DISCLAIMERDISCLAIMERThis slide deck in its original and unaltered format is for educational purposes and is

current as of April 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. Thesematerials may discuss therapeutic products that have not been approved by the US

Food and Drug Administration and off-label uses of approved products. Readersshould not rely on this information as a substitute for professional medical advice,

diagnosis, or treatment. The use of any information provided is solely at your own risk,and readers should verify the prescribing information and all data before treating

patients or employing any therapeutic products described in this educational activity.

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DISCLAIMERDISCLAIMERParticipants have an implied responsibility to use the newly acquired information

to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for

patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by

clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s

product information, and comparison with recommendations of other authorities.

DISCLOSURE OF UNLABELED USEDISCLOSURE OF UNLABELED USEThis activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM and IMER do not recommend the

use of any agent outside of the labeled indications.  

The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of PIM and IMER. Please refer to the official

prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclosure of Conflicts of InterestDisclosure of Conflicts of InterestMichael W.N. Deininger, MD, PhDMichael W.N. Deininger, MD, PhD

Reported a financial interest/relationship or affiliation in the form of: Consultant, Ariad Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation; Contracted Research, Bristol-Myers Squibb Company, Celgene Corporation, Genzyme, Inc.

Learning ObjectivesLearning ObjectivesUpon completion of this activity, Upon completion of this activity,

participants should be better able to:participants should be better able to:

Assess patient and disease characteristics for selecting optimal frontline therapies for patients with CML

Identify the characteristics that define a relapsed patient with CML

Evaluate the role of mutational analysis for individualizing therapy choices for patients with CML

Identify investigational agents in clinical development for patients with CML

Activity AgendaActivity Agenda

Activity Overview (5 mins)

Interactive Clinical Debates (50 mins)

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

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

Questions & Answers (5 mins)

Interactive Clinical DebatesInteractive Clinical Debates

Clinical Debate 1: Clinical Debate 1: How Do You Choose the Optimal How Do You Choose the Optimal

Frontline Therapy for Patients With CML?Frontline Therapy for Patients With CML?

CML: Epidemiology and EtiologyCML: Epidemiology and Etiology In the US, there were 4,870 cases in 2010 and an

expected 5,430 cases in 2012

15% of all adult leukemias

Incidence increases significantly with age

– Median age: ~ 67 years

– Prevalence increasing due to current therapy

– Most patients present in CP

• Majority of CML-related deaths due to progression to AP/BC

– 50% of CML patients are asymptomatic at diagnosis

Risk factors

– Radiation exposure

CML = chronic myeloid leukemia; CP = chronic phase; AP = accelerated phase; BC = blast crisis.NCCN, 2012; Jemal et al, 2010; ACS, 2012; Richardson et al, 2009; Bacarrani, Cortes, et al, 2009.

Chronic Phase Blast Phase

Most CML Patients Are Diagnosed Most CML Patients Are Diagnosed in the Chronic Phasein the Chronic Phase

BCR

ABLABL

BCRABLABL

BCR{q11

PhPh

9q+

2222

99

{q34 ABLABL

Ph Is the Result of t(9;22)(q34;q11)Ph Is the Result of t(9;22)(q34;q11)

Ph = Philadelphia.

9

22

Ph

9q+

The Cytogenetic Hallmark of CML The Cytogenetic Hallmark of CML Is the Philadelphia ChromosomeIs the Philadelphia Chromosome

22q- = Ph chromosome

Courtesy of Christl Müller, Leipzig.

RT-PCR RT-PCR forfor BCR-ABL BCR-ABL

RT-PCR for BCR-ABL in CML

1) Qualitative RT-PCR allows for the diagnosis of CML

2) Quantitative RT-PCR is used to quantify the amount of disease

3) Allows for the identification of cryptic BCR-ABL translocations

4) Does not require a bone marrow aspirate for optimal results

RT-PCR = real time polymerase chain reaction.Suh et al, 2000; Menif et al, 2009; Adapted from Rollins et al, 2000.

Cycle 1 yields 2

molecules

Cycle 2 yields 4

molecules

Cycle 3 yields 8 molecules; 2 molecules

(in white boxes)

match target sequence

Denaturation: Heat briefly to separate DNA strands

Annealing: Cool to allow primersto form hydrogen bond with ends of target sequence

2

1

Extension: DNA polymerase adds nucleotides to the 3” end of each primer

3New nucleo-tides

Primers

Target sequence

Monitoring Response: Monitoring Response: Sensitivity of Strategies Sensitivity of Strategies

Complete Hematologic Response

Diagnosis: 1012 Leukemia Cells

Cytogenetics

Blood Counts

PCR

Undetectable Range

Complete Cytogenetic Response

Major Molecular Response

100%

10%

1%

0.1%

Complete Molecular Response

4.5 log = 0.0032%

BCR-ABL Kinase Activity Is BCR-ABL Kinase Activity Is Essential for CML PathogenesisEssential for CML Pathogenesis

NALM-1 cells (Ph+)

0.1 0.5 1.0 5.0 10

Imatinib (M)

BCR-ABL-

Deininger et al, 1997.

