A Video Viewpoint: Expert Discussions on CML Clinical Debates

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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.

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Disclosure of Conflicts of InterestDisclosure of Conflicts of Interest Jorge E. Cortes, MD, has no real or apparent conflicts of interest

to report.

Michael W.N. Deininger, MD, PhD, reported a financial interest/relationship or affiliation in the form of: Consultant, Ariad Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation; Contracted Research, Bristol-Myers Squibb Company, Celgene Corporation, Genzyme, Inc.

Jerald P. Radich, MD, reported a financial interest/relationship or affiliation in the form of: Consultant, Ariad Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Incyte Corporation, Novartis Pharmaceuticals Corporation, Pfizer, Inc.; Contracted Research, Novartis Pharmaceuticals Corporation.

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

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

Describe the laboratory tests needed to accurately diagnose/monitor CML

Employ strategies for selecting optimal frontline therapies based on individual patient characteristics

Explain how to define and identify a relapse

Describe the role of mutational analysis in individualizing second-line treatment

List investigational agents in clinical development for patients with relapsed/refractory disease

Provide accurate and appropriate counsel as part of the treatment team

Introduction to Faculty PanelIntroduction to Faculty Panel

Jorge E. Cortes, MD

– Professor, Leukemia

– The University of Texas M. D. Anderson Cancer Center

Michael W. N. Deininger, MD, PhD

– Chief – Division of Hematology and Hematologic Malignancies

– Huntsman Cancer Institute University of Utah

Jerald P. Radich, MD

– Professor

– Fred Hutchinson Cancer Research Center

Activity AgendaActivity Agenda

Roundtable Expert Discussions on CML Clinical Debates: A Collaborative Video Viewpoint Series with Medscape

Pre-Assessment

Panel Introduction

Clinical Debate 1: What Is the Optimal Frontline Therapy for Patients With CML? (30 mins)

Case study

– What laboratory tests should be ordered and how should the results be interpreted to make an accurate diagnosis? If CML is confirmed, how should first-line therapy be chosen based on patient characteristics? How should patients be monitored?

– Avoiding diagnosis pitfalls: RT-PCR vs. FISH vs. bone marrow biopsyInterpreting PCR resultsHow do patient comorbidities influence choice of first-line therapy?The latest trial data on alternatives to frontline imatinib: Second-generation TKIs

Activity Agenda (cont.)Activity Agenda (cont.) Clinical Debate 2: What Constitutes a Relapse and How Should the

Relapsed/Refractory Patient Be Treated? (30 mins)

Case study:

– How can a relapse be confirmed? What is the role of mutational analysis in choosing between an imatinib dose increase, second-line TKI, novel agent in a clinical trial, or stem cell transplant?

– Defining hematologic, cytogenetic, and molecular response: What constitutes an optimal response? A relapse?

– When should first-line therapy with imatinib be stopped and a new agent administered?

– What is the role of cytogenetic testing in treatment choice for the relapsed/refractory patient?

– What are the investigational novel agents in clinical development available to patients with T315I mutations and/or relapsed/refractory disease?

Post-Assessment

Roundtable Expert Discussions Roundtable Expert Discussions on CML Clinical Debates: on CML Clinical Debates:

A Collaborative Video Viewpoint A Collaborative Video Viewpoint Series With MedscapeSeries With Medscape

Clinical Debate 1:Clinical Debate 1:What Is the Optimal Frontline What Is the Optimal Frontline

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

Case Study 1: Case Study 1: Newly Diagnosed CMLNewly Diagnosed CML

47-yr-old teacher found to have elevated WBC (53 x 109/L) on routine blood work while trying to purchase life insurance policy

Initial work-up

– WBC (53 x 109/L), platelets (583 x 109/L), peripheral blood blasts (6%), basophils (2%)

– Spleen palpable 7 cm below costal margin

PMH includes diabetes mellitus well controlled with insulin

CML = chronic myeloid leukemia; WBC = white blood count; PMH = past medical history.

Case Study 1Case Study 1Laboratory TestingLaboratory Testing

You suspect a diagnosis of CML

What is your recommendation for initial work-up of this patient?

– Bone marrow aspiration with differential

– Cytogenetic analysis

– Peripheral blood FISH

– Real-time PCR in peripheral blood

– Mutations analysis

– Leukocyte alkaline phosphatase

– Vitamin B12 levels

FISH = fluorescent in situ hybridization; PCR = polymerase chain reaction.

Case Study 1:Case Study 1:Diagnosis and Result InterpretationDiagnosis and Result Interpretation

Bone marrow with 8% blasts, 3% basophils

Cytogenetics: 46XY, t(9;22;11) in 20/20 metaphases

FISH shows 98% interphases with a BCR-ABL fusion signal and deletion of the derivative 9 gene

Ph = Philadelphia; ACA = additional chromosomal abnormalities.

Case Study 1:Case Study 1:Diagnosis and Result Interpretation (cont.)Diagnosis and Result Interpretation (cont.)

How would you interpret these results?

– Classic Ph chromosome

– Varian Ph chromosome

– Clonal evolution

– ACA

– Blast phase

– An error in reporting

Ph = Philadelphia; ACA = additional chromosomal abnormalities.

What Is Clonal EvolutionWhat Is Clonal Evolution

X xx

Clonal evolution

X xx ACA

(Clonal “selection”)

X x

Diploid

Variant Ph

X xx

X x9 22

Case Study 1:Case Study 1:DiagnosisDiagnosis

Based on these results what phase do you consider this patient to be in?

– Chronic phase

– Late chronic phase

– Second chronic phase

– Accelerated phase

– Blast phase

17

Chronic Accelerated Blastic

• Asymptomatic (if treated)

• None of criteria for accelerated or blast blast phase

• Blasts 15%

• Bl + pros 30%

• Basophils 20%

• Plts < 100,000/mcl

• Clonal evolution

• Blasts 30%

• Extramedullary

disease with localized

immature blasts

CML PhasesCML Phases

Past 3-5 years 12-18 months 3-9 months

Present 25+ years 4-5 years 6-12 months

Choosing First-Line TherapyChoosing First-Line Therapy

If the patient has a healthy brother and sister, what are the options for first-line treatment?

