CHRONIC MYELOID LEUKEMIA (CML) Managing the Long and the Short of It

Jeffrey H Lipton PhD MD

Princess Margaret Cancer Centre

Professor of Medicine

University of Toronto

CAGPO Annual Conference

St. John’s, NFLD

October 24, 2014

Disclosure

Research Support/P.I. BMS, Novartis, Roche, Pfizer (Wyeth), Merck

(Schering), Teva (ChemGenex), Ariad

Employee

Consultant BMS, Novartis, Roche, Merck, Teva, Pfizer, Alexion,

Ariad, CSL Behring

Stockholder

Speakers Bureau

Scientific Advisory Board BMS, Novartis, Roche. Pfizer, Teva, Alexion, Ariad, CSL

Behring

Other

Disclosure

• This presentation is assisted by unrestricted sponsorship by Pfizer Canada Inc

• Under the guidance of the Rx&D Code of Canada

• Content is determined by the speaker

• Any off label uses of drugs will be indicated

Ice Breaker Just by Show of Hands

• How many of you will be involved in the diagnosis of new malignancies versus managing patients already diagnosed?

• How many of you in this room treat or will be treating leukemias?

• How many of you in this room treat or will be treating CML?

• How many of you feel comfortable with the concept of “targeted therapy”?

Goals of this Presentation

• Gain an understanding of CML, the disease

• Understand the concept of targeted therapy

• Know the options for first line therapy in CML

• Learn the importance of monitoring disease and side effects of patients on therapy

• Understand the principles of when to switch therapy, ie second or third line

• What to do when targeted therapy does not appear to be working

What is chronic myeloid leukemia? Biology and Epidemiology

The Philadelphia Chromosome (Ph)

1

p210BCR-ABL

p185BCR-ABL 2-11

2-11

Chromosome 9

bcr

Chromosome 22

abl

2-11

Exons

Introns

CML Breakpoints

ALL Breakpoints

BCR-ABL gene structure

Nowell PC, Hungerford DA. Science. 1960;132:1497-1501.

Forrest et al, 2008; Bakshi et al, 2008; Nowell and Hungerford. JNCI. 1960;25. Rowley 1973.

Diagnosis of CML

Choosing a Treatment Path

Pre History or what we did in the days before

targeted therapy

A walk through history • Arsenic Lissauer, 1865

• Radiotherapy Pusey, 1902

• Busulfan Galton, 1953

• Hydroxyurea Fishbein et al, 1964

• Autografting Buckner et al, 1974

• Allogeneic BMT (SD) Doney et al, 1978

• Interferon Talpaz et al, 1983

• Allogeneic BMT (UD) Beatty et al, 1989

• Donor Leukocytes Kolb et al, 1990

CML Milestones

22

1st description of pts w/ CML features

Philadelphia chromosome identified

Translocation identified as 22q to distal end of 9

RT

IFNa

Busulfan

TKI efficacy against BCR-ABL characterized

Allogeneic SCT

Imatinib

Nilotinib, Dasatinib

Bosutinib, OM, ponatinib

1840 1900 1940 1950 1960 1970 1980 1990 2000 2010

Arsenic

BCR-ABL Kinase activity characterized

Quintas-Cardama et al. Mayo Clin Proc. 2006; 81: 973-88

Y ears from Referral

Pro

po

rtio

n S

urv

ivin

g

1.0

0.8

0.6

0.4

0.2

0.0 0 2 4 6 8 10 12 14

95% Y ear T otal Dead

Imatinib 230 7 1990-2000 960 334 1982-1989 365 265 1975-1981 132 127 1965-1974 123 122

Improved Survival of Early Chronic Phase CML

CML Survival After Allogeneic SCT (FHCRC)

*Includes both matched related and unrelated donors.

Patients receiving allografts at the Fred Hutchinson Cancer Research Center from 1995 to the present.

Figure is courtesy of Dr. Ted Gooley.

1.0

0.8

0.6

0.4

0.2

0

Pro

ba

bili

ty o

f S

urv

iva

l

0 2 4 6 8 10 12 14 16

Yrs After Transplantation

Chronic phase (n = 576) Accelerated phase (n = 125) Blast crisis/remission (n = 62) Blast crisis (n = 44)

PMH CML Transplant Results

Zaretsky, BMT (2007) Zaretsky 2007

What is Targeted Therapy? Just the facts ma’am…

WWII – ENOLA GAY AND HIROSHIMA – 1944

AKA – Conventional Chemotherapy

US PRECISION BOMBING OF IMPERIAL GUARD BUILDING – IRAQ 2003

AKA Targeted Therapy

Therapy of Newly Diagnosed Patients with CML

What are the goals of CML therapy?