BCR-ABL

K56232D

32p210 BCR-A

BL

MDACC = The University of Texas M. D. Anderson Cancer Center.Quintas-Cardama & Cortes, 2006.

Imatinib Greatly Improved SurvivalImatinib Greatly Improved Survivalin CML-CP (MDACC data)in CML-CP (MDACC data)

Case Study 1Case Study 1

A 60-year-old man presents to his PCP with a history of left-sided abdominal pain, poor appetite, and loss of 10 kg of body weight

PMH is significant for interstitial lung disease with right heart failure and recurrent pleural effusions. A recent EKG shows a QTc interval of 433 ms.

Physical exam reveals splenomegaly (14 cm under left rib cage)

PCP = primary care physician; PMH = past medical history; EKG = electrocardiogram.

Laboratory FindingsLaboratory Findings

HGB 10.1 g/dL, WBC 321/nL, platelets 810/nL

Diff: 25% segs, 23% bands, 17% myelocytes, 10% promyelocytes, 8% basophils,6% monocytes, 4% lymphocytes, 9% blasts

Bone marrow: 7% blasts, 5% basophils

Cytogenetics: 46XY,t(9;22)[20]

HGB = hemoglobin; WBC = white blood count; Diff = differentials; segs = segmented neutrophils.

Case Study 1: Question 1Case Study 1: Question 1

Which diagnostic tests would you add?

1) FISH for BCR-ABL

2) BCR-ABL mutation screening

3) CT abdomen/pelvis ± contrast

4) None of the above

5) All of the above

FISH = fluorescent in situ hybridization; CT = computed tomography.

Case Study 1: Question 2Case Study 1: Question 2

Which information is not important for decision-making?

1) Spleen 14 cm

2) WBC 321/nL

3) PLTs 810/nL

4) Peripheral blood blasts 9%

5) History of pleural effusions

PLTs = platelets.

Case Study 1: Question 3Case Study 1: Question 3

Which of the following are acceptable therapeutic choices?

1) Imatinib 400 mg QD

2) Imatinib 400 mg BID

3) Nilotinib 300 mg BID

4) Dasatinib 100 mg QD

5) Only 1, 2, and 3

6) Only 1, 3

7) Only 1, 3, and 4

NCCN, 2012; Sprycel® prescribing information, 2010; Tasigna® prescribing information, 2011; Gleevec® prescribing information, 2010.

Case Study 1: Question 4Case Study 1: Question 4The patient is started on nilotinib 300 mg BID.

Which two statements about monitoring this patientare incorrect?

1) Blood counts should be monitored weekly until stable

2) Monitoring transaminases and lipase is unnecessary

3) A BMB and karyotyping at 3 months are standard of care

4) Once a complete cytogenetic response has been documented monitoring continues with qPCR only

5) Annual BMB should continue indefinitely

BMB = bone marrow biopsy.

Getting Things Right at DiagnosisGetting Things Right at Diagnosis

History and physical exam: Record spleen size in cm below costal margin Complete blood count Bone marrow aspirate with marrow differential Conventional cytogenetics Do not treat leukocytosis with imatinib!

The Bare Minimum

Bone marrow trephine FISH for BCR-ABL Diagnostic PCR for BCR-ABL Flow cytometry

Optional

Mandatory in case of Ph-negative karyotype

NCCN, 2012.

Getting Things Right at Diagnosis Getting Things Right at Diagnosis (cont.)(cont.)

Low risk < 0.8

Intermediate risk 0.8–1.2

High risk > 1.2

Establish Disease Phase PLT < 100 Blood or marrow blasts > 15% Basophils > 20% Blasts and promyelocytes > 30% Blasts > 30%

Establish Sokal Risk Score = Exp [0.0116 (Age – 4.34)] + 0.0345 (Spleen – 7.51) + 0.188 [(PLT/700)2 – 0.563] + 0.0887 (PB blasts – 2.1)

NCCN, 2012.

New CML Risk Score (Eutos Score) for New CML Risk Score (Eutos Score) for Patients Treated With ImatinibPatients Treated With Imatinib

PFS = progression-free survival.Hasford et al, 2011.

