1

Winship Cancer Institute of Emory University

Contemporary and FutureApproaches in Management of CML

Hagop Kantarjian, MDChairman and Professor, Department of Leukemia 

University of TexasM. D. Anderson Cancer Center

Disclosures

• Received research funding:

– Ariad, BristolMyers Squibb, Novartis, and Pfizer

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Cure of CML (Almost…). Brief Perspective

•IFN – α induced CGCR in 10-30%; CGCR associated with long-term survival; potential cure 5-7% (1983; 1990)

•Ph and BCR-ABL molecular events identified (1980s)

•BCR-ABL abnormalities caused CML in animal models (1990); BCR-ABL legitimate Rx target

•Development of TKIs → CGCR 80-90%; 10-yr survival 80-95%

4

CML. Historical vs. Modern PerspectiveParameter Historical Modern

•Course Fatal Indolent

•Prognosis Poor Excellent

•10-yr survival 10% 84 - 90%

•Frontline Rx Allo SCT;

IFN-Imatinib; nilotinib; dasatinib

•Second line Rx ? New TKIs; allo SCT

3

CML Survival by Era

Harrison’s Principles of Internal Medicine. 2014

Population-Based CML Outcome in Sweden

•3173 pts Dx in 1973-2008; median age 62 yrs

Bjorkholm, JCO 29: 2514; 2011

21%

23%

37%

54%

80%

4

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

• Incidence 4700 per year• Age-matched mortality ratio vs

normal population = 1.50• Accounts for increased US

population to 410 million in 2050

Year

Nu

mb

er o

f C

ases

CML - Increasing Prevalence Over Time

Huang. Cancer 118:3123;2012

CML Transformation. Survival by Era

5

CML Ph-Associated CG and Molecular Events

10

LTR LTRBCR/ABL

CML

STEM CELL

BCR-ABL Expression Sufficient for CML Induction

(Daley et al., Science 1990)

6

11

Do We Need Bone Marrow At Dx?

• Assess % of blasts and basos (10-15% have CML transformation at Dx)

• Confirm Ph by CG; detect clonal evolution

• FISH can be falsely positive

• QPCR can be falsely positive or negative

Hyper CVAD + TKIs in CML Lymphoid BP

• 42 pts; HCVAD and imatinib (n=27) or dasatinib (n=15)

• CR 90%, CGCR 58%, CMR 25%, FCM-MRD negative 42%

• Median remission 14 mos; median survival 17 mos; 18 (47%) had allo SCT.

12

Strati. Cancer 120: 373; 2014

7

13

Poor Prognostic Factors in CML

• Older age

• Splenomegaly

• Anemia

• Thrombocytosis, thrombocytopenia

• Blasts, promyelocytes, basophils

• Marrow fibrosis

• Cytogenetic clonal evolutionPrognostic Models: Sokal, Hasford (Euro), MDACC

Kantarjian. Blood 119:1981;2012

8

15

IRIS. PFS Associated With CGCR At 12 Mos, Not With Sokal Risk

n= 179 99% n= 91 95%n= 49 95%

Estimated rate at 60 months

p=0.16 p=0.09

p=0.200 (overall)

Low riskIntermediate riskHigh risk

% w

ithou

t PD

to A

P/B

C

0

10

20

30

40

50

60

70

80

90

100

Months since randomization0 6 12 18 24 30 36 42 48 54 60 66

Developmental Therapeutics in CMLFDA Approval

Agent Salvage Frontline

Interferon 1986 1986

Imatinib 2001 2002

Nilotinib 2007 2010

Dasatinib 2006 2010

Ponatinib 2012

Bosutinib 2012

Omacetaxine 2012Kantarjian. NEJM 346:645;2002. Kantarjian. NEJM 354:2542;2006. Talpaz. NEJM 354; 2531: 2006. Kantarjian. NEJM 362:2260:2010. Kantarjian. Lancet Oncol 12: 841; 2011. Cortes. NEJM 367: 2075; 2012. Cortes. Blood 120: 2573; 2012. Cortes. AJH e-Pub 2/2013.