• Basically: – to keep people from progressing from chronic phase to

advanced phase. People rarely die from CML in chronic phase

• Ideally: – To reduce the tumor load or molecular level of bcr-abl to

undetectable disease

– To be able to maintain this response off therapy

• Cynically: – To keep people alive with CML, so they can die from

something else

Tyrosine Kinase Inhibitors Currently Available and Approved in Canada for First-Line Therapy*

Imatinib

brand – Gleevec (Novartis)

generic – Apotex – already problems with back orders!

generic – Teva

generic – Cobalt, just approved

Dasatinib

brand – Sprycel (BMS)

Nilotinib

brand – Tasigna (Novartis)

*Health Canada approval and provincial reimbursement are not synonymous

IRIS

IFN-a +

Ara-C

Imatinib

Crossover

n = 553

n = 553 13 (2%)

364 (66%)

14 (3%)

359 (65%)

Discontinued study

treatment 181 (33%)

RANDOMI Z E

Hochhaus A. et al, Blood. 2007; 110, 11. Abstract 25. ASH 2007 Oral Presentation

Response with 1st-Line Imatinib at 60 Months

Months since randomization to imatinib mesylate

% R

esp

on

din

g

98%

92%

87% 80%

84%

0

10

20

30

40

50

60

70

80

90

100

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

MCR

CCR

CHR

96%

85%

69%

CCR = complete cytogenetic response.

Druker BJ, et al. N Engl J Med. 2006;355:2408-2417.

CCR IM = 68%

IFN/Ara-c = 7%

OS on First-Line Imatinib (IRIS Study)

Deininger M, et al. ASH Annual Meeting Abstracts. 2009;114:1126.

Months Since Randomization

Aliv

e %

12 24 36 48 60 72 84

Survival: deaths associated with CM L Overall Survival

96 108

10

30

50

70

90

Estimated overall survival

at 8 years was 85%

(93%, considering only

CML-related deaths)

IRIS 8-Year Update Results: 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

Estimated rate of freedom from progression to AP/BC at 8 years = 92%

Wit

hE

ve

nt,

%

3.3

7.5

4.8

1.7

0.80.3

1.4 1.31.5

2.8

1.8

0.90.5

0 00.4

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7 8

Year

EventLoss of CHR,Loss of MCyR,AP/BC,Death during treatment

AP/BC

Deininger, ASH 2009

Survival After Progression to AP/BP %

Aliv

e

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 = 34 Died = 23 Alive = 11

Saglio et al, 2011.

2nd Generation TKIs vs Imatinib Treatment-Naïve CP-CML

37

Primary Endpoint: MMR at 12 Months

ENESTnd

Follow-up 5 years

Imatinib 400 mg QD (N = 260)

Dasatinib 100 mg QD (N = 259) N = 519 108 centers 26 countries

*Stratified by Hasford risk score.

Primary Endpoint: Confirmed CCyR at 12 Months

DASISION RANDOMIZED

N = 846 217 centers 35 countries

*Stratified by Sokal risk score.

Follow-up 5 years

Rates of MR4.5 by 5 years were consistently higher with nilotinib vs imatinib in

patients with low, intermediate, or high Sokal risk scores

Second-Generation TKIs Produce Deeper MRs Compared With Imatinib

Data cutoff: May 22, 2013

By 5 Yearsa

11%, P < .0001

7%, P < .0001

1%

Δ 6% to 10%

31%

52%, P < .0001

54%, P < .0001

Δ 21% to 23%

By 4 Yearsa

40%, P < .0001

37%, P = .0002

23%

Δ 14% to 17%

100

0 2 6

90

80

70

60

50

40

30

20

10

0

Pati

en

ts W

ith

MR

4.5

, %

Time Since Randomization, calendar years 3 1

Nilotinib 300 mg BID (n = 282)

Nilotinib 400 mg BID (n = 281)

Imatinib 400 mg QD (n = 283)

4 5

By 1 Yeara

Saglio G, et al. Blood. 2013;122(21) [abstract 92].

a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.

Second-Generation TKIs Produce Deeper MRs Compared With Imatinib

60

50

40

30

20

0

0 12 24 36 48 60

12%

21%

37%

P < .030

Months

% W

ith

MR

4.5

10

34%

3%

9%

2%

18%

23% 30%

Dasatinib 100 mg QD n = 259

Imatinib 400 mg QD n = 260

Cortes J, et al. Blood. 2013;122(21);[abstract 653].

Branford S, et al. Clin Cancer Res. 2007;13:7080-7085.