Eutos Score = (7 x basophils) + (4 x spleen size)

High risk: > 87Low risk: ≤ 87

Requires Confirmation

PFS

Is There A Role for Peripheral Blood Is There A Role for Peripheral Blood FISH for Monitoring Response?FISH for Monitoring Response?

Good correlation between BM, FISH, and karyotyping

CBA = chromosome banding analysis; CCgR = complete cytogenetic response; I-FISH = interphase fluorescence in situ hybridization; PCgR = partial cytogenetic response.Testoni et al, 2009.

Distribution of I-FISH Data According to CBA Data

Cytogenetic response by I-FISH, n (%)

Cytogenetic response by CBA < 1% BCR-ABL+ nuclei

1%–5% BCR-ABL+ nuclei

> 5% BCR-ABL + nuclei

CCgR (n = 537), no Ph+ metaphases 444 (82.7) 71 (13.2) 22 (4.1)

PCgR (n = 77), 1%–35% Ph+ metaphases 7 (9.1) 32 (41.6) 38 (49.3)

p Value < .001 < .001 < .001

Is There A Role for Peripheral Blood Is There A Role for Peripheral Blood FISH for Monitoring Response? (cont.)FISH for Monitoring Response? (cont.)

In Favor

Wide accessibility Excellent correlation with marrow

cytogenetics in patients on IFN-α

r = 0.98

Against

IFN-α results not validated in patients on imatinib Not validated prospectively with clinical end points Does not detect clonal evolution Limited sensitivity and dynamic range compared to qPCR

IFN = interferon.Le Gouill et al, 2000.

% Ph +

100

80

60

40

20

0

0 20 40 60 80 100 % Ph +

Therapy StandardsTherapy Standards

Chronic Phase Imatinib

Nilotinib

Dasatinib

(IFN-α)

(Hydroxyurea)

Advanced Phase Dasatinib

Nilotinib

Allotransplant

(Imatinib)

(Hydroxyurea)

NCCN, 2012.

Study Comparison Patients / Randomization

Major End Points

Author

IRIS IM 400 mg QD IFN / Ara-C

1,106 / 1:1 PFS O’Brien et al, 2003

TOPS IM 400 mg QD

IM 400 BID

476 / 1:2 MMR at 12 months

Cortes et al, 2010

ENESTnd IM 400 mg QD NIL 300 mg BID NIL 400 mg BID

846 / 1:1:1 MMR at 12 months

Saglio et al, 2010

DASISION IM 400 mg QD DAS 100 mg QD

519 / 1:1 CCyR at 12 months

Kantarjian et al, 2010

Choosing a TKI for First-Line TherapyChoosing a TKI for First-Line Therapy

TKI = tyrosine kinase inhibitor; IM = imatinib; NIL = nilotinib; DAS = dasatinib; MMR = major molecular response; CCyR = complete cytogenetic response.

OS = overall survival.Deininger et al, 2009.

OS on First-Line Imatinib OS on First-Line Imatinib (IRIS Study)(IRIS Study)

CCyR with >=3 log reductionCCyR with <3 log reductionNo CCyR

% w

ithou

t pro

gres

sion

0

10

20

30

40

50

60

70

80

90

100

Months since randomization0 6 12 18 24 30 36 42 48 54 60

IRIS Study: PFS by Molecular Response IRIS Study: PFS by Molecular Response at 12 Months on First-Line Imatinib at 12 Months on First-Line Imatinib

95% 89% 72%

Estimated Rate at 54 Months

} p < .001} p = .068

Deininger et al, 2009.

CCyR with ≥ 3 log reductionCCyR with < 3 log reductionNo CCyR

IRIS Study 7-Year Follow-Up: Prognostic Significance IRIS Study 7-Year Follow-Up: Prognostic Significance of Molecular Response on First-Line Imatinib of Molecular Response on First-Line Imatinib

p = .014 p = .0006

P=0.001p = .019

Hughes et al, 2010.

Not All Data Are As Good As IRIS Data: Not All Data Are As Good As IRIS Data: Hammersmith Hospital ExperienceHammersmith Hospital Experience

CHR = complete hematologic response; EFS = event-free survival; MCyR = major cytogenetic response.de Lavallade et al, 2008.

Event: Also off IM due to lack of MCyR or toxicity

63%

The Community Experience: Only A Minority The Community Experience: Only A Minority of Patients Do Well Enough to Remain on IMof Patients Do Well Enough to Remain on IM

CCRe = complete cytogenetic response equivalence.Lucas et al, 2008.