– Imatinib 400 mg

– Imatinib 800 mg

– Dasatinib 100 mg daily

– Nilotinib 300 mg bid

– Nilotinib 400 mg bid

– SCT

bid = twice daily; SCT = stem cell transplant.

Patient Characteristics: Patient Characteristics: Influencing Therapy Influencing Therapy

How do patient comorbidities influence choice of first-line therapy?

bid = twice daily; SCT = stem cell transplant.

Improving Frontline Therapy in Improving Frontline Therapy in CMLCML

Standard-dose imatinib

High-dose imatinib

Imatinib-based combinations

Second generation TKI

– Dasatinib

– Nilotinib

– Bosutinib

TKI = tyrosine-kinase inhibitor.NCCN, 2011.

Results With Imatinib in Early Results With Imatinib in Early CP-CML: IRIS Trial at 8 YrsCP-CML: IRIS Trial at 8 Yrs

304 (55%) patients on imatinib on study

Projected results at 8 yrs

– CCyR: 83%

• 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP

– EFS: 81%

– TFS: 92%

• If MMR at 12 mos: 100%

– Survival: 85% (93% CML-related)

Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, 0.4%

CP-CML = chronic-phase CML; CCyR = complete cytogenic response; AP = accelerated phase; BP = blast phase; EFS = event-free survival; TFS = transformation-free survival; MMR = major molecular response; IRIS = International Randomized Study of Interferon and STI571.Deininger et al, 2009.

Kantarjian et al, 2011.

Survival in Early CP-CMLSurvival in Early CP-CML

Long-Term Outcome With Imatinib Long-Term Outcome With Imatinib in Early CP-CML (ITT)in Early CP-CML (ITT)

Pro

bab

ility

(%

)

1.0

0.8

0.6

0.4

0.2

0.1

0.9

0.7

0.5

0.3

6054481260

Time From Start of Imatinib Therapy (mos)

4236302418

SurvivalPFS

EFSCHR

Loss of MCyR

63%

de Lavallade et al, 2008.

TOPS: Rate of MMR Over Time TOPS: Rate of MMR Over Time by Imatinib Dose (ITT)by Imatinib Dose (ITT)

476 patients with early CP-CML randomized to imatinib 400 mg daily vs. 800 mg daily

Outcome at 24 mosPercent (%)

400 mg 800 mg

CCyR 76 76

MMR 54 51

EFS 95 95

PFS 97 98

Significant impact of dose intensity/treatment interruptions on MMR rate

TOPS = tyrosine kinase inhibitor optimization and selectivity: ITT = intent-to-treat; PFS = progression-free survival.Baccarani, Druker, et al, 2009.

High-Dose Imatinib as Initial Therapy in CMLHigh-Dose Imatinib as Initial Therapy in CML 281 patients Rx’d with imatinib 400 mg (n = 73) or 800 mg (n = 208)Overall Response (%) 400 mg 800 mg p ValueCCyR 87 91 .49MMR 78 87 .06CMR 39 49 .21

CMR = complete molecular response.

Pemmaraju et al, 2010.

0 12 24 36 48 60 72 84 96 108 1200.0

0.2

0.4

0.6

0.8

1.0

400mg 800mg

Total73

208

No.event1522

p = 0.01

0 12 24 36 48 60 72 84 96 108 120

1

0.8

0.6

0.4

0.2

0

800 mg 400 mg

Total CMR 206 100 71 28

p = 0.04

Time to CMR EFS

Significance of OCT-1 Activity Significance of OCT-1 Activity in Response to Imatinibin Response to Imatinib

Transporter responsible for imatinib cell influx Not required for second generation TKI

Outcome DosePercent (%)

p ValueLow OCT-1 High OCT-1

MMR < 600 mg 27 92 .021

600 mg 72 87 .093

EFS < 600 mg 27 67 .018

600 mg 61 80 .241

TFS < 600 mg 73 100 .048

600 mg 100 100 NS

OCT-1 = organic cation transporter-1; NS = not significant.White, Dang, et al, 2010.

Imatinib + IFN as Frontline Imatinib + IFN as Frontline Therapy for CMLTherapy for CML

CML-IV

– 1,014 patients randomized to IM 400 mg, IM 800 mg, or IM 400 mg + IFN-α (median dose: 1.7 MU/d)

– No improvement in response rate of 5-yr PFS with IFN

SPIRIT

– 636 patients randomized to IM 400 mg, IM 600 mg, IM + ara-C, and IM 400 mg + Peg-IFNα-2a

– Higher rate of MMR, SMRa, and CMR at 24 mos

– No difference in 4-yr EFS

MDACC

– 91 patients randomized to IM 800 mg ± Peg-IFN-2b

– No difference in response, EFS, PFSa ≤ 0.01%.IM = intramuscular prospective randomized trial; SPIRIT = STI571; ara-C = cytarabine; SMR = superior molecular response; MDACC = The University of Texas M. D. Anderson Cancer Center.Hehlmann et al, 2011; Preudhomme et al, 2010; Cortes et al, 2011.

EFS by Treatment in Early CP-CMLEFS by Treatment in Early CP-CML

Cortes, O’Brien, et al, 2009.

Time (mos)

Pro

bab

ility

EF

S (

%)

0 12 24 36 48 60 72 84 96 108 1200.0

0.2

0.4

0.6

0.8

1.0

Imatinib 400 mg Imatinib 800 mg Dasatinib Nilotinib

Total73

2087678

Events152221 p = 0.01

Nilotinib Vs. Imatinib in Newly Nilotinib Vs. Imatinib in Newly Diagnosed CML (ENESTnd)Diagnosed CML (ENESTnd)

Primary end point: MMR at 12 mos

Key secondary end point: Durable MMR at 24 mos

Other end points: CCyR by 12 mos, time to MMR and CCyR, EFS, PFS, time to AP/BC on study treatment, OS including follow-up

Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg bid (n = 282)RANDOMIZEDa

Nilotinib 400 mg bid (n = 281)

N = 846 217 centers 35 countries

Follow-Up 5 yrs

aStratification by Sokal risk score.ENESTnd = evaluating nilotinib efficacy and safety in clinical trials - newly diagnosed patients; OS = overall survival.Larson et al, 2010.