Un

det

ecta

ble

BC

R-A

BL,

%

60

80

100

20

40

0

P < .0001

72%

1 2 3 4 5 6

Years on imatinib

5%

MMR by 12 months (n = 24)

No MMR by 12 months (n = 29)

Pre

MMR by 12 Months is Predictive of Undetectable BCR-ABL Transcript Levels

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

Nu

mb

er

of

Pat

ien

ts, n

On Core Treatment and After Discontinuation

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

9

6

19 P = .0496

P = .0076

41

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

In the IRIS study, cumulative progression rates in the first 3 years of therapy were approximately 6% on imatinib1

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

3.2% 2.1% 6.7%

* Progression to AP/BC or death following progression.

1. Hochhaus A, et al. Leukemia. 2009;23(6):1054-1061.

Data cut-off: 27Jul2011.

ENESTnd 3-Year Update

Saglio G, et al. Blood. 2011;118(21):208-209 [abstract 452].

DASISION: First-Line Dasatinib vs. Imatinib in CML-CP. Progression to AP/BP

• No patient who achieved MMR progressed to accelerated or blast phase

• 2 patients who achieved CCyR progressed to accelerated or blast phase (1 with dasatinib, 1 with imatinib)

5

9

0

5

10

15

Progressed to AP/BP

(n)

3.5%

1.9%

Dasatinib 100 mg QD

Imatinib 400 mg QD

It is difficult comparing drugs and outcomes outside of direct randomizations

where the same language is spoken!

Jabbour and Lipton, 2013

Efficacy Data from Studies Using Second Generation Drugs First Line

44 Jabbour and Lipton, 2013

Achievement of MMR is associated with – Longer duration of CCyR1-4

– Higher rates of EFS5 and PFS6

Durable MMR is associated with improved PFS7

Early, deep MR is associated with EFS,5,8-10 PFS,6,10,11 higher

OS11 and deeper MRs12

MR4.5 may predict survival better than CCyR13

Deeper MR (MR4 or MR4.5) is a prerequisite for many treatment-free remission trials14-17

MR4, molecular response ≥ 4-log reduction; MR4.5, molecular response ≥ 4.5-log reduction.

1. Iacobucci I, et al. Clin Cancer Res; 2006:12,3037-3042. 2. Cortes J, et al. Clin Cancer Res. 2005;11:3425-3432. 3. Paschka P, et al. Leukemia. 2003;17:1687-1694. 4. Press RD, et al. Blood. 2006;107:4250-4256. 5. Press RD, et. al. Clin Cancer Res. 2007;13:6136-6143. 6. Hughes TP, et al. New Engl J Med. 2003;349:1423-1432. 7. Kantarjian H, et al. Cancer. 2008;112:837-845. 8. Müller MC, et al. Blood. 2008;112:129 [abstract 333]. 9. Osborn MP, et al. Blood. 2009;114:461-462 [abstract 1125].

10. Marin D, et al. J Clin Oncol. 2012;30:232-238. 11. Hanfstein B, et al. Leukemia. 2012;26(9):2096-2102. 12. Branford S, et al. Clin Cancer Res. 2007;13:7080-7085. 13. Hehlmann et al. J Clin Oncol. 2014 Feb 10;32(5):415-23. 14. Mahon FX, et al. Lancet Oncol. 2010;11(11):1029-1035. 15. Rousselot P, et al. Blood. 2011;118(21) [abstract 3781]. 16. Matsuki E, et al. Blood. 2011;118(21) [abstract 3765]. 17. Ross M, et al. Haematologica. 2012;97(s1):74 [abstract 0189].

Importance of Achieving Deep Molecular Response

So, you may ask, how do you choose which drug to use?

• Provincial or private payer guidelines and/or reimbursement may make this an easy choice

• A good initial history, physical and baseline bloodwork assessment may help define co-morbidities which make one drug preferable over another

• Lifestyle review including shift work and eating habits may help define a preferable drug

• At diagnosis, there are no response/resistance criteria to help with the decision

• For many patients, it will be like…

More drugs means more choices!

Monitoring

When we talk about monitoring…

• It is usually assumed that we are dealing with response to therapy

• Although this is in part correct, it is also important to check for

– Compliance

– Side effects that may influence compliance

– Additional medications that may have been changed or added by other treaters

Decisions based on monitoring visits include…

• Whether to continue with current management

• Whether to change management because of failed response

• Whether to change management because of side effects (INTOLERANCE)

– Dosing change

– Drug change

• Whether discontinuation of therapy on protocol for those with deepest responses

Therapy Efficacy Monitoring

Monitoring CML

Hematological response (HR)

• Measure of blood count and differentials

Cytogenetic response (CyR)

• Chromosome banding analysis of bone cell metaphases

Molecular Response

• Measurement of BCR-ABL1 transcript levels

1.