TOPS 24-Mos Update: Study DesignTOPS 24-Mos Update: Study Design

PFS, OS

Imatinib 400 mg/day (n = 157)

Imatinib 800 mg/day (400 mg BID; n = 319)

MMR* at 12 months

2:1 randomization

N = 476

Total 5 years (planned)

Data cut-off of December 31, 2008.*BCR-ABL/control gene ≤ 0.1% utilizing the International Scale.

Patients enrolled at 103 sites in 19 countries, first patient first visit June 2005 Cytogenetic analysis every 6 months until CCyR, then every 12 months Molecular analysis by PCR every month for Months 1–3, then every 3 months

TOPS = Tyrosine Kinase Inhibitor Optimization and Selectivity.Cortes, Baccarani, et al, 2010.

TOPS Trial: Imatinib 400 mg Vs. 800 mg: TOPS Trial: Imatinib 400 mg Vs. 800 mg: MMR Rates Over Time (ITT)MMR Rates Over Time (ITT)

ITT = intent to treat.Cortes, Baccarani, et al, 2010.

Impact of Dose Intensity* on Cumulative Impact of Dose Intensity* on Cumulative CCyR Rates, 800 mg ArmCCyR Rates, 800 mg Arm

% P

atie

nts

Ach

ievi

ng

CC

yR

p = .001

800 mg Arm800 mg Arm

*Dose intensity (total amount of drug received divided by the number of days on treatment including days of zero dose) in the first 12 months of treatment.

p = .510

Cortes, Baccarani, et al, 2010.

Event-Free Survival* (ITT)Event-Free Survival* (ITT)

400 mg

800 mg

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42

% P

atie

nts

With

out

Eve

nt

Months Since Randomization

EFS at 24 Months95% for Both Arms

*EFS; time between randomization and death, progression to AP/BC, loss of MCyR [Ph+ bone marrow cells > 35%] or loss of CHR.

Baccarani et al, 2009.

Nilotinib in CP1 First-Line: Nilotinib in CP1 First-Line: 3-Year Update of ENESTnd3-Year Update of ENESTnd

Saglio et al, 2011.

Primary end point: MMR at 12 months

Patient DispositionPatient Disposition

Few patients discontinued treatment since the 2-year follow-up

– 4% on nilotinib 300 mg BID; 5% on nilotinib 400 mg BID; 6% on imatinib

Saglio et al, 2011.

% W

ith

MM

R

33

Months Since Randomization

73%, p < .0001

70%, p < .0001

53%

By 3 Years

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 21 24 27 30

55%, p < .0001

51%, p < .0001

27%

By 1 Year

Δ 24%–28%

Δ 17%–20%

Nilotinib 300 mg bid

Nilotinib 400 mg bid

Imatinib 400 mg qd

282

281

283

n

36

Cumulative Incidence of MMRCumulative Incidence of MMR

Saglio et al, 2011.

Patients With High Sokal Risk Have the Patients With High Sokal Risk Have the Largest Improvement of MMR by 3 YearsLargest Improvement of MMR by 3 Years

77 7567

63

54

39

0

10

20

30

40

50

60

70

80

Low Intermediate High

Nilotinib 300 mg BID Imatinib 400 mg QD

% W

ith

MM

R

n = 103 104 101 101 78 78

p = .0264 p = .0020p = .0004

Δ 14% Δ 21% Δ 28%

Saglio et al, 2011.

Nilotinib 300 mg bid

Nilotinib 400 mg bid

Imatinib 400 mg qd

282

281

283

n

% W

ith

MR

4.5

40

30

20

10

0

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

11%, p < .0001

7%, p < .0001

1%

By 1 Year

Δ 6%–10%

36

32%, p < .0001

28%, p = .0003

15%

By 3 Years

Δ 13%–17%

Months Since Randomization

Cumulative Incidence of CMRCumulative Incidence of CMR

26%

21%

10%

By 2 Years

Saglio et al, 2011.

Progression to AP/BC: Including Events Progression to AP/BC: Including Events After Discontinuation (ITT Analysis)After Discontinuation (ITT Analysis)

Nu

mb

er o

f P

atie

nts

(n

)

On Core Treatment and After Discontinuation

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

96

19p = .0496

p = .0076

Off treatment progression information was prospectively collected for all patients every 3 months after discontinuation

HR = 0.5 [0.2, 1.0]HR = 0.3 [0.1, 0.8]

3.2% 2.1% 6.7%

HR = hazard ratio.Saglio et al, 2011.

Survival After Progression to AP/BCSurvival After Progression to AP/BC%

Ali

ve

Months Since Progression

100

90

80

70

60

50

40

30

20

10

0

0 6 12 18 24 30 36

Median Survival 10.5 months

Progressed = 34Died = 23Alive = 11

Saglio et al, 2011.

