Michael J. Mauro MD

Updates from ASH 2010:Second and Third Generation TKIs for CMLCompound-Specific Toxicities of TKIs in CML

Michael J. Mauro MD

IRIS 8-Year Update – 37%* Unacceptable Outcome

Sustained CCyR on study; 53%

No CCyR, 17%*

Lost CCyR, 15%*

Safety, 5%*

Lost-regained CCyR; 3%CCyR Other 7%

Deininger M et al. Blood. 2009;114(22):462. Abstract # 1126.

Main Causes of Treatment Failure With Imatinib Primary resistance Secondary resistance Progression to AP/BC Toxicities/chronic AEs

2

1 2 3 4 5 6 7 80

2

4

6

8

3.3

7.5

4.8

1.70.8

0.3

1.4 1.31.5

2.81.8

0.9 0.50 0

0.4

Year

% With Event

Annual Event Rates: Imatinib Arm

Estimated EFS at 8 years = 81%1 progression to AP/BC and 2 non–CML-related deaths occurred in year 8

Event: Loss of CHR Loss of MCyR AP/BC Death during treatment

AP/BC

Deininger M et al. ASH 2009, Poster 1126.

Study Design and Endpoints in ENESTnd

Nilotinib 300 mg BID, n=282Randomized*

N=846217 centers35 countries

Nilotinib 400 mg BID, n=281

Imatinib 400 mg QD, n=283

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

Follow-up 5 years

*Stratification by Sokal risk score. Hughes T et al. ASH 2010, Abstract #207.

Patient Disposition in ENESTnd

Patient DispositionNilotinib

300 mg BIDn=282

Nilotinib400 mg BID

n=281

Imatinib400 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 9

Abnormal laboratory values 2 3 1

Death 1 <1 0

Protocol violation 2 2 1Other reason 4 3 4

*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 studyData cut-off: 20Aug2010.Hughes T et al. ASH 2010, Abstract #207.

Cumulative Incidence of MMR* in ENESTnd

% With MMR

0 3 6 9 12 15 18 21 24 27 30 33

nNilotinib 300 mg BID 282Nilotinib 400 mg BID 281Imatinib 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<0.0001Δ 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

30

20

10

0

CCyR Rates* by 24 Months in ENESTnd

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD0

20

40

60

80

10087 85

77

% CCyR

n=282 n=281 n=283

P=0.0018

P=0.016

Data cut-off: 20Aug2010.*ITT population.Hughes T et al. ASH 2010, Abstract #207.

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD0

2

4

6

8

10

12

14

23

12

Number of Pa-tients

Progression to AP/BC* in ENESTnd

• 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.

0.7% 1.1% 4.2%

P=0.0059

P=0.0196

n=282 n=281 n=283

8

Anemia Neutropenia Thrombocytopenia0

5

10

15

20

25

4

1210

4

11 12

5

21

9

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

% of Patients

Overall Grade 3/4 Myelosuppression Any Time on Study in ENESTnd

n=279

Data cut-off: 20Aug2010.Hughes T et al. ASH 2010, Abstract #207.

n=277 n=280

Study Drug-Related Nonhematologic Adverse Events (≥10% in Any Group) in ENESTnd

% of Patients TreatedNilotinib 300 mg BID

n=279Nilotinib 400 mg BID

n=277Imatinib 400 mg QD

n=280All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4

Nausea 14 <1 21 1 34 0Diarrhea 8 <1 7 0 26 1Vomiting 5 0 9 1 18 0Peripheral edema 5 0 6 0 15 0Facial edema <1 0 2 0 11 <1Eyelid edema <1 0 2 <1 16 <1Periorbital edema <1 0 1 0 14 0Muscle spasms 8 0 7 <1 27 <1Rash 32 <1 37 3 13 2Headache 14 1 22 1 9 <1Pruritus 16 <1 13 <1 6 0Alopecia 9 0 13 0 5 0Myalgia 10 <1 10 0 11 0Fatigue 11 0 9 <1 10 <1

Data cut-off: 20Aug2010.Hughes T et al. ASH 2010, Abstract #207.