2.

3.

1. Maslak P. ASH Image Bank. 2008; 8-0067. http://ashimagebank.hematologylibrary.org. Copyright American Society of Hematology 2008. 2. Quintas-Cardama A, et al. Leukemia. 2007;21:2394–2396. Image reprinted by permission from Macmillian Publishers Ltd. Copyright 2007. 3. Baccarani M, et al. J Clin Oncol. 200;27:6041–6051.

Defining Response

53

Type of Response Definition

CHR Complete Hematologic Response Normal differential, WBC, platelets ≤ ULN

MCyR Major cytogenetic Response 0-35% Ph+ marrow metaphases

CCyR Complete Cytogenetic Response 0% Ph+ marrow metaphases

MMR Major Molecular Response BCR-ABL/ABL ≤ 0.1%

(International Scale)

CMR Complete Molecular Response Undetectable BCR-ABL

(test of sensitivity ≥ 4.5 logs)

First-line Treatment Milestones Have Evolved • The European LeukemiaNet (ELN) recommendations for optimal responses have shifted

to deeper responses 3 to 6 months earlier in treatment • Similarly, failure criteria occur 3 months earlier vs 2009 ELN recommendations

1. Baccarani M, et al. J Clin Oncol. 2009;27(35):6041-6051. 2. Baccarani M, et al. Blood. 2013;122(6):872-884.

2009 ELN2

2013 ELN3

BCR-ABLIS = 10%

a Platelet count < 450 × 109/L, white blood cells (WBC) < 10 × 109/L, differential count without immature granulocytes, and < 5% basophils; b 36% to 65% Ph+ metaphases; c 1% to 35% Ph+ metaphases; d No Ph+ metaphases; e BCR-ABLIS ≤ 0.1%; f BCR-ABL to ABL (or other housekeeping gene) ratio ≤ 0.1%.

BCR-ABLIS, BCR-ABL transcripts measured on the International Scale; CCyR, complete cytogenetic response; mCyR, minor cytogenetic response; PCyR, partial cytogenetic response.

BCR-ABLIS = 1%

BCR-ABLIS = 0.1%

BCR-ABLIS = 0.0032%

ELN Definition of Optimal Response in Newly Diagnosed Patients

3 months 6 months 12 months Beyond 12 months

1012

1011

1010

109

108

107

106

Number of leukaemic cells

CHR (<1-log reduction)

CCyR (2-log reduction)

MMR (3-log reduction)

≈4.5-log reduction

Time Diagnosis

BC

R-A

BL1

tra

nsc

rip

ts (

log 1

0)

Haematologic

Cytogenetic

Baccarani M, et al. Blood. 2006;108:1809–1820; Radich JP. Blood. 2009;114:3376–3381

Correlation Between Response and Disease Burden: Molecular Response

RT-qPCR, reverse transcription - quantitative polymerase chain reaction

RQ-PCR

The Treatment Milestones in Ph+ CML Continue to Evolve: Earlier and Deeper

≤ 1% ≈ 2-log

≤ 10% ≈ 1-log

≤ 0.1%IS ≈ 3-log

Goal of Therapy

CHR1 MCyR1,2 MMR3

MR4.5 and beyond5-7

Deeper

molecular

responses4

1970 2000 1990 1980 1960 Today

Leukemic Burden

1. Cortes JE, et al. Am J Med. 1996;100(5):555-570. 2. Rosti G, et al. Semin Hematol. 2003;40(2 suppl 2):56-61. 3. Baccarani M, et al. Blood. 2006;108(6):1809-1820. 4. Saglio G, et al. Blood. 2013;122(21):[abstract 92].

Leukemic

Reduction3,a

≤ 0.0032%IS ≈ 4.5-log

5.Radich JP. Clin Lymphoma Myeloma. 2009;9(suppl 4):S391-S394. 6. Hughes TP, et al. Blood. 2010;116(19):3758-3765. 7. Press RD, et al. Clin Cancer Res. 2007;13(20):6136-6143.

CHR, complete hematologic response; CML, chronic myelogenous leukemia; MCyR, major cytogenetic response; MMR, major molecular response; MR4.5, molecular response with 4.5-log reduction below baseline; Ph+, Philadelphia chromosome positive.

0.1%

1%

0.01%

10%

0.001%

100%

International Scale

Local Assay

BCR - ABL / ABL

BCR - ABL / BCR

BCR - ABL / GUS

Different primers/probes

TaqMan

LightCycler

Rotorgene

Others

IRIS standardised baseline

MR4

MR5

MMR = MR3

0% Ph+ (CCyR)

35% Ph+

Standardization of RQ-PCR for BCR-ABL: The International Scale (IS)

Hughes T, et al. Blood. 2006;108:28-37.