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CML. So Many Choices

Therapy of CML in 2014•Frontline

- imatinib 400 mg daily- nilotinib 300 mg BID- dasatinib 100 mg daily

•Second / third line- nilotinib, dasatinib, bosutinib, ponatinib, omacetaxine

- allogeneic SCT•Other

- decitabine, pegasys- hydrea, cytarabine, combos of TKIs and

with TKIs- investigational: hedgehog inhibitors,

JAK2 inhibitors, IL3-DT

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CML. The Next Questions

•Frontline CML Rx: imatinib vs. second TKIs

•Can we cure CML molecularly? Is it necessary?

•Role and timing of allo SCT

•Monitoring of CML

•Others: prevalence, pregnancy CG abn., Rx DC

Results with Imatinib in Early CP CML – The IRIS Trial at 8-Years

• 304 (55%) patients on imatinib on study• Projected results at 8 years:

- CCyR 83%- 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP

- Event-free survival 81%- Transformation-free survival 92%

- If MMR at 12 mo: 100%- Survival 85% (93% CML-related)

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

Deininger. Blood 114: abst 1126, 2009

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Frontline Rx with Dasatinib or Nilotinib at MDACC

•Parallel studies with nilotinib (400 mg BID) or dasatinib (100 mg QD or 50 mg BID)

Nilotinib Dasatinib

% Response N=100 N=93

CGCR by 12 mos 93 99

MMR by 12 mos 73 83

3-yr Survival 100 99

3-yr TFS 97 100

3-yr EFS 91 91

3-yr FFS 78 80

Rx discontinuation 11 9

Quintas-Cardama. Blood 118: abst 454, 2011. Pemmaraju. Blood 118; abst 1700; 2011

TKI Frontline Therapy in CML Long-Term Outcome By Response Time

Event-Free Survival Transformation-Free Survival

p<0.001

Jain. Blood 122: abst 2728; 2013

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Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg BID (n = 282)

RANDOMIZED*

Nilotinib 400 mg BID (n = 281)

• N = 846

• 217 centers

• 35 countries

* Stratification by Sokal risk score.

10 years of follow-up are planned

ENEST-nd. Study Design

Kantarjian. Blood 120:abst 1676;2012

Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML

• 846 pts randomized to nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281), or imatinib 400 mg QD (n=283)

• Minimum follow-up 5 years

Outcome Nil 300 Nil 400 IM 400

% CCyR* 87 85 77

% MMR** 77 77 60

% BCR-ABL ≤0.0032%** 54 52 31

% Transformed AP/BP 3.5 2.1 7.1

% 5-yr EFS 92 95 91

% 5-yr OS 94 96 92* by 24 months, ** by 60 months (K-M)

Saglio. Blood 122: abst 92; 2013

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ENESTnd. Progression to AP/BC on Core Rx

Saglio. Blood 122: abst 92; 2013

P = .0059

P = .0185

P = .0009

P = .0085

4.2% 0.7% 1.1% 6.0% 1.1% 1.8%

Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281)Imatinib 400 mg QD (n = 283)

Nilotinib vs. Imatinib in CML-CP. Adverse Events and Grade 3/4 Myelosuppression

Fluid retention

Diarrhea

Headache

Muscle cramps

Nausea

Pruritus

Rash

Vomiting

Anemia

Neutropenia

Thrombocytopenia

Any grade

Grade 3/4

0.10 0.2 0.3 0.4 0.5-0.1-0.2-0.3-0.4-0.5

Rate difference (imatinib - nilotinib) with 95% CI

Favors imatinib Favors nilotinib (300 mg BID)

Hochhaus. Haematologica. 2010;95(s2):459 [abst 1113]

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ENEST-nd.Cardiac and Vascular Events by 4 Years (All Grades)

Patients With an Event,

n (%)

Nilotinib300 mg

BIDn = 279

Nilotinib400 mg

BIDn = 277

Imatinib400 mg

QDn = 280

IHD 11 (3.9) 21 (7.6) 5 (1.8)

PAOD 4 (1.4) 6 (2.2) 0 (0)