10

QTcF Changes in ENESTnd

% of PatientsNilotinib

300 mg BIDn=279

Nilotinib400 mg BID

n=277

Imatinib400 mg QD

n=280

QT >500 msec 0 0 0QTcF increase from baseline

>60 msec<1* <1* 0

Maximum QTcF increase from baseline, msec

10.4 12.4 7.3

Larson RA et al. ASH 2010, Abstract 2291.Hughes T et al. ASH 2010, Abstract 207.TASIGNA PI 2010.

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

*Not associated with clinical signs or symptoms of arrhythmia.

WARNING: QT PROLONGATION AND SUDDEN DEATHSTASIGNA 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.

• 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%

11

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.

3 6 12 18 24 300%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

78%

96% 96% 95% 92%81% CCyR

PCyR<PCyRNEOFF

GIMEMA* 3-Year Update: Complete Cytogenetic Response Rates

N=73 (ITT)

Rosti G et al. ASH 2010, Abstract 359.

Only 1 patient had a confirmed loss of CCyR

Months

GIMEMA 3-Year Update: Survival Rates

Failures: 2009 ELN criteria.Events: failure, or treatment discontinuation for any reason.Rosti G et al. ASH 2010, Abstract 359.

Overall Survival

97%

Progression-Free Survival

Failure-Free Survival Event-Free Survival

100

80

60

40

20

00 12 24 36

97%

97% 91%

100

80

60

40

20

00 12 24 36

100

80

60

40

20

00 12 24 36

100

80

60

40

20

00 12 24 36

Total, n 73Progressions, n 1Unrelated death 1

Total, n 73Deaths, n 2

Total, n 73Failures, n 1Unrelated death 1

Total, n 73Events, n 6

14

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 Rosti G et al. Haematologica. 2010;95(s2):459 [abstract 1114] (oral).

15

Dasatinib Clinical Updates: DASISION 18 month and SWOG-S0325

16

Randomize

1:1

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.

DASISION Study

Dasatinib 100 mg QD, n=259• Treatment-naïve

Ph+ CML* (N=519)• 108 centers• 26 countries

Imatinib 400 mg QD, n=260

Follow-up 5 years

*Stratified by Hasford score.

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;362:2260-2270.

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

Patient Disposition and Treatment Discontinuations in DASISION

Treated Patients, n (%)

Dasatinib 100 mg QDN=259

Imatinib 400 mg QDN=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) 11 (4)

Nonhematologic 9 (3) 8 (3)

Hematologic 7 (3) 3 (1)

Unrelated AE 4 (2) 1 (<1)

Death 4 (2) 1 (<1)Other 8 (3) 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 imatinibShah et al. ASH 2010, Abstract 206.

Confirmed CCyR in DASISION*

Month 12 Month 180

20

40

60

80

100

77 7867 70

Dasatinib 100 mg QD Imatinib 400 mg QD

Percent of Patients

P=0.0086 P=0.0366

* ITT population


n=259 n=260

MMR Rates (ITT) by Month of Treatment

Month 3 Month 6 Month 9 Month 120

10

20

30

40

50

8

27

39

46

0.4

8

18

28

Dasatinib 100 mg QD Imatinib 400 mg QD

Molecular Response

(%)

MMR, BCR-ABL <0.1%

P<0.0001


n=259 n=260

Transformation to Advanced-Phase CML in DASISION

Dasatinib 100 mg QD Imatinib 400 mg QD0

1

2

3

4

2.3

3.5

Progressed to AP/BC (%)