Apparent Fluctuating Levels of Residual Disease

0 12 18 24 30 36 42 48 54 60

0.0001

0.001

0.01

0.1

1

10

100

BC

R-A

BL/

AB

L %

IS

Months

MMR

MR4.5

6

Definitions of Deep Molecular Response

1.Baccarani et al. Blood. 2013;122:872–84.

2.Cross NCP, et al. Leukemia. 2012;26:2172–2175.

MR4.0

MR4.5

1012

1011

1010

109

≈ 5-log reduction

CCyR (2-log)

MMR (3-log)

CHR (<1-log)

108

107

106

MR4.0: >4.0-log reduction in BCR-ABL1 transcripts either (i) detectable disease with <0.01 % BCR–ABL1 IS or (ii) undetectable disease with >10,000 ABL1 or >24,000 GUSB transcripts

MR4.5: >4.5-log reduction in BCR-ABL1 transcripts either (i) detectable disease with <0.0032% BCR–ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 or >77,000 GUSB transcripts

Deep MRs are defined as:1

IS, international scale.

What to do when you expect that the drug is not working

• Determine if this is an intolerance issue or a resistance issue

• If intolerance, see if the dosing, schedule, use of co-meds can be changed

• If resistance, first determine if it is a compliance issue

• If not compliance, check – Mutation status

– Evidence of clonal progression

Microelectronic Monitoring System

(MEMS 6 Trackcap)

• Records the time of opening the container

• Most reliable method of measuring adherence

• Our patients: not told about

the chip

Marin et al, Blood 2008

Marin et al, Blood 2008

Six-year probability of MMR according to the measured adherence rate

726660544842363024181260

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Months from start of imatinib therapy

Pro

babili

ty

of

MM

R

Adherence >90%, n= 64

Adherence ≤90%, n= 23

p <0.0001

726660544842363024181260

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

726660544842363024181260 726660544842363024181260

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Months from start of imatinib therapy

Pro

babili

ty

of

MM

R

Adherence >90%, n= 64

Adherence ≤90%, n= 23

p <0.0001

Marin et al, Blood 2008

• Per ELN recommendations, BCR-ABL > 10% at 6 months is considered treatment failure and the patient should receive another treatment

Optimal Responses1

3 mo Ph+ ≤ 35% and/or BCR-ABL ≤ 10%

6 mo Ph+ 0% and/or BCR-ABL < 1%

12 mo BCR-ABL ≤ 0.1% (MMR)

At any time BCR-ABL ≤ 0.1% (MMR)

Failures1

3 mo Ph+ > 95%

6 mo Ph+ > 35% and/or BCR-ABL > 10%

12 mo BCR-ABL > 1%

At any time Loss of CCyR; CCA/Ph+; confirmed loss of MMRa;

mutations

1. Baccarani M, et al. Blood. 2013;122(6):872-884.

The 2013 ELN Recommendations Support Switching Treatments in Patients With Treatment Failures

CCA, clonal chromosomal abnormalities.

Impact of 6 month versus 3 month assessment on outcome of molecular response

Kim et al 2014

Tyrosine Kinase Sensitivity in CML bcr-abl Mutations

BMS Canada, unpublished

Tyrosine Kinase Inhibitors Currently Available and Approved in Canada for Salvage Therapy*

Imatinib brand – Gleevec (Novartis) generic – Apotex! generic – Teva generic – Cobalt, just approved Dasatinib brand – Sprycel (BMS) Nilotinib brand – Tasigna (Novartis) Bosutinib brand – Bosulif (Pfizer) *Health Canada approval and provincial reimbursement are not synonymous

Hematologic and cytogenetic response

100 mg QD 50 mg BID 140 mg QD 70 mg BID

CHR

MCyR

CCyR

100

80

60

40

20

0

90 93

88 87

42 42 45 45

59 57 56 54

%

Dasatinib dose and schedule optimization in CP-CML

Hochhaus, ASH 2006

Progression-free survival

● Progression was defined as confirmed AP / BP, loss of CHR / MCyR, or increasing WBC count