Saglio. Blood 120: abst 92; 2013

Dasatinib Versus Imatinib Study In Treatment-naïve CML (DASISION). Trial Design

● Primary endpoint: Confirmed CCyR by 12 months

● Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival

Follow-up

5 yearsRandomized*

Imatinib 400 mg QD (n=260)

Dasatinib 100 mg QD (n=259)• N=519

• 108 centers

• 26 countries

*Stratified by Hasford risk score

Kantarjian. NEJM. 362: 2260, 2010

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Dasatinib vs Imatinib in Newly Diagnosed Chronic Phase CML

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

• Minimum follow-up 48 mo

Outcome Das 100 IM 400% CCyR* 86 82% MMR** 74 60% BCR-ABL ≤0.0032%** 34 21% Transformed AP/BP 5 7% 4-yr PFS 90 90% 4-yr OS 93 92

Cortes. Blood 122: abst 653; 2013

* by 24 months, ** by 48 months (K-M)

DASISION. Transformation to AP/BP CML by 4 Years

0

2

4

6

8

10

12

14

16

18

20

Pat

ien

ts,

n

On Study Including Follow-up Beyond Discontinuation (ITT)

Dasatinib 100 mg QD Imatinib 400 mg QD

8 (3.1%)

14 (5.4%)

12 (4.6%)

18 (6.9%)

Cortes. Blood 122: abst 653; 2013

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DASISION. Forest Plot Comparing Differences in AE Rates for Dasatinib and Imatinib

Rate Difference (dasatinib-imatinib) with 95% CI

Any grade

Grade 3/4

Diarrhea

Nausea

Neutropenia

Vomiting

Superficial edema Pleural effusion Myalgia

Fatigue Headache Rash

Thrombocytopenia Anemia

Fluid retention

Favors dasatinib Favors imatinib

–40 0 20 40–20

Kantarjian. JCO. 29:abst 6510; 2011

CML. Relative Risks of Uncommon Events

Imatinib RR Dasatinib RR Nilotinib RR

Marrow/tumor bleed

14-27 Pleural effusion

17-60 Femoral artery necrosis

409

Conjunct.bleed

9.4 Pericardialeffusion

10 PAOD 191

Effusion-ascites

4.5-5.6 PAH 4.0 Coronary stenosis

185

Anginas 7.2

MI 4.9

Arterial ischemia

4.0

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Frontline Rx with Imatinib vs. Second Generation TKIs

Parameter Imatinib 2nd TKIs

•Efficacy excellent even better

• %12-mo CGCR 65-70 80-85

MMR 20-25 40-45

AP- BP 3.5 0.4-2

•Tolerances excellent even better

•Follow up (yrs) 10 6-7

•Cost ($/yr) 90,000 90,000 – 120,000

CML. What Happens in 2015?

Parameter Imatinib 2nd TKIs

•Efficacy excellent even better

• Tolerance excellent even better

•Cost ($/yr) 2-10,000 90-120,000

•%5 – 10 yr survival

survival 80 – 90 ? > 90

EFS 50-60 ???

→ the difference at 5 yrs in EFS and OS determines frontline Rx

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CML- Possible Future Rxs• Most differences in events in ENEST-nd

and DASISION are in intermediate-high risk Sokal. Most differences in transformation in first 1-2 yrs

• Achieving PCR ≤ 10% at 3-6 mos and CGCR by 6 mos protects against events

• Possible strategies

1) imatinib in low-risk Sokal

2) nilotinib-dasatinib in higher risk Sokal for 1 year on until CGCR then change to imatinib

MSD and MUD SCT in CP-CML

Overall Survival Leukemia-Free Survival

Arora. JCO 2009; 27: 1644-52

• 3514 MDS & 1052 URD SCT from CIBMTR from 1988 to 2003

• All in CP1; median age 35-37

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Risk Assessment for SCT in CMLRisk factor Group ScoreDonor type HLA-identical sibling 0