6/259 9/260

• 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


Grade 3/4 Myelosuppression Any Time on Study: DASISION

Anemia

Neutropenia

Thrombocytopenia

0 10 20 30

7

20

10

11

22

19

Dasatinib 100 mg QDImatinib 400 mg QD

% of Patients

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


Drug-Related Nonhematologic AEs (≥10%) in DASISION

% of Patients

Dasatinib100 mg QD

N=259

Imatinib400 mg QD

N=260All Grades All Grades

Fluid retention 23 43 Superficial edema 10 36 Pleural effusion 12 0

Diarrhea 18 19Rash 11 17Nausea 9 21Fatigue 8 11Myalgia 22 38Vomiting 5 10

Grade 3/4 AEs were infrequent (≤1%) with either treatment


24

SWOG-S0325 Dasatinib vs Imatinib in Newly Diagnosed CML Patients: 12-Month Efficacy

*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.

% of Patients Treated

Derived ITT*† Evaluable

Dasatinib 100 mg QD

n=123

Imatinib 400 mg QD

n=123

Dasatinib 100 mg QD

n=123

Imatinib 400 mg QD

n=123

2-SidedP 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 NA 100 99 0.65

PFS AT 12 NA NA 99 96 0.20

PatientsDasatinib

100 mg QDn=123

Imatinib400 mg QD

n=123All grades thrombocytopenia (3/4), % 57 (18) 33 (8)

All grades pleural effusion* (3/4), % 14 (2) 2 (1)

Prolonged QT† (3/4), % 2 (1) 1 (0)

Deaths, n 3 4

CML-related deaths 1 2

Cardiac 0 1

Other 2 1

SWOG-S0325 Dasatinib vs Imatinib in Newly Diagnosed CML Patients: 12-Month Safety

*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.

Phase 1 Study of Ponatinib: Best Response to Therapy

Best ResponseOverall T315I* Non-T315I

Chronic(n=38)

%

Advanced(n=17)

%

Chronic(n=9)

%

Advanced(n=5)

%

Chronic(n=29)

%

Advanced(n=12)

%)HematologicMHR 95 35 100 20 93 42CytogeneticMCyR 66 24 100 20 55 25CCyR 53 12 89 0 41 17MolecularMMR 42 – 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.

Median follow-up:

Bosutinib: Response Rates at 12 Months (ITT)

CCyR MMR0

102030405060708090

100

70

39

68

26

Bosutinib (n=250)Imatinib (n=252)

Response Rate (%)

P=0.601

P=0.002

Newly Diagnosed Ph+ CML-CP PatientsCCyR, Primary Endpoint

Gambacorti-Passerini et al. ASH 2010, Abstract 208.

TIDEL-II: Selective Escalation of Imatinib Therapy and Early Switching to Nilotinib

Yeung DT et al. ASH 2010, Abstract #209.

TIDEL-I TIDEL -II

Start Rx with imatinib 600 mg

Dose adjust to imatinib 800 mg for failing target

Dose escalate if imatinib <1000 mg, D22

Allow switch to nilotinib

ü

û

ü

û

ü üüüTI

DEL

-II

TIDE

L -I

PK

NIL47%

67%

MM

R ra

tes a

t 12

mon

ths

Nilotinib300 mg BID

(n=282)

Nilotinib400 mg BID

(n=281)

Imatinib400 mg QD

(n=283)MMR, % by 12 months by 18 months

5566

5162

2740

CCyR, % by 12 months by 18 months

8084

7882

6574

ENESTnd (18 months) 24% of imatinib patients were dose escalated Dose escalation was not permitted in nilotinib arms

Larson RA et al. ASH 2010, Abstract 2291Kantarjian et al. NEJM. 2010:362;2260.