N No. progressed

100 mg QD 166 14

50 mg BID 166 13

140 mg QD 163 14

70 mg BID 167 18

0 2 4 6 8 10 12

Months

Pro

po

rtio

n p

rog

ress

ion

-fre

e

1.0

0.8

0.6

0.4

0.2

0

Dasatinib dose and schedule optimization in CP-CML

Hochhaus, ASH 2006

78% 64%

Months Since Start of Treatment

Wit

ho

ut

Pro

gre

ssio

n, %

Total = 321

Failed = 88

lll = Censored observations

Nilotinib - Phase II CML-CP

Time to Progression

Kantarjian, ASH 2007

95% 91%

Months Since Start of Treatment

Ali

ve,

%

Total = 321

Failed = 25

lll = Censored observations

Nilotinib - Phase II CML-CP

Survival

Kantarjian, ASH 2007

Bosutinib Progression-free Survival

Mutation status CP 2L CP 3L ADV

No mutation, n 132 46 52

PFS rate at 1 year 92% (84.5%–95.6%) 80% (62.3%–90.2%) 43% (28.0%–57.5%)

PFS rate at 2 years 86% (76.8%–91.3%) 80% (62.5%–90.2%) 34% (19.8%–48.9%)

Any mutation, n 79 40 65

PFS rate at 1 year 87% (76.2%–92.9%) 82% (63.7%–91.9%) 42% (28.1%–54.3%)

PFS rate at 2 years 70% (57.3%–80.0%) 77% (56.2%–88.9%) 30% (17.7%–44.1%)

CP, chronic phase chronic myeloid leukemia; 2L, second-line setting; 3L, third-line setting; ADV, advanced leukemia; PFS, progression-free survival.

PFS rates at 1 year (48 weeks) and 2 years (96 weeks) were based on Kaplan-Meier estimates.

Time to progression/death (months)

Pro

ba

bilit

y o

f p

rog

res

sio

n-f

ree

s

urv

iva

l (%

) 100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 68 58 60 62 64 66

Patients with any mutation

CP 2L

CP 3L

ADV

Bosutinib Overall Survival

Mutation status CP 2L CP 3L ADV

No mutation, n 132 46 52

OS rate at 1 year 97% (92.0%–98.8%) 93% (79.6%–97.7%) 65% (51.2%–76.2%)

OS rate at 2 years 95% (89.0%–97.4%) 88% (72.5%–94.6%) 55% (40.4%–67.4%)

Any mutation, n 79 40 65

OS rate at 1 year 97% (90.0%–99.3%) 88% (72.5%–94.6%) 54% (41.3%–65.6%)

OS rate at 2 years 82% (71.6%–89.4%) 79% (62.9%–89.2%) 46% (33.7%–58.0%)

CP, chronic phase chronic myeloid leukemia; 2L, second-line setting; 3L, third-line setting; ADV, advanced leukemia; OS, overall survival.

OS rates at 1 year (48 weeks) and 2 years (96 weeks) were based on Kaplan-Meier estimates.

Time to death (months)

Pro

ba

bilit

y o

f o

ve

rall

su

rviv

al

(%)

100

90

80

70

60

50

40

30

20

10

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 68 58 60 62 64 66

Patients with any mutation

CP 2L

CP 3L

ADV

BELA Trial: Bosutinib vs Imatinib

• Bosutinib had a higher incidence of GI toxicities and similar rates of myelosuppression compared to imatinib

• Reduction of BCR-ABL:ABL transcript to ≤ 10% at 3, 6, and 9 months were associated with higher rates of MMR and CCyR for both bosutinib and imatinib

Bosutinib, n = 250 Imatinib, n = 252

30-months CCyR 56% 61%

Cumulative CCyR 70% 81%

30-month MMR 45% 43%

Cumulative MMR 61% 50%

Progression to AP or BP 1.6% 5.2%

Deaths 3.6% 5.2%

Newly Diagnosed CML CP N = 502

Bosutinib (500 mg QD), n = 250

Imatinib (400 QD), n = 252 R

Gambacorti-Passerini C, et al. ASCO Meeting Abstracts. 2012;6512.

So how do you chose which drug to use in salvage?

• All the criteria for front line choice

• PLUS

– Directed by a mutation

– Directed by a side effect of the front line drug that may also be present with one of the salvage drug

Side Effects

Short Term

• Usually defined by the fact that they show up early, are often short lived or can be controlled with co-medications or changes in administration

• Are usually mild, ie grade 1 or 2 and although annoying, usually do not interfere with taking the drug

Drug and Short Term Side Effects

• Imatinib – Rash, GI symptoms, MSK symptoms, edema, LFT

abnormalities

• Dasatinib – Rash, abdominal discomfort, headache

• Nilotinib – Abdominal discomfort, pancreatic and LFT

abnormalities, increased blood sugars and cholesterol

• Bosutinib – Abdominal discomfort, diarrhea, LFT abnormalities

Potential Long-Term Drug Toxicities and Choice of TKI

BACKGROUND 1

• Significant side effects or adverse events that occur when a patient is started on a TKI can either be managed with simple options, dose changes or co-medications

