenomenon noted in the literature
LGL lymphocytosis (associated with pleural effusions)
Mustjoki S, et al Leukemia (8):
Colitis
Shimokaze T, et al Hematol Oncol (6):448
Opportunistic infections (EBV, CMV), skin cancers
Sillaber et al. Eur J Clin Invest 39; 1098, 2009

54. What Have We Been Looking for in CML Therapy?
Therapy that is well tolerated
Therapy that engendered key threshold responses at specified time points
The value of “response speed” has been heavily debated
Therapy that would reduce or eliminate relapse and progression events
Likely a host of different events to mitigate
Subverting preexisting “resistance”?
Preventing development of resistance?
Subverting resistance and progression are most crucial
The clinical course of CP CML treated and responsive to initial TKIs is undoubtedly superior to salvage treatment with resistant CP CML and vastly different from AP/BC CML

55. Why Waiting May Be Too Risky
Aside from Sokal or Hasford score, no prognostic tool widely available to sort out who needs more therapy
Treatment at suboptimal response or failure is salvage therapy, and disease biology and long-term outcome may be different
Is there a plateau in PFS curves, and do we know the kinetics of late resistance during treatment with second-generation TKIs?
Narrower/highly resistant spectrum, likelihood of subsequent mutations after initial detection may require third-generation Abl kinase inhibitors (such as AP24534) or more patients moving on to stem cell transplant

56. Reaction to Availability of 2nd-Generation TKIs for Front-Line Use
Without a tool to select patients destined for optimal response to imatinib, second-generation TKIs should be used as primary therapy in CP CML
While more time will add strength to the argument, early difference in PFS in light of depth of response may be quite relevant
“Treating all to benefit a few”?
While this may appear true now, some of the most important questions lie ahead with regard to ability to discontinue therapy and “cure” CML; as the number of patients living with CML grows, the magnitude of this potential increases exponentially

57. Estimate of Rapidly Increasing CML Prevalence
250
200
150
Prevalence of CML
(no. in the United States in thousands)
100
Assuming an incidence of ~5000 cases/year;
mortality of 2% per year;
plateau prevalence = 5000 x 100/2 = 250,000 50
2000
2010
2020
2030
2040
2050
2060
Kindly shared by Hagop Kantarjian, MD, MDACC.

58. Manage After Treatment Failure or Prevent of Treatment Failure
Front-Line Gleevec
Front-Line 2G TKI
The question of how long patients will respond to TASIGNA remains unanswered at this point

59. For the de novo Patient, Treatment Choice Will Be Driven by a Number of Factors
Access
Cost
Patient preference
Physician preference/familiarity
Comorbidities and anticipated toxicity
Tolerability
Response outcome
Remission rates
Duration
Relapse risk

60. Clinical messages in CML must be carefully delivered as we continue to move forward rapidly……
HemOnc today, 11/25/10