Rates of CCyR and MMR From ENESTnd and DASISION

These data are from separate studiesDASISION (18 months) 15% of imatinib patients were dose escalated 6% of dasatinib patients were dose escalated

Dasatinib100 mg QD

(n=259)

Imatinib400 mg QD

(n=260)

46n/a

28n/a

7778

6670

ENESTnd DASISION

30

Rates of Progression From ENESTnd and DASISION

ENESTnd (18 months) No patient who achieved MMR progressed to AP/BC 4 patients who achieved CCyR on imatinib progressed

to AP/BC

These data are from separate studiesDASISION (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)

Nilotinib300 mg BID

(n=282)

Nilotinib400 mg BID

(n=281)

Imatinib400 mg QD

(n=283)AP/BCn (%)

2 (0.7)P = 0.006

1 (0.4)P = 0.003 12 (4.2)

Dasatinib100 mg QD

(n=259)

Imatinib400 mg QD

(n=260)6 (2.3)P = NS 9 (3.5)

ENESTnd DASISION

31

Larson RA et al. ASH 2010, Abstract 2291Kantarjian et al. NEJM. 2010:362;2260.

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

The toxicity spectrum of TKIs

MyelosupressionTransaminase

Electrolyte ΔQT prolongation

Imatinib:Edema/fluid retention;

myalgias, hypophosphatemia

Dasatinib:Pleural/pericardial effusions

Bleeding risk

Bosutinib:Diarrhea/Nausea/Emesis

Rash; ?Pleural effusion

Nilotinib:Pancreatic enzyme

elevationIndirect hyperbilirubinemia

0

2

4

6

8

10

% o

f Pati

ents 7

3

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

Additional eventsbetween 12 and 24 months

4

9

34

8

< 1

5

0

8

6

Lipase ↑ ALT ↑ Total bilirubin ↑ Glucose ↑

ENESTnd:Selected Grade 3/4 Biochemical Abnormalities

Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207]

Nilotinib in CML-CP 2nd line: Cmin and hyperbilirubinemia

100

Median Nilotinib Cmin (ng/mL)

% W

ith G

rade

3/4

Bili

rubi

n El

evati

on

60

40

20

0

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)

Giles F et al, ASH 2010 Abstract #890

• 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’

Nilotinib in CML-CP 2nd line: Cmin and lipase elevation

Nilotinib Cmin Quartile (ng/mL)

% W

ith L

ipas

e El

evati

on All grade incidence

33

Grade 3/4 incidence

10080604020

0

3450 53

% W

ith L

ipas

e El

evati

on 5040302010

0

< 451

39/119

(451,620)

40/118

(620,859)

59/118

≥ 859

63/119

Nilotinib Cmin Quartile (ng/mL)

13 14 1523

< 451

16/119

(451,620)

17/119

(620,859)

18/119

≥ 859

27/119

n/N =

n/N =

P = 0.001

P = 0.193


Phase 1 Study of Ponatinib Dose Escalation

Dose N Patients Enrolled

N Patients Evaluable

N Patients w/DLT DLT Event

2 mg capsules 3 3 0 -





45 mg capsules 13 12 1 Rash

45 mg tablets 12 9 1 Pancreatic

60 mg capsules 13 12 4 Pancreatic

60 mg tablets 5 5 2 Fatigue; ALT

Cortes J, ASH 2010 Abstract #210

0 6 12 18 24 360

20

40

60

80

100

% P

atien

ts w

ith M

MR

Time (months)

Nilotinib in CP-CML 2nd line:Dose Interruption and time to response (n = 229)

Cumulative dose interruption:No interruption <7 days7-14 days

14- 28 days≥ 28 days

Time to MMR vs. dose interruptionTime to CCyR vs. dose interruption

P = .0000993*

0 6 12 18 24 360

20

40

60

80

100

% P

atien

ts w

ith C

CyR

Time (months)*Log-rank test

P = .00091*

Dose interruptions were 4% of total days of exposure1

ENESTnd Substudy:Adverse events in Patients with Type 2 Diabetes

Intestinal obstruction (1) and suicide (1)

Ischemic heart disease (1)None for ‘diabetes’

Saglio G et al, ASH 2010 Abstract #3430

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


Hyperglycemia AEs, ENESTnd

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


CCyR by 12 mo: Type II DM versus overall, ENESTnd


Lymphocytosis with Dasatinib Therapy

• 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;116:772-782.2. Schiffer C, et al. 2010 ASCO abstract #6553.