• Occasionally a drug will have to be switched because of a severe or intractable AE

• Patients who get out a few years, tolerate their therapy and respond may be on their TKI for many years

BACKGROUND 2

• Some patients will be eligible for discontinuing their therapy because of deep durable responses, the definition of which is still not standardized

• It is likely though that many patients will be on lifelong therapy and dealing with issues that may be associated with their particular therapy will need to be addressed

Fundamental Realities

• Generally, no specific medication is absolutely contraindicated, resistance aside

• Some TKIs in some people may pose a greater potential risk of side effects

• Choice of a TKI that has the potential for issues will therefore involve a risk/benefit analysis after getting full medical information, followed by a detailed discussion with the patient and more aggressive monitoring and possible intervention

Caveat

• I will look at problems that can continue to show up in patients even after years of therapy and at new late problems

• I will look at the “red flags” that have been raised with TKIs

• I will not comment on whether the definitions of these issues are correct or appropriate or whether studies were designed to collect this data accurately

• I am not going to talk about cause and effect, or patient risk going into treatment, just the observed associations that are likely significant and need thought and monitoring

Imatinib

Long Term AE’s with Imatinib

• In general, after more than a decade of usage, there have been no new long term adverse advents identified with imatinib

• Persistence of low grade chronic side effects such as edema, gastrointestinal sensitivity and musculoskeletal problems continue

• Imatinib has continued to be a safe long term tolerated medication in those individuals who are responding

Dasatinib

Long Term AE’s with Dasatinib Pleural Effusions

• Pleural effusions, likely of an immunologic etiology, and possibly of an “innocent by-stander” effect, continue to be an issue

• Effusions can occur for the first time or recur years after starting the drug and constant vigilance is necessary

• Dose reductions do not necessarily prevent recurrence

Long Term AE’s with Dasatinib

• The exact incidence of PAH with dasatinib is not known but is probably under reported

• Despite the severity, it is not a common side effect

• Symptoms including dyspnea in the absence of pleural effusions or evidence of congestive heart failure need to be investigated

• Confirmation of PAH requires aggressive work up with echocardiography and probably heart catheterization

• Early intervention with discontinuation of dasatinib is essential as PAH is essentially not reversible significantly in this scenario

Occurrence of PAH in Patients Treated With Dasatinib: Key Learnings

• Approximately 42,000 patients with CML or Ph+ ALL have received dasatinib worldwide

– 70 cases of PH identified1-8

• 20 PAH cases confirmed by RHC and dasatinib was considered the most likely cause

• In most cases, patients had received previous treatment for CML

– PAH cases primarily identified via postmarketing surveillance

• In total, 2866 patients have been treated with dasatinib in clinical trials8,9

– 3 cases of PAH determined by RHC have been identified

• 1 case in CA180-005 (START-A: 2nd-line dasatinib in CML-AP)

• 2 cases in CA180-035 (2nd-line dasatinib in CML-BP, CML-AP, Ph+ ALL)

1. Rasheed W, et al. Leuk Res 2009;33:861-864; 2. Mattei D, et al. Bone Marrow Transplant 2009;43:967-968; 3. Dumitrescu D, et al. Eur Respir J 2011;38:218-220; 4. Hennigs JK, et al. BMC Pulm Med 2011;11:30;

5. Orlandi EM, et al. Leuk Res 2012;36:e4-6; 6. Philibert L, et al. Fundam Clin Pharmacol 2011;25(suppl 1); 7. Montani D, et al. Circulation 2012;125:2128-2137; 8. Bristol-Myers Squibb. Sprycel (dasatinib) EMEA summary of product characteristics,

revised December 2010; 9. Bristol-Myers Squibb. Sprycel (dasatinib) US prescribing information, revised October 2011

Nilotinib

a Patients with normal glycemic status at baseline who were evaluable for change in glycemic status by 3 years. b Patients with prediabetes by 3 years had either FGL ≥ 1.1 to < 1.26 g/L

or HbA1c ≥ 5.7% to < 6.5%, or met both criteria. c Patients with diabetes by 3 years had either FGL > 1.26 g/L or HbA1c > 6.5%, or met both criteria.

d Patients who met the HbA1c criterion for prediabetes or diabetes, respectively. Adapted from Rea D, et al: Blood 2012; 120(21):[abstract 1686].