MUD 1Stage CP 0

AP 1BP, ≥2nd CP 2

Age <20 020-40 1>40 2

Sex match All other 0M-rec/F-don 1

Time from Dx <12 mo 0>12 mo 1

Gratwohl. Lancet 1998; 352: 1087-92

Outcome After SCT by EBMT Score

Score% withscore

% at 5 years

LFS OS TRM RI

0 2 62 76 21 26

1 18 61 73 21 23

2 28 44 59 35 32

3 28 34 49 47 31

4 15 28 38 53 28

5 7 37 39 45 41

6 2 15 19 81 32Gratwohl. Lancet 1998; 352: 1087-92

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Overall Survival With TKI After Imatinib Failure or With SCT

This image cannot currently be displayed.

Months

% a

live

100

80

60

40

20

0

91%

0 3 6 9 12 15 18 21 24 27 30

Shah. Blood; 2014[E-pub ahead of print]Kantarjian. Blood 2009; 114: Abs # 1129;

Gratwohl . Lancet 1998; 352: 1087-92 Months Since Start of Treatment

100

90

80

70

60

50

40

30

20

10

0

% A

live

0 3 6 9 12 15 18 21 24 27 30 3633

87%

~55% Dasatinib

Nilotinib

75%

Dasatinib

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CML. Role and Timing of allo SCTStatus TKIs Allo SCT

AP-BP Interim Rx to MRD ASAP

IM failure in CP, T315I

Ponatinib interim Rx to MRD

ASAP

IM failure in CP –no CE, no mutations, good initial response

Long-term second line TKIs

Third line post second TKI failure

IM failure in CP –CE, bad mutations, no CG response

Interim Rx to MRD Second line

Older ≥65 – 70 post IM failure

Long-term May forgo allo SCT for many yrs of QOL

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CML Monitoring• Establish confirmed CGCR in first year (BM

at 6-12 mo)

• In CGCR

- FISH and QPCR every 6 mos

- If MMR (QPCR < 0.1%), may monitor with QPCR only (watch for false results)

- If QPCR ↑ by 0.5 – 1 log and/or loss of MMR (PCR> 0.1%) → monitor more frequently

• Mutations studies if resistance / need to change TKIs

• Change TKI only for loss of CGCR, not based on MMR/QPCR 41

When to Look For Mutations?•Mutation analysis in 1301 pts receiving imatinib or 2nd

generation TKI (GIMEMA)Clinical condition % PositiveFailure 27

No CHR at 3 mo 19No CyR at 6 mo 11No PCyR at 12 mo 17No CCyR at 18 mo 17Loss CCyR 31Loss CHR 50

Suboptimal 5No CyR at 3 mo 7No PCyR at 6 mo 5No CCyR at 12 mo 8No MMR at 18 mo 0Loss MMR 4

Soverini. Blood 118:1208 and abst 112, 2011

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Analysis of Mutations in CML

• If CG or hematologic relapse, mutations studies help

• No role for mutation studies pre-Rx or in imatinib responding patients

• T315I: no role for new TKIs; allo SCT or others (HU, ara-C, HHT, “T315I inhibitors”)

• Y253H, E255K/V, F359V/C/I : dasatinib• V299L,T315A, F317L/V/I/C : nilotinib

Kantarjian. Blood 111:1774, 2007. Soverini. Blood 118 : 1208 ,2011

New Criteria for Failure and “Warning”

Baccarani. Blood 2013;122:872-884

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MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS

Kantarjian H. Cancer. 2008;112:837–845.

EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx (Landmark)

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% Survival/TFS by Early Molecular Response

Study QPCR < 10% QPCR > 10%

Marin ( 8-yr) 93 54

MD Anderson (10-yr)

98 94

ENEST-nd 97 87

DASISION 97 86

BELA 98 88

Marin JCO 30: 232; 2012. Jain. Blood 120: abst 70,2012; Hochhaus. Blood 120:abst 167; 2012; Saglio. Blood 120: abst 1675; 2012;Brummendorf. Blood 120: abst 69; 2012.

The Problem with the 3 Months Response

Tran

scri

pts

Time3 mo

10%

Are these the same?

Are these the same?