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)

Lymphocytosis with Dasatinib TherapySchiffer C et al, ASH 2010 Abstract #358

45

Months

10

0

90

80

6

100

70

60

50

40

30

20

0

3 9 12 15 18 21 24 27 30 33

Lym

phoc

ytos

is (%

)

SUBJECTS AT RISKDASATINIBIMATINIB

258

258

229

254

210

248

201

246

195

244

194

243

192

243

190

243

190

243 243

190

243

0

0

190

Dasatinib 26% (68/258)Imatinib 6% (15/258)

P<0.0001

Cumulative Incidence of Lymphocytosis, DAS vs IMSchiffer C et al, ASH 2010 Abstract #358

Cumulative response rates according to presence of lymphocytosis (minimum follow-up 15 months)

Lymphocytosis CCyR cCCyR MMR

Dasatinib Yes 93% 85% 68%(n=258) No 85% 76% 54%

Imatinib Yes 53% 53% 27%(n=258) No 83% 72% 42%

46CCyR=complete cytogenetic response; cCCyR=confirmed CCyR; MMR=major molecular response


Landmark analysis of response at 12 monthsby presence of lymphocytosis

47

Lymphocytosis by 12 months

cCCyR inpatients on

treatment at 12 months

MMR inpatients on

treatment at 12 months

Dasatinib Yes 26% 86% 56%(n=225) No 74% 83% 41%

P=0.546 P=0.0496Imatinib Yes 5% 67% 25%(n=228) No 95% 69% 29%

P=1.0 P=1.0

cCCyR=confirmed complete cytogenetic response; MMR=major molecular response


Fluid-related adverse events

• 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

*** 22% vs 9 %, 95% CI 4-24%

QTc prolongation with 2G TKIs in front-line

ENESTnd DASISIONNilotinib

300 mg BID

• No patients with QTc >500ms

• <1% QTc >60ms

Nilotinib400 mg BID


• <1% QTc >60ms

Imatinib400 mg QD



Imatinib400 mg QD

• QTc >500ms in 0.4%

• 5% QTc >60ms

Dasatinib100 mg QD

• QTc >500ms in 0.4%

• 5% QTc >60ms

Nilotinib phase II data

QTc and relationship to nilotinib trough concentration

Nilotinib in CML-CP 2nd Line: Cmin (steady state)

by disease phases

Nilo

tinib

Cm

in (n

g/m

L)* 5000

4000

3000

2000

1000

0

1165 1190 998.5

CPn = 200

APn = 81

BPn = 88

Disease Phase


Larson R et al, ASH 2010 Abstract #2291

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)

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

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 2009 23(8):1398-405

• ColitisShimokaze T, et al Hematol Oncol. 2009 26(6):448

• Opportunistic infections (EBV, CMV), skin cancersSillaber et al. Eur J Clin Invest 39; 1098, 2009

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

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

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

Estimate of Rapidly Increasing CML Prevalence

Kindly shared by Hagop Kantarjian, MD, MDACC.

Assuming an incidence of ~5000 cases/year;mortality of 2% per year;plateau prevalence = 5000 x 100/2 = 250,000

2000 2010 2020 2030 2040 2050 2060

250

200

150

100

50

0

Prevalence of CML

(no. in the United States in thousands)

Manage After Treatment Failureor

Prevent of Treatment Failure

Front-Line 2G TKI

Success with imatinib

Successful 2nd-line

TKI

Treatment failure

Success

Failure

Front-Line Gleevec

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

Clinical messages in CML must be carefully delivered as we continue to move forward rapidly……

HemOnc today, 11/25/10

Michael J. Mauro MD

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