Nilotinib Vs. Imatinib in Nilotinib Vs. Imatinib in Newly Diagnosed CP-CMLNewly Diagnosed CP-CML

846 patients randomized to nilotinib 300 mg bid (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg QD (n = 283)

Minimum follow-up: 24 mos

Outcome Nil 300 Nil 400 IM 400

% CCyRa 87 85 77

% MMRa 71 67 44

% BCR-ABL ≤ 0.0032%a 26 21 10

% Discontinued Treatment 18 21 22

New Mutation (No.) 10 8 20

aBy 24 mos.Larson et al, 2011; Kantarjian, Hochhaus, et al, 2011.

ENESTnd: Progression to AP/BCENESTnd: Progression to AP/BCN

o. P

atie

nts

0.7% 0.7%

Nilotinib 300 mg bid Nilotinib 400 mg bid Imatinib 400 mg QD

p = .0059

p = .0196

p = .0003

p = .0089

Including Clonal Evolution1.1% 4.2% 1.8% 6.0%

Progression events after discontinuation of treatment occurred in an additional 7, 2, and 6 patients (excluding clonal evolution) in nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively; progression within 60 days of discontinuation occurred in 1, 1, and 2 of these patients across respective arms

Larson et al, 2011; Kantarjian, Hochhaus, et al, 2011.

Dasatinib Vs. Imatinib Study inDasatinib Vs. Imatinib Study inTreatment-Naïve CML (DASISION)Treatment-Naïve CML (DASISION)

Trial Design Trial Design

Primary end point: Confirmed CCyR by 12 mos

Secondary/other end points: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; OS

Follow-Up

5 yrsRandomizeda

Imatinib 400 mg QD (n = 260)

Dasatinib 100 mg QD (n = 259)N = 519

108 centers

26 countries

aStratified by Hasford risk score.DASISION = dasatinib vs. imatinib study in treatment-naive CML patients.Kantarjian, Shah, et al, 2011.

Dasatinib Vs. Imatinib in Newly Dasatinib Vs. Imatinib in Newly Diagnosed CP-CMLDiagnosed CP-CML

519 patients randomized to dasatinib 100 mg QD (n = 259) or imatinib 400 mg QD (n = 260)

Median follow-up: 24 mos

Outcome Das 100 IM 400

% CCyR 86 82

% MMR 64 46

% BCR-ABL ≤ 0.0032% 17 8

% Discontinued Therapy 23 25

New Mutations (No.) 10 10

Kantarjian, Shah, et al, 2011.

n/N 6/259 13/260 9/259 15/260

(%)

On Study Including Follow-Up Beyond Discontinuation

DASISION: Transformation DASISION: Transformation to AP/BP CML (ITT)to AP/BP CML (ITT)

Dasatinib 100 mg QD Imatinib 400 mg QD


100

DASISION: Cumulative Incidence of MMRDASISION: Cumulative Incidence of MMR

0 10 20 30 40

MMR (%)

100

80

60

40

20

0

Time (mos)

By 12 mos46%

28%

By 24 mos64%

46%

p < .0001

Dasatinib 100 mg QD

Imatinib 400 mg QD


DASISION: CMRDASISION: CMR4.54.5 Rates (ITT) Rates (ITT) by Month of Treatmentby Month of Treatment

(%)

12 mos 24 mos6 mos 18 mos

Dasatinib 100 mg QD Imatinib 400 mg QD100


Bosutinib Efficacy and Safely in Newly Bosutinib Efficacy and Safely in Newly Diagnosed CML (BELA): Study DesignDiagnosed CML (BELA): Study Design

Eligibility criteria: Cytogenetic diagnosis of Ph+ CP-CML 6 mos prior; No prior therapy other than hydroxyurea or anagrelide

Primary end point: CCyR rate at 12 mos

Secondary end points:

– MMR rate at 12 mos

– Time to CCyR and MMR

– Time to and rate of transformation to AP/BP CML, survival

– Safety and tolerability

Phase III Open-Label Trial in Newly Diagnosed

CP-CML

N = 502

139 Sites, 31 Countries

Stratification Factors:Geographical Region (3 regions), Sokal score

Bosutinib 500 mg/day

(n = 250)

Imatinib 400 mg/day

(n = 252)

5-yr follow-up

5-yr follow-up

RANDOMIZE

1-yr analysis

BELA = bosutinib efficacy and safety in CML.Gambacorti-Passerini et al, 2011.

Bosutinib Vs. Imatinib in Bosutinib Vs. Imatinib in Newly Diagnosed CP-CMLNewly Diagnosed CP-CML

502 patients randomized to bosutinib 500 mg QD (n = 250) or imatinib 400 mg QD (n = 252)

Minimum follow-up: 18 mos

Response at 12 mos Bos 500 IM 400

% CCyRa 79 79

% MMRa 55 45

% CMRa 18 10

% Discontinued Therapya 33 26

Gambacorti-Passerini et al, 2011.

aBy 18 mos.

Outcome by Frontline Therapy Outcome by Frontline Therapy in CP-CML: BELAin CP-CML: BELA

9 33 5 94 13

Gambacorti-Passerini et al, 2011.

1 3 6 9 12 15 18 21 24

IM800

10%

1%CCyR

0.1%MMR

Day 22 IM < 1,000 ng/mL

IM600

Nilotinib

IM800

IM800

IM800

Yeung et al, 2010.