MyelosuppressionRash

Non-adherence

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BCR-ABL Transcripts < 10% at 6 mos Associated with Better Outcome

Response

3 Mo 6 Mo No. % Survival

% PFS % FFS

≤ 10 ≤1 342 97 97 87

≤ 10 1-10 42 100 97 79

≤ 10 > 10 10 89 90 51

> 10 ≤ 1 18 100 100 76

> 10 1-10 36 100 94 79

> 10 > 10 35 74 69 11

Brandford. Blood 122: abst 254; 213

Criteria for Response/Failure and Change of Rx

Time (mo)

Imatinib Second TKIs

3-6 Major CG;QPCR ≤ 10%

CG CR;QPCR ≤ 1%

12 CG CR CG CR

Later CG CR CG CR

• CG ≤ 35% ≈ QPCR ≤ 10%• CGCR ≈ QPCR ≤ 1%

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Important Response Categories in CML

Response Translates into:

CCyR Significantly improved survival

MMRModest improvement in EFS;possible longer duration CCyR; no survival benefit

CMRPossibility of Rx discontinuation (clinical trials only)

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My Golden Rules in CML Monitoring

• Do not discard a TKI unless there is loss of CGCR (not MMR) at the maximum tolerated adjusted dose that does not cause grade 3-4 or chronic grade 2 (affecting QOL) toxicities

• Dose ranges–imatinib 300-400mg/D (rarely 200mg/D)–nilotinib 200-400mg BID (rarely 200mg/D)–dasatinib 20-100mg/D

• Mutation studies only if CG or hematologic relapse

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CGCR, Not “Deep Molecular Response MR 4.5” Associated with Survival in CML (German CML Study IV)• 1,551 pts Rx with IM 400, 800mg, with ara-C or IFN

• Cumulative CGCR 70%, MMR 80%, MR 4.5 70%, confirmed MR 4.5 54%; 8-yr OS 86%

• “Confirmed MR 4.5 at 4 yrs predicted higher 8-yr OS” (p=.047%)

Hehlmann. JCO 32: 415; 2014

Imatinib Treatment Discontinuation STIM1 and STIM2

STIM1 STIM2

•100 pts•Median follow-up 55 mo (range, 9-72)

•127 pts•Median follow-up 16 mo (range, 0-27)

Mahon et al. ASH 2013; Abstracts #255 & 654

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CG Abnormalities in Ph-negative Metaphases with IM Frontline Therapy

Overall Survival Progression-Free Survival

• 21/258 (9%) patients developed CG abnormalities in Ph-metaphases after median 36 mo

• Most common abnormalities: -Y (n=9; 43%), +8 (n=9; 43%), -7 (n=5; 17%)

• 1 (5%; 0.4% overall) developed AML [-7]

Jabbour. Blood 110:2991-5, 2007

Warning?

Warning?

Imatinib and Pregnancy• Rare syndrome of fetal malformations

(exomphalos, kidneys, bones) in 3/125

• Stop imatinib if pregnancy

• Female partners of males on TKIs →no problems

• If pregnancy / children highly desired: achieve durable CMR on TKIs then hold TKI and proceed with pregnancy / delivery under closer monitoring (e.g. FISH/QPCR every 2-3 mos)

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Inhibition of Bcr-AblATP-binding

T315I-activeNon-kinase InhibitionBcr-Abl Abl & Src

Imatinib Dasatinib Ponatinib Omacetaxine

Nilotinib Bosutinib Decitabine

INNO-406

AZD 0530

Survival with Dasatinib in CML-CP Post IM Failure

70-76%

Shah. Blood. 123: 2317; 2014

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Ponatinib (AP24534). Pan-BCR-ABL Inhibitor

• Rationally designed inhibitor of BCR-ABL

• Active against T315I mutant- Unique approach to

accommodating gatekeeper residue

• Potent activity against an array of BCR-ABL variants

• Also targets other therapeutically relevant kinases:

- Inhibits FLT3, FGFR, VEGFR and PDGFR, and c-KIT

• Once-daily oral activity in murine models

O’Hare T. Cancer Cell. 2009;16