Newly Acquired Alteration of Glucose Metabolism in the ENESTnd Study

Glycemic Status by 3 Years in Patients With Normal Glycemic Status at Baseline

Nilotinib 300 mg BID

(n = 91)a

Nilotinib 400 mg BID

(n = 92)

Imatinib 400 mg QD

(n = 88)a

Pre-diab.b Diabetesc Prediab.b Diabetesc Prediab.b Diabetesc

Patients with newly acquired

alteration of glucose

metabolism,

n (%)

34

(37.4)

16

(17.6)

43

(46.7)

16

(17.4)

34

(38.6)

1

(1.1)

HbA1c altered,

n (%)d

25

(27.2)

4

(4.4)

42

(43.8)

6

(6.3)

27

(29.0) 0

Cardiac and Vascular Events by 4 Years in the ENESTnd Study (All Grades)

Patients With an Event, n (%)

Nilotinib

300 mg BID

n = 279

Nilotinib

400 mg BID

n = 277

Imatinib

400 mg QD

n = 280

IHD 11 (3.9) 14 (5.1) 3 (1.1)

PAOD 4 (1.4) 5 (1.8) 0 (0)

IHD, ischemic heart disease; PAOD, peripheral arterial occlusive disease. Data cutoff: July 27 2012.

Adapted from Kantarjian HM, et al: Blood 2012; 120(21):[abstract 1676].

Bosutinib

Long Term CV AE’s with Bosutinib (Salvage and BELA Studies)

Pooled 2L/3L/4L 1L BOS*

(n=818) BOS*

(n=570) BOS* (n=248)

IM† (n=251)

Median (range) tx duration, mo –

11.1 (0.03-83.4)

33.1

(0.03-49.6)

33.3

(0.5-46.9)

Cardiac TEAEs (any grade), %

18.2 19.6 14.9 9.2

Cardiac arrhythmia 5.7 6.5 4.0 2.0

Coronary artery disorder

3.4 4.2 1.6 1.2

Heart failure 2.9 3.9 0.8 0.8

Myocardial disorder

2.1 2.8 0.4 0

Pericardial disorder 2.9 3.5 1.6 0

Vascular hypertensive disorder

6.7 6.8 6.5 4.4

*500 or †400 mg/d starting dose

Gambacorti-Passerini et, ASCO 2014

Tyrosine Kinase Inhibitors and Other Medications Currently Not Approved in Canada for Salvage

Therapy

Ponatinib

– brand Iclusig (Ariad)

Omacetaxine

– brand Synribo (Teva)

When is a TKI not the treatment of choice for salvage?

• Persistent hematological toxicity

• Clonal progression

• Some clonal abnormalities in Ph-neg cells

• Unusual mutation such as t315i if ponatinib not available

• Uncontrolled heart failure

Allo SCT for CML in the Imatinib Era

Saussele S, et al. Blood. 2010;115:1880-1885

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 12 24 36 48 6 18 30 42

Mos After Transplantation

Surv

ival P

robabili

ty

Elective, n = 19, 3-yr survival: 88%

Imatinib failure in 1 CP, n = 37, 3-yr survival: 94%

Advanced phase, n = 28, 3-yr survival: 59%

What does a physician taking care of a patient with CML need to remember

and need to do?

Issues for the GPO

Most important things to remember

• Newly diagnosed chronic phase CML patients have a life expectancy virtually the same as age matched controls

• Monitoring the patient and the disease are equally important

• Since patients will likely not die from CML, making sure that they do not die from other diseases that are treatable is equally important

Necessary Information

• At starting therapy – A good patient history, physical and baseline

laboratory assessment is necessary to sort out best choice of drug given disease status and if choice is an option

• During monitoring – Careful assessment in conjunction with primary

physician and/or other specialist to identify, modify, or treat co-morbidities or side effects

– Monitoring must include more than just disease response assessments

Drug Choice

• Deciding on what TKI to use depends on a number of issues: – Drug availability

• This varies from jurisdiction to jurisdiction

– Disease status • First line or salvage

• Previous responses

• Presence of kinase mutations

– Patient status • Co-morbidities

• Previous adverse events on therapy

Must knows if you are to manage CML

• Know the drugs, especially the potential side effects

• Know the disease, especially the aspects of response or resistance

• Know the milestones – what to look for and when • Know the options for management at any time

point, including the non-TKI options • Know a mentor – someone you can learn from

and someone who is available to answer questions

The Future - Maybe

Duration of Therapy: Is TKI Therapy Forever?

• Do patients need to stay on TKI therapy forever? – STIM trial

• RFS after discontinuation of imatinib, N = 100 – 6-mo: 45%, 12 mo: 43%, 24 mo: 41%

106

100

80

60

40

20

0

Su

rviv

al

Wit

ho

ut

Mo

lec

ula

r

Rela

pse

Pts at Risk, n 100 57 36 28 27 23 20 16 6

Mahon FX, et al. Lancet Oncol. 2010;11(11):1029-1035.