Selective Dose Escalation and Selective Dose Escalation and Early Switch for CML TherapyEarly Switch for CML Therapy

105 patients, median follow-up: 21 mos (12–36 mos)

Still on Rx: 88% (65% imatinib, 23% nilotinib)

13% 12%22% 21%

30%

0%

10%

20%

30%

40%

50%

60%

70%

80%

3 6 9 12 15 18 21 24

101 103 103 105 76 59 48 33

18%

48%

61%67%

71%

80% 77%82%

MMR

CMRIS ≤ 0.0032%

Time Points (mos)

MMR after switch to nilotinib: For intolerance 91%, for suboptimal response 9%

TIDEL = trial of imatinib with dose escalation in CML.Yeung et al, 2010.

TIDEL II Primary End Point: 12-mos MMRTIDEL II Primary End Point: 12-mos MMR

Impact of OCT-1 Activity on Response to Impact of OCT-1 Activity on Response to Dose Increase or Change to Nilotinib Dose Increase or Change to Nilotinib

63 patients with ≥ 12-mos follow-up and OCT-1 activity assessed

12-mos MMR

MutationsIM to 800 mg

MMR on IM

800 mg

Switched to Nil

MMR on Nil

Low OCT-1 (n = 26)

37% 19% 23% 17% 42% 10%

High OCT-1 (n = 37)

81% 0% 8% 100% 14% 100%

White, Saunders, et al, 2010.

Probability of Resistance by Probability of Resistance by Molecular Response at 3 MosMolecular Response at 3 Mos

Hughes et al, 2006.

83%

5%

0%

P <0.001

-5

15

35

55

75

95

0 5 10 15 20 25 30

Time on Imatinib (mos)

Pro

ba

bili

ty o

f Re

sist

an

ce (

%)

0–1 log (n = 10)

> 1–2 log (n = 22)

> 2 log (n = 20)

Probability of MMR and Progression by Probability of MMR and Progression by Early Molecular Response to ImatinibEarly Molecular Response to Imatinib

BCR-ABL/ABL

Transcript Levels

% Probability Outcome by Transcript Levels at Specified Mos

MMR (mos) Progression (mos)

3 6 12 3 6 12

≤ 0.1 100 96 97 4 1 3

> 0.1–1 84 69 61 3 7 2

> 1–10 53 44 20 11 9 8

> 10 33 15 7 13 23 50

p < .001 p < .001 p < .001 p < .001 p < .001 p < .001

Quintas-Cardama, Kantarjian, et al, 2009.

7-Yr Outcome by Molecular Response: 7-Yr Outcome by Molecular Response: All PatientsAll Patients

LandmarkPercent (%)

MMR No MMR

6 mosEFS 85 84TFS 96 93OS 90 89

12 mosEFS 91 79TFS 99 90OS 93 89

18 mosEFS 95 75TFS 99 90OS 95 90

Hughes et al, 2010.

7-Yr Outcome by Molecular Response: 7-Yr Outcome by Molecular Response: Only Patients With CCyROnly Patients With CCyR

LandmarkPercent (%)

MMR No MMR

6 mosEFS 85 93TFS 96 98OS 90 93

12 mosEFS 91 92TFS 99 96OS 93 97

18 mosEFS 95 86TFS 99 96OS 95 96

Hughes et al, 2010.

OS by 12-Mos Response OS by 12-Mos Response in CP-CMLin CP-CML

848 patients randomized to IM 400 mg, IM 800 mg, or IM 400 mg + IFN


Hehlmann et al, 2011.

Time to Loss of CCyR by Time to Loss of CCyR by Molecular Response at 18 MosMolecular Response at 18 Mos

Hughes et al, 2010.

167 patients with CP-CML treated with frontline dasatinib or nilotinib Median follow-up: 33 mos (range: 3–66 mos)

Mos on Therapy Response Total (%)

3 (N = 160)

Optimal 160 (100)

Sub-optimal 0

Failure 0

6 (N = 155)

Optimal 152 (98)

Sub-optimal 3 (2)

Failure 0

12 (N = 129)

Optimal 128 (99)

Sub-optimal 1 (1)

Failure 0

18 (N = 119)

Optimal 99 (84)

Sub-optimal 14 (12)

Failure 5 (4)

Jabbour et al, 2011a.

Optimal Response to Second TKIs: Optimal Response to Second TKIs: Frontline Response (N = 167)Frontline Response (N = 167)

Long-Term Outcome by Response Long-Term Outcome by Response at 6 Mos From Start of Therapyat 6 Mos From Start of Therapy

435 CP-CML patients treated with frontline imatinib 400 (n = 73), imatinib 800 (n = 208), dasatinib (n = 76), or nilotinib (n = 78)

EFS OS

Jabbour et al, 2011b.

CML Frontline Therapy – 2011 CML Frontline Therapy – 2011

Frontline therapy: New standard

– Imatinib is good

– Second generation TKI (dasatinib, nilotinib, bosutinib) are better

– Sequential therapy?

– Adequate monitoring and management of AEs

Failure to therapy

– New definitions (no CCyR at 6 mos)?

– Prompt identification and action of suboptimal response if imatinib therapy

No need to change if responding to imatinib

How Should Patients Be How Should Patients Be Monitored?Monitored?

Which of the following tests would you use to monitor your patient?

1) Cytogenetic analysis

2) FISH

3) PCR

4) Mutation analysis

5) Imatinib plasma levels

6) All of the above

53

Monitoring Procedures in CMLMonitoring Procedures in CML

CG: looks at all chromosomes; but: tedious; needs metaphases; only 20 cells counted (SD ± 15%); painful BM

FISH: faster; 200 cells; PB; but: false + up to 5-10%; no information on other chromosomes

PCR: most sensitive; PB; evaluable in CCyR; predicts for relapse; but: not standardized; no information on other chromosomes; variability up to 0.5 log; use 1 source (PB) and 1 reliable lab

Monitoring Recommendations for Monitoring Recommendations for CML According to the ELN 2009CML According to the ELN 2009

Objective Recommended frequency

HematologicEvery 2 wk until CHR, then at least every 3 mo or as required

Cytogenetic

At diagnosis, 3 mo, 6 mo and every 6 mo until confirmed CCyR, then every 12 mo if molecular monitoring not assured

At failure or unexplained myelosuppression

Molecular Every 3 mo until MMR confirmed, then every 6 mo

MutationsIn case of failure or suboptimal response, or before change to 2nd TKI

Baccarani et al. JCO 2009; 27: 6041-51

7-Year Outcome by Molecular 7-Year Outcome by Molecular Response – Patients with CCyRResponse – Patients with CCyR

LandmarkPercentage

MMR No MMR

6 mo

EFS 85 93

TFS 96 98

OS 90 93

12 mo

EFS 91 92

TFS 99 96

OS 93 97

18 mo

EFS 95 86

TFS 99 96

OS 95 96

Hughes T, et al. 2010.