Overall Survival Overall Survival

Of 38 total deaths on study, 23 were following progression to AP/BC

CI = confidence interval.Saglio et al, 2011.

Dasatinib in CP1 First-Line Dasatinib in CP1 First-Line 2-Year Update of 2-Year Update of

DASISIONDASISION

Primary end point Confirmed CCyR by 12 months

Other key end points Rates of CCyR and MMR, times to CCyR and MMR, time in CCyR (measure of duration), PFS, OS

Follow-up

5 yearsRandomized*

Imatinib 400 mg QD (N = 260)

Dasatinib 100 mg QD (N = 259) Treatment-naïve

CML-CP patients

(N = 519)

108 centers

26 countries*Stratified by Hasford risk score

Hochhaus et al, 2011.

Cumulative Incidence of MMRCumulative Incidence of MMR

Months

100

80

60

40

20

0

Dasatinib 100 mg QD

Imatinib 400 mg QD

0 3 6 9 12 15 18 21 24 27

65%

47%

47%

28%

Δ 19%

Δ 18%

Response achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.

% o

f P

atie

nts

By 24 monthsBy 12 months

Hochhaus et al, 2011.

Cumulative Incidence of CMRCumulative Incidence of CMR

Dasatinib 100 mg QD

Imatinib 400 mg QD

0 3 6 9 12 15 18 21 24 27

100

80

60

40

20

0

By 24 months17%

9%

Months

Response achieved by 24 months; calculated from randomized subjects with typical BCR-ABL transcripts.

% o

f P

atie

nts

Hochhaus et al, 2011.

BCR-ABL Levels at 3 Months*BCR-ABL Levels at 3 Months*

0

20

40

60

80

100

84%

64%

16%

36%

% o

f P

atie

nts

BCR-ABL Level at 3 Months

Dasatinib 100 mg QD

Imatinib 400 mg QD

n/N 198/235 154/239 37/235 85/239

≤ 10% > 10%

*Calculated from total number of evaluable patients with PCR assessments at 3 months.

> 1–10%

≤ 1%

> 1–10%

≤ 1%

Hochhaus et al, 2011.

Cumulative Incidence of CCyR Within 24 Months Cumulative Incidence of CCyR Within 24 Months According to BCR-ABL Level at 3 MonthsAccording to BCR-ABL Level at 3 Months

0 6 12 18 24 30

0 6 12 18 24 30Months Months

% C

CyR

% C

CyR

Dasatinib 100 mg QD Imatinib 400 mg QD

≤ 1% > 1–10% > 10%

BCR-ABL at 3 months

100

80

60

40

20

0

100

80

60

40

20

0

98%

38%

64%

98%100%94%

24 months 24 months

Hochhaus et al, 2011.

Transformation to AP/BP According to Transformation to AP/BP According to BCR-ABL Level at 3 MonthsBCR-ABL Level at 3 Months

0

2

4

6

8

10

Total

% T

rans

form

atio

n

Dasatinib 100 mg QD

Imatinib 400 mg QD

2.6%

> 10%

5.0%

≤ 1%

1.8%

0%

1.2%

9.4%

BCR-ABL Level at 3 Months

n/N 6/235 12/239 2/112 0/32 1/86 4/122 3/37 8/85

3.3%

8.1%

> 1–10%

Hochhaus et al, 2011.

OS According to BCR-ABL Level OS According to BCR-ABL Level at 3 Months at 3 Months

% A

live

% A

live

≤ 1%> 1–10%> 10%

Months

BCR-ABL Level at 3 months

≤ 1%> 1–10%> 10%

BCR-ABL Level at 3 months

Dasatinib 100 mg QD Imatinib 400 mg QD

100

80

60

40

20

00 6 12 18 24 30 36 42

Months0 6 12 18 24 30 36 42

100

80

60

40

20

0

For ≤ 10% vs. > 10% comparison: p = .0137 For ≤ 10% vs. > 10% comparison: p = .0081

Hochhaus et al, 2011.

Nilotinib and Dasatinib Are Better Nilotinib and Dasatinib Are Better Tolerated Than ImatinibTolerated Than Imatinib

Nilotinib / Dasatinib Better

NIL DASIM IM

Nausea

Saglio et al, 2011; Hochhaus et al, 2011.

ENESTnd Vs. DASISION ENESTnd Vs. DASISION Communalities

– Superiority of experimental arm in terms of primary end point

– Equal or better tolerability of experimental arm

– High drop out rates

– No difference in OS

ENESTnd DASISION

Risk stratification Sokal Hasford

Dose escalation in experimental arm

No Yes

Assessment of progression On therapy Up to 60 days post d/c of therapy

Differences in Design

d/c = discontinuation.Larson et al, 2011; Kantarjian et al, 2011.

ENESTnd Vs. DASISION ENESTnd Vs. DASISION An Unallowed ComparisonAn Unallowed Comparison

ENESTnd DASISIONCCyR 24 months (%) 87/85a 86a

MMR 24 months (%) 62/59b 64a

PFS superior in experimental arm Yes No

Assessment of progression On therapyUp to 60 days post d/c

of therapy

aResponse by time point.bResponse at time point.Larson et al, 2011; Kantarjian et al, 2011.

SO325 Trial DesignSO325 Trial Design Randomization

– Imatinib 400 mg/d vs. dasatinib 100 mg/d

Stratification

– Hasford risk category: Low vs. intermediate vs. high

Number of patients

– N = 240 (120/arm)

Assessment schedule

– Molecular and hematologic response: 3, 6, 9, 12 mos

– Cytogenetic response: 6, 12 mos

Radich et al, 2010.

BCR-ABL mRNA LevelBCR-ABL mRNA Level

Radich et al, 2010.

Median BCR-ABL reduction: Dasatinib 3.3 log vs. imatinib 2.8 log, p = .048

Clinical Debate 2: Clinical Debate 2: How Should the Relapsed/Refractory How Should the Relapsed/Refractory

CML Patient Be Treated?CML Patient Be Treated?

Case Study 2Case Study 2

A 49-year-old man with CML has been on imatinib 400 mg daily for 7 years

He was diagnosed in chronic phase and achieved CCyR after 6 months

His qPCR levels on the international scale have fluctuated between 0.09% and 0.4%, but the most recent test showed an increase to 5.6%

Comorbidities include diabetes mellitus, polyarthritis, and depression, for which he is managed by 3 additional specialists

He is asymptomatic and physical exam is negative

Case Study 2: Question 1Case Study 2: Question 1

Which are the appropriate next steps?

1) Thorough ‘questioning’ for non-compliance

2) Thorough review of co-medications

3) Repeat qPCR

4) Bone marrow biopsy

5) Imatinib drug level testing

6) All of the above

7) Only 1, 2, and 3

8) Only 1, 2, 3, and 5

Case Study 2: Question 2Case Study 2: Question 2A thorough history reveals no evidence for non-compliance and there was no recent change in medications. The repeat PCR test reveals a level of 7.2IS.

What is your next step?

1) Bone marrow biopsy with cytogenetics

2) Screening for BCR-ABL kinase domain mutations on a blood sample

3) Screening for BCR-ABL kinase domain mutations on a bone marrow sample

4) Only 1, 2, and 3

5) Only 1 and 2

Case Study 2: Question 3Case Study 2: Question 3You receive the following results:

Normocellular marrow with micromegakaryocytes, 2% blasts

Mutation screening positive for F359V BCR-ABL mutation

Cytogenetics 46XY[15]/46XY,t(9;22),inv(3)[5]

What is your next step?

1) Increase imatinib to 800 mg BID

2) Switch to nilotinib 400 mg BID

3) Switch to dasatinib 140 mg QD

4) Evaluate for allotransplant

5) Only 2 and 4

6) Only 3 and 4

Resistance Work-UpResistance Work-Up

Failure to reach milestones or loss of response

NCCN, 2012.

Complete Diagnostic Work-Up Physical exam BMB Karyotyping BCR-ABL mutation screen

No

When Is BCR-ABL Mutation When Is BCR-ABL Mutation Analysis Indicated?Analysis Indicated?

Failure to reach milestones Loss of response, progression

Controversial Routine at diagnosis in patients with AP/BC? Routine monitoring in high-risk patients? Which is the optimal technology? Which is the right qPCR trigger?

Universally Accepted

NCCN, 2012.

Which Increase of BCR-ABL Is the Right Which Increase of BCR-ABL Is the Right Trigger for BCR-ABL Mutation Screening?Trigger for BCR-ABL Mutation Screening?

NCCN guidelines: 10-fold ELN recommendations: 5-fold If you live in Australia: 2-fold

More than 2-fold rise Stable or decreasing

Mutations (%)

resistance (%)

34/56 (61)

31/34 (91)

1/158 (0.6)

1/1 (100)

No mutations (%)

resistance (%)

22/56 (39)

13/22 (59)

157/158 (99)

1/157 (0.6)

Brandford et al, 2004.

Receiver Operating Characteristic Analysis Receiver Operating Characteristic Analysis to Define Optimal qPCR Triggerto Define Optimal qPCR Trigger

Press et al, 2009.

Jmax (2.6-fold)

0 10 20 30 40 50 60 70 80 90 100

1 – Specificity (%)

Sen

siti

vity

(%

)100

90

80

70

60

50

40

30

20

10

0

What Are the Non-Transplant What Are the Non-Transplant Options for Patients With Relapse? Options for Patients With Relapse?

(Imatinib dose escalation)

Nilotinib

Dasatinib

Experimental agents

NCCN, 2012.

Dasatinib: PFS and OS in CML-CP Dasatinib: PFS and OS in CML-CP After IM FailureAfter IM Failure

Months

100

80

60

40

20

0

24 months12 months

91%

PFS

80%387N

24 months12 months

97%

OS

94%387N

% o

f P

atie

nts

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

Stone et al, 2007.

Nilotinib: PFS and OS in CML-CP Nilotinib: PFS and OS in CML-CP After IM FailureAfter IM Failure

Months Since Start of Treatment

% A

live

Adapted from Kantarjian et al, 2007.

Patients With Cytogenetic Response to Patients With Cytogenetic Response to Second-Line TKIs at 3 Months Do Well Second-Line TKIs at 3 Months Do Well

Proportions of patients ultimately achieving 12 MMCyR

Tam et al, 2008.

Months From 12-Month Landmark

Pro

po

rtio

n A

live

(%

)

Time point, response n 12 MMCyR, no. (%)

3 months

Minor cytogenetic 15 10 (67)

Complete hematologic response or hematologic failure

42 3 (7)

6 months

Minor cytogenetic 16 8 (50)

Complete hematologic response or hematologic failure

39 1 (3)

Blast Crisis: PFS on DasatinibBlast Crisis: PFS on Dasatinib%

No

t P

rog

ress

ed

100

80

60

40

20

0

Months0 3 6 9 12 15 18 21 24 27 30

Lymphoid Blast

Myeloid Blast

Gambacorti et al, 2007.

Dasatinib for IM Failure in CP: Frequency of Baseline Dasatinib for IM Failure in CP: Frequency of Baseline BCR-ABL Mutations by In Vitro ICBCR-ABL Mutations by In Vitro IC5050 to Dasatinib to Dasatinib

IC50 ≤ 3 nM (n = 248)

M244V, G250E, Y253F/H/K, F311L, M351T, E355G, F359C/I/V, V379I, L387M, H396P/R

Unknown IC50 to dasatinib (n = 74)38 different BCR-ABL mutations

No BCR-ABLmutation(n = 421)

52%

IC50 > 3 nM(n = 42)

5%

2% T315I (n = 20) IC50 > 200 nM

1% Q252H (n = 6)

2% F317L (n = 13)

< 1% V299L (n = 1)

3% E255K/V (n = 25)

31%

9%

Patients with resistance or suboptimal response to imatinib

Müller et al, 2008.

Response Rates by In Vitro IC50 to Response Rates by In Vitro IC50 to Dasatinib (excluding T315I)Dasatinib (excluding T315I)

96

73

54

43

94

58

47

34

82

34

2518

0

20

40

60

80

100

CHR MCyR CCyR MMR

Unknown (n=83)

≤3 nM (n=254)

>3 nM (n=44)

IC50 to dasatinib

%

Müller et al, 2008.

Nilotinib Efficacy According to Nilotinib Efficacy According to Baseline BCR-ABL Mutations in CML-CPBaseline BCR-ABL Mutations in CML-CP

Baseline Mutations in Imatinib-Resistant Patients (N = 202)

IC50-based grouping

IC50 ≤ 150 nM M244V, L248V, G250E,

Q252H, E275K, D276G, F317L, M351T, E355A, E355G, L387F, F486S

IC50 > 150 nM Y253H, E255K/V,

F359C/V

IC50 > 10,000 nM T315I

*Mutations without available IC50 data.

45%

24%

4%

4%

15%

5%

3%

No Mutation

IC50 ≤ 150 nM

Y253H

E255K/V

F359C/V

T315I

Others*

Hughes et al, 2009.

O’Hare et al, 2007.

The The ““DefaultDefault”” Mutant T315I Is Resistant to Mutant T315I Is Resistant to All Currently Approved BCR-ABL TKIsAll Currently Approved BCR-ABL TKIs

NCCN Guidelines: NCCN Guidelines: Treatment Options Based on BCR-ABL Treatment Options Based on BCR-ABL

Kinase Domain Mutation StatusKinase Domain Mutation Status

BCR-ABL KD Mutation Treatment Recommendation

T315I HSCT or clinical trial

V299L, T315A, F317L/V/I/C Consider nilotinib rather than dasatinib

Y253H, E255K/V, F359V/C/I

Consider dasatinib rather than nilotinib

Any other mutation Consider high dose imatinib or dasatinib or nilotinib

NCCN, 2012.

Drug Therapy Options for Patients With Drug Therapy Options for Patients With Failure on Second-Line TKI TreatmentFailure on Second-Line TKI Treatment

Third generation ABL kinase inhibitors

– Ponatinib

– Bosutinib

– DCC-2036

Non-targeted agents

– Omacetaxine

Inhibitors of other pathways

– Hedgehog/SMO inhibitors

– Beta-catenin inhibitors

National CML Society, 2011; Hu et al, 2009; Jagani et al, 2010; NCCN, 2012.

Ponatinib (AP24534): Binding to ABLPonatinib (AP24534): Binding to ABLT315IT315I

AP24534

Imatinib

T315I

N

N

O

ONH

N NF3C

H2N

OHAP24534

O’Hare et al, 2009, 2011.

T315I 11 > 3,125 > 200 > 2,000

BCR-ABLCellular Proliferation – IC50 (nM)

AP24534 Imatinib Dasatinib NilotinibNative 0.5 224 0.8 13

Treatment-Emergent AEs (≥ 20% any grade)

N (%; N = 74)

Any Grade ≥ Grade 3

Fatigue 26 (35) 0 (0)Constipation 25 (34) 0 (0)Rash 25 (34) 1 (1)Headache 24 (32) 0 (0)Arthralgia 23 (31) 2 (3)Nausea 22 (30) 0 (0)Abdominal pain 20 (27) 3 (4)Pyrexia 17 (23) 2 (3)Muscle spasms 16 (22) 0 (0)Vomiting 16 (22) 0 (0)Thrombocytopenia 20 (27) 15 (20)Neutropenia 10 (14) 6 (8)Anemia 14 (19) 6 (8)

Data October 15, 2010

Phase I Study of Ponatinib: Phase I Study of Ponatinib: SafetySafety

DLT: Pancreatitis

DLT = dose-limiting toxicity.Cortes et al, 2010.

Response to Ponatinib Response to Ponatinib

Best Response to CML-CP

N (%; 55 evaluable)

Overall

(N = 38)

T315I*

(N = 9)

Non-T315I

(N = 29)

Hematologic

CHR** 36 (95) 9 (100) 27 (93)

Cytogenetic

MCyR 25 (66) 9 (100) 16 (55)

CCyR 20 (53) 8 (89) 12 (41)

Data October 15, 2010

Cortes et al, 2010.

Best Response to CML-AP

N (%; 55 evaluable)

Overall

(N = 17)

T315I*

(N = 5)

Non-T315I

(N = 12)

Hematologic

MHR 6 (35) 1 (20) 5 (42)

Cytogenetic

MCyR 4 (24) 1 (20) 3 (25)

CCyR 2 (12) 0 (0) 2 (17)

*Includes only those with T315I status confirmed at study entry.

T315I detection in the context of TKI failure

Determine disease phase

CP AP/BC

Investigational agent

Tx candidate

Allograft in remission

Treatment Approach for T315I Detection Treatment Approach for T315I Detection and TKI Failureand TKI Failure

NCCN, 2012.

No Tx candidate

Evaluate for allograft

Chemotherapy or IA

Survival After Allogeneic Transplant Survival After Allogeneic Transplant in Patients With Imatinib Failurein Patients With Imatinib Failure

Saussele et al, 2010.

Key TakeawaysKey Takeaways Imatinib, nilotinib, and dasatinib are all approved options for

frontline therapy

Nilotinib and dasatinib are superior to imatinib in newly diagnosed CML-CP in surrogate end point (CCyR; MMR; CMR)

Improved PFS (statistically significant for nilotinib)

Longer follow-up required to ascertain positive effect on OS

Good monitoring starts with complete staging at diagnosis

Milestones define responses as optimal, suboptimal, or failure and are dependent on the type of therapy (will be updated for new TKIs)

Key Takeaways (cont.)Key Takeaways (cont.)

Treatment recommendations are outlined in the NCCN guidelines for specific BCR-ABL kinase domain mutations (eg, dasatinib for F359V/C/I mutations). However:

– Ponatinib is the most promising salvage therapy option for patients who failed second-line TKIs, including those with the T315I mutation

Allotransplant remains an important salvage option and is a mandatory consideration in case of progression to AP/BC

The following targeted agents are options for patients who fail second-line TKIs: Ponatinib, bosutinib, DCC-2036