Clinical Debate 2:Clinical Debate 2:What Constitutes a Relapse and What Constitutes a Relapse and

How Should the Relapsed/Refractory How Should the Relapsed/Refractory Patient Be Treated?Patient Be Treated?

Case Study 2: CML Post Case Study 2: CML Post Imatinib TherapyImatinib Therapy

A 52-yr-old woman with an HLA-identical sibling started therapy with imatinib 400 mg daily upon diagnosis of CP-CML.

She has now received imatinib 400 mg daily for 6 mos.

CG at 12 mos shows Ph+ 50%.

HLA = human leukocyte antigen.

Confirming RelapseConfirming Relapse

How can relapse be confirmed?

How can you define hematologic, cytogenetic and molecular response?

What constitutes an optimal response?

Case Study 2: Response Post Case Study 2: Response Post Imatinib TherapyImatinib Therapy

How would this response be labeled?

– Failure

– Secondary resistance

– Suboptimal response

– Optimal response

Criteria for Failure and Suboptimal Criteria for Failure and Suboptimal Response to ImatinibResponse to Imatinib

Time (mos)Response

Failure Suboptimal Optimal

3 No CHR No CG Response < 65% Ph+

6 No CHR> 95% Ph+ ≥ 35% Ph+ ≤ 35% Ph+

12 ≥ 35% Ph+ 1%–35% Ph+ 0% Ph+

18 ≥ 5% Ph+ No MMR MMR

Any

Loss of CHRLoss of CCyR

MutationCE

Loss of MMRMutation

Stable or Improving MMR

Baccarani, Cortes, et al, 2009.

CML Post Imatinib Therapy:CML Post Imatinib Therapy:ManagementManagement

How would you manage this patient now?

– Continue imatinib 400 mg QD

– Increase imatinib dose

– Change to dasatinib 100 mg QD

– Change to nilotinib 400 mg bid

– Allogeneic BMT

BMT = bone marrow transplant.

CML Post Imatinib Therapy (cont.)CML Post Imatinib Therapy (cont.)

The patient has now received imatinib 400 mg daily for 12 mos with good tolerance. You repeat a cytogenetic analysis and it shows 10% Ph+ metaphases.

How would you label this response now?

– Failure




CML Post Imatinib Therapy:CML Post Imatinib Therapy:Management (cont.)Management (cont.)

How would you manage this patient now:

– Continue imatinib 400 mg QD

– Increase imatinib dose



– Allogeneic BMT

Response Post Imatinib Therapy Response Post Imatinib Therapy (cont.)(cont.)

The patient has now received imatinib for 18 mos, the last 6 mos at 800 mg/d. The patient has a sustained CCyR but has not achieved an MMR.

How would you label this response:

– Failure




CML Post Imatinib TherapyCML Post Imatinib Therapy(cont.)(cont.)

How would you manage this patient now:

– Continue imatinib 400 mg bid



– Start an investigational option

– Allogeneic BMT

Cytogenetic TestingCytogenetic Testing

What is the role of cytogenetic testing in treatment choice for the relapsed/refractory patient?

Long-Term Outcome With Imatinib Long-Term Outcome With Imatinib in Early CP-CML (ITT)in Early CP-CML (ITT)

Pro

bab

ility

(%

)

1.0

0.8

0.6

0.4

0.2

0.1

0.9

0.7

0.5

0.3

6054481260

Time From Start of Imatinib Therapy (mos)

4236302418

SurvivalPFS

EFSCHR

Loss of MCyR

63%

de Lavallade et al, 2008.

Frequency of Suboptimal Response Frequency of Suboptimal Response With Imatinib TherapyWith Imatinib Therapy

Time on Rx (mos) Response

% With Responsep Value

400 mg 800 mg

3Optimal 100 99

NSSuboptimal 0 0Failure 0 1

6Optimal 83 96

.002Suboptimal 12 1Failure 6 3

12Optimal 70 92

< .001Suboptimal 17 4Failure 13 3

18Optimal 44 52

.005Suboptimal 33 43Failure 23 5

Alvarado et al, 2009.

EFS by Response to Imatinib at 18 MosEFS by Response to Imatinib at 18 Mos

Alvarado et al, 2009.

Time (mos)

Treatment Options for Imatinib Treatment Options for Imatinib Resistant CMLResistant CML

Higher doses of imatinib

Second generation TKIs

Allogeneic SCT

Third generation TKIs (ie, T315I inhibitors)

Others: Omacetaxine, decitabine, hedgehog inhibitors

NCCN, 2011; Cortes, Khoury, Nicolini, et al, 2009; Kantarjian et al, 2003; Zhao et al, 2009.

Treatment Recommendations Treatment Recommendations for CP-CML According to ELNfor CP-CML According to ELN

Status Recommendation

First-line

All Imatinib 400 mg

Second-line

IM Intolerant Dasatinib or nilotinib

Suboptimal Imatinib same dose, or dose, or dasatinib or niloitnib

Failure Dasatinib or nilotinib; SCT if AP/BP or T315I

Third-line

Second TKI Suboptimal Conitnue same; SCT if warnings and EBMT score ≤ 2

Second TKI Failure SCT

ELN = European LeukemiaNet; SCT = stem cell transplant; EBMT = European Group for Blood and Marrow Transplantation. Baccarani, Cortes, et al, 2009.

Is There a Role for Imatinib Is There a Role for Imatinib Dose Escalation?Dose Escalation?

CCyR 50% if cytogenetic failure to imatinib 400 mg, 5% if hematologic failure

Uses

– Suboptimal response: Long-term benefit unclear

– Failure

• Second generation TKI unavailable or impractical

• Loss of CyR

• Sensitive mutations

Breccia et al, 2011.

Dasatinib in CP-CML After Imatinib FailureDasatinib in CP-CML After Imatinib Failure

Parameter (%) N = 167

MCyR (2-yr) 63

CCyR (2-yr) 50

5-yr MMR 445-yr PFS 575-yr OS 78Pleural Effusion 24

Grade 3–4 4

Mutations persisting or developing after dasatinib discontinuation for loss of response: V299L, T315I, and F317L

60-mos follow-up of dose optimization study

35% still on treatment: 46% still at 100 mg QD (35% < 100 mg QD)

Shah et al, 2011.

PFS With Dasatinib After Imatinib FailurePFS With Dasatinib After Imatinib Failure

Progression was defined as increasing WBC count, loss of CHR or MCyR, ≥ 30% increase in Ph+ metaphases, confirmed AP/BP disease, or death

PFS rate (95% CI)

n 12 mos 24 mos 36 mos 48 mos 60 mos

100 mg QD 167 91% 81% 72% 63% 57% (48–67)

70 mg bid 168 87% 76% 68% 66% 61% (52–70)

140 mg QD 167 87% 75% 61% 56% 51% (40–62)

50 mg bid 168 86% 76% 73% 69% 67% (58–75)

Not

Pro

gres

sed

(%)

1.0

0.8

0.6

0.4

0.2

0.0

0 6 12 18 24 30 36 42 48 54 60 66

Time (mos)

CI = confidence interval; CHR = complete hematologic response.

Shah et al, 2011.

OS With Dasatinib After Imatinib FailureOS With Dasatinib After Imatinib Failure

OS rate (95% CI)

n 12 mos 24 mos 36 mos 48 mos 60 mos

100 mg QD 167 96% 91% 88% 82% 78% (72–85)

70 mg bid 168 94% 88% 81% 75% 73% (66–80)

140 mg QD 167 96% 94% 86% 83% 79% (72–86)

50 mg bid 168 96% 91% 85% 82% 75% (68–82)

Aliv

e (%

)

1.0

0.8

0.6

0.4

0.2

0.0

0 6 12 18 24 30 36 42 48 54 60 66

Time (mos)

Shah et al, 2011.

Nilotinib in CP-CML Post Imatinib FailureNilotinib in CP-CML Post Imatinib Failure

Kantarjian, Giles, et al, 2011.

321 patients with imatinib resistance (71%) or intolerance (29%)

Median age – 58 yrs; median exposure – 19 mos

Nilotinib 400 mg po bid ≥ 6 mos

Median dose intensity 789 mg/d

Grade 3–4 ↓ platelets 31%, neutrophils 31%; lipase elevation 17% (pancreatitis < 1%), bilirubin 8%

Outcome Percent (%)CHR 85MCyR/CCyR 59/44

Resistant 56/41Intolerant 66/51

24-mos OS/PFS 87/64

EFS With Nilotinib After Imatinib EFS With Nilotinib After Imatinib Failure in CP-CMLFailure in CP-CML


64% at 24 mos

OS With Nilotinib After OS With Nilotinib After Imatinib Failure in CP-CMLImatinib Failure in CP-CML


Bosutinib (SKI–606) in CML and Ph+ ALLBosutinib (SKI–606) in CML and Ph+ ALL Src-Abl inhibitor 30x more potent than IM

– No inhibition of PDGFR, c-kit

321 CP patients; median time from diagnosis 52 mos

Bosutinib 400–600 mg/d; phase II 500 mg/d


PDGFR = platelet-derived growth factor receptor; ALL = acute lymphocytic leukemia.Cortes et al, 2008.

Response (%) in CP, prior imatinib only (N = 102)

Resistant(n = 69)

Intolerant(n = 33)

CHR 81 82

MCyR 45 51

CCyR 32 40

MMR 42 39

CMR 22 32

Grade 3–4 toxicity: Thrombocytopenia 21%, neutropenia 12%, diarrhea 8%, rash 7%

Better Outcome on Dasatinib Better Outcome on Dasatinib With Earlier InterventionWith Earlier Intervention

Quintás-Cardama, Cortes, et al, 2009.

Patients on dasatinib studies analyzed by failure status on imatinib: loss of MCyR vs. loss of CHR

Status at IM Failure No.Percent (%)

CCyR MMR

Loss of MCyR 151 72 60

Loss of CHR and MCyR 33 42 29

Loss of CHR (never MCyR) 109 26 26

Dasatinib Early Intervention EFS and OSDasatinib Early Intervention EFS and OS

Quintás-Cardama, Cortes, et al, 2009.

EFS OSLoss of MCyR

Loss of CHR

Loss of MCyR and CHR

Mechanisms of Resistance to Mechanisms of Resistance to ImatinibImatinib

BCR-ABL dependent

– Mutations in ABL

– Amplification/overexpression

– Remigration of BCR-ABL to cytoplasm

BCR-ABL independent

– Decreased hOCT1 expression

– Increased MDR expression

– Increased alpha-1 acid glycoprotein

– Overexpression of Src-related kinases

Quiescent stem cells (persistence)

le Coutre et al, 2000; Weisberg et al, 2000; Mahon et al, 2000; Gamacorti-Passerini et al, 2000; Vigneri et al, 2001.

Sensitivity of Mutations to TKISensitivity of Mutations to TKIBa/F3 cell proliferation IC50 (nM)

Imatinib Nilotinib Dasatinib

WT 260 13 0.8M244V 2,000 38 1.3G250E 1,350 48 1.8Q252H 1,325 70 3.4Y253F 3,475 125 1.4Y253H > 6,400 450 1.3E255K 5,200 200 5.6E255V > 6,400 430 11V299L 540 ND 18T315A 971 61 125T315I > 6,400 > 2,000 > 200F317L 1,050 50 7.4F31TV 350 ND 53E355G 2,300 ND 1.8F359V 1,825 175 2.2V379I 1,630 51 0.8H396P 850 41 0.6H396R 1,750 41 1.3

O’Hare et al, 2007.Resistant / Moderately Sensitive / Sensitive

CCyR by Mutations in CML Treated with CCyR by Mutations in CML Treated with Second Generation TKI After IM FailureSecond Generation TKI After IM Failure

86/169 (51%) patients treated had mutation

– CP 30/59 (51%), AP 41/71 (58%), BP 15/39 (38%)

Mutations classified into high, intermediate, and low sensitivity to dasatinib or nilotinib based on IC50

Jabbour et al, 2009.

Chronic Phase Accelerated Phase

T315I and F359V recovered after treatment with SKI-606

Cortes et al, 2007.

Spectrum and Frequency of BCR-ABL KD Spectrum and Frequency of BCR-ABL KD Mutations Recovered After TKI TherapyMutations Recovered After TKI Therapy

No MCyR (27)

MCyR (59)

0

0.2

0.4

0.6

0.8

1

0 12 24 36Time (mos on imatinib)

Pro

ba

bili

ty o

f R

esi

sta

nce

(%

)

Time to Response to Second Generation TKITime to Response to Second Generation TKI

Response at 12 mos

% AP/BP/Death/CHR Loss Next Year

MCyR 3%

No MCyR 17%

113 CP-CML patients receiving nilotinib (n = 43) or dasatinib (n = 70) after imatinib failure

Tam et al, 2008.

p = .003

CG Response at 3–6 mos Probability MCyR at 12 mosNone 3%–7%

≥ mCyR > 50%

MSD and MUD SCT in CP-CML MSD and MUD SCT in CP-CML 3,514 MDS and 1,052 URD SCT from CIBMTR from 1988–2003

All in CP1; median age: 35–37

OS LFS

LFS = leukemia-free survival.Arora et al, 2009.

Saussele et al, 2010.

Pro

babl

ity o

f su

rviv

al

HSCT in advanced phase, n= 28, 3 year survival 59%

HSCT after IM failure in 1st CP, n= 37, 3 year survival 94%

Elective HSCT, n=19, 3 year survival 88%

n=84

Months after transplantation

Median age: 38 yrs (21–56 yrs)Median time from Dx: 18 mo (5–54 mos)

Allo-SCT for CML in the Imatinib Era Allo-SCT for CML in the Imatinib Era

Allo-SCT After Imatinib ResistanceAllo-SCT After Imatinib Resistance 47 patients with imatinib resistant CML

34 CP, 9 AP, 4 BP

19 (40%) with ABL1 mutations (4 with T315I)

15/19 had AP, BP, or second CP

Jabbour, Cortes, et al, 2011.

EFS by Mutational Status

Group No.2-yr EFS, % (95%

CI)

2-yr OS, %

(95% CI)All patients 47 49 (35–64) 63 (49-78)

ABL1 mutation 19 36 (14–58) 44 (20-67) No mutation 28 58 (39-77) 76 (59-93) p value .05 .02

Phase CP 16 62 (39-86) 72 (49-96) AP 31 44 (25-61) 59 (41-77) p value .27 .30

CP only ABL1 mutation 4 25 (0-67) 33 (0-87) No mutation 12 75 (50-99) 81 (58-100) p value .20 .13

AP/BP only ABL1 mutation 15 40 (15-65) 46 (20-71) No mutation 16 45 (18-72) 72 (48-96) p value .20 .12

OS by Mutational Status

Jabbour, Cortes, et al, 2011.

Allo-SCT After Imatinib ResistanceAllo-SCT After Imatinib Resistance

SCT in CML According to ELN 2009SCT in CML According to ELN 2009Searching for family donor

At diagnosis Patients in AP/BPPatients < 20 yrsPatients with warning factors

At imatinib failure All patients

Searching for unrelated donor

At diagnosis Patients in AP/BP

At imatinib failure Patients who progressed to AP/BP, or with T315I, or with hematologic resistance

During/after second TKI Patients with TKI failurePatients with a suboptimal response and EBMT risk 0–2

Performing allo-SCT

At diagnosis Patients in AP/BP (pretreatment with TKI recommended)

At imatinib failure Patients in AP/BP (pretreatment with second generation TKI recommended), or with T315I

Failure to second TKI All patients


Criteria for Failure to Second Criteria for Failure to Second Generation TKI (ELN) Generation TKI (ELN)

Time (mos) Suboptimal Failure Warning

Baseline NA NA Imatinib Heme Resistance

CEMutations

3 Ph+ 36%–65% Ph+ > 95%New mutation

Ph+ 66%–95%

6 Ph+ 1%–35% Ph+ 66%–95%New mutation

Ph+ 36%–65%

12 No MMR Ph+ > 35%New mutation


Dasatinib and Nilotinib in Advanced Dasatinib and Nilotinib in Advanced Phase CML After Imatinib FailurePhase CML After Imatinib Failure

Accelerated phase (dasatinib, nilotinib)

– MaHR: 50%–60%

– MCyR: 30%–40%

• CCyR: 19%–30%

– PFS: 40%–50% at 24 mos

Blast phase (dasatinib)

– MaHR: 30%–40%

– MCyR: 30%–50%

– Median PFS: 3–5 mosMaHR = major hematologic response.Kantarjian et al, 2010; Kantarjian, Hochhaus, et al, 2011; Kantarjian, Giles, et al, 2011b.

Survival of Patients With T315ISurvival of Patients With T315I

CML CP (n=82, dead=37)

CML AP (n=38, dead=16)

CML BP (n=56, dead=48)

Ph+ ALL (n=46, dead=32)

Nicolini et al, 2009. Jabbour et al, 2008.

0 6 12 18 24 30

Time

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

CP AP BP

No.169

12

No. Failure109

12

Use of Second Generation TKI as Third-Line TherapyUse of Second Generation TKI as Third-Line Therapy 37 patients treated with dasatinib (n = 29) or nilotinib (n = 8) after 2 TKI failure

MCyR: CP 25%, AP 33%, BP 25%

Failure •Loss CHR•Loss MCyR•Loss of CCyR•Discontinuation for toxicity•Transformation to AP/BP•Death

Failure-Free Survival

Garg et al, 2009.

CML Resistance to TherapyCML Resistance to Therapy

Goal of therapy in CML: Improve long-term outcome

Current results could be improved

Definition of resistance evolving

Early end points critical for long-term benefit

Early treatment intervention required for optimal long-term benefit

Good treatment options available

– Better treatment options needed

What Is The Role of Mutational What Is The Role of Mutational Analysis?Analysis?

When would you test for mutations on a patient like this:

– At the time imatinib is started

– At the time suboptimal response is detected

– At the time resistance to imatinib is documented

– At regular intervals during therapy

– I would not check for mutations

Investigational Agents for Investigational Agents for Relapsed/Refractory DiseaseRelapsed/Refractory Disease

What are the investigational novel agents in clinical development available to patients with T315I and/or relapsed/refractory disease?

Treatment Options for CML Treatment Options for CML With T315I or After With T315I or After ≥ 2 TKI≥ 2 TKI

Multi-kinase inhibitors

– MK-0457 (RIP)

– AP24534 (Ponatinib)

– DCC-2036

– PHA-739358

– XL-228

– KW-2449

Omacetaxine (homoharringtonine)

Other approaches (eg, HSP-90 inhibitors, histone deacetylase inhibitors, etc.)

Combination therapyXu et al, 2011; Eiring et al, 2011; King et al, 2011; Nguyen et al, 2011; Kim et al, 2011.

Ponatinib (AP24534) in Ponatinib (AP24534) in Refractory CMLRefractory CML

Orally administered multikinase inhibitor with activity against all mutants including T315I

At 40nM inhibits emergence of resistant clones

Phase I study in 74 patients: 60 CML (44 CP, 7 AP, 9 BP), 4 Ph+ ALL, 6 AML FLT3 ITD, 4 Other

Prior TKI (Ph+ diseases): 2 in 95%, 3 in 65%

Mutations in 63%, T315I in 28%

MTD 45 mg, DLT pancreatitis

MTD = maximum tolerated dose; DLT = dose-limiting toxicity; ITD = internal tandem duplication.Cortes et al, 2010.

Phase I Study of Ponatinib (AP24534)Phase I Study of Ponatinib (AP24534)Best Response to Therapy CP-CML Best Response to Therapy CP-CML

Best Response

N (%)

Overall

(N = 38)

T315Ia

(n = 9)

Non-T315I

(n = 29)

Hematologic

CHRb 36 (95) 9 (100) 27 (93)

Cytogenetic

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

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

aIncludes only those with T315I status confirmed at study entry.bIncludes new CHRs and baseline CHRs.Cortes et al, 2010.

Omacetaxine for CML With T315I Omacetaxine for CML With T315I Response to TherapyResponse to Therapy

81 patients with T315I CML

Omacetaxine 1.25 mg/m2 bid x 14 days, then x 7 days

Prior TKI: 1 in 21%, 2 in 53%, and 3 in 26%

ResponseNo. (%)

CPN = 49

APN = 17

BPN = 15

Hematologic 42 (86) 6 (35) 7 (47)CHR 42 (86) 5 (29) 3 (20)HI NA 3 (18) 1 (7)RCP NA 1 (6) 4 (27)

Cytogenetic 20 (41) 1 (6) –MCyR 13 (27) 1 (6) –

CCyR 9 (18) 1 (6) –Minimal 7 (14) – –

Median survival: CP = NR (65% at 24 mos); AP = 19 mos; BP 2 mos

Cortes, Khoury, et al, 2009.

Response to Bosutinib Third-Line TherapyResponse to Bosutinib Third-Line Therapy Dual Src and Abl inhibitor, no effect over c-kit or PDGFR

114 patients who failed imatinib (600 mg) and dasatinib or nilotinib

Response (%)

IM + D resistant(n = 36)

IM + D intolerant(n = 51)

IM + NI resistant(n = 27)

CHR 61 80 78

MCyR 29 37 29

CCyR 9 34 17

PCyR 21 3 13

MMR 8 36 6

Khoury et al, 2010.

SCT for CML With T315ISCT for CML With T315I 8 patients received 9 SCT

– 7 MUD, 2 CB

Stage: 2 CP (in PCyR), 3 AP (active disease), 4 second CP from LyBP (1 mCyR, 2 MMR, 1 CMR with extramedullary disease)

Best response: 4 CMR (2 CP, 2 second CP), 3 CCyR (2 AP, 1 BP), 1 CHR (AP), 1 early death


– 3 died (5, 8, and 10 mos post SCT) with relapse

– 5 alive:

• 2 CP in CMR (14 and 42 mos post SCT)

• 1 AP in CCyR (26 mos) with persistent T315I

• 1 AP in CHR (39 mos) with persistent T315I

• 1 BP in CMR (10 mos post second SCT)

MUD = matched unrelated donor; CB = cord blood; LyBP = lymphoid blast phase; CMR = complete molecular response.Velev et al, 2010.

Take Home Message – CML 2011 Take Home Message – CML 2011

• Frontline therapy: new standard–Imatinib is good–2nd generation TKI (dasatinib, nilotinib , bosutinib?)

are better–Sequential therapy?

• Failure to therapy:–New definitions (no CCyR at 6 months)?–Change quickly if imatinib therapy

• No need to change if responding to imatinib• Good (but not great) 2nd line therapy• Future needs:

–3rd line (Ponatinib 2nd and 1st line?)–Treatment discontinuation

A Video Viewpoint: Expert Discussions on CML Clinical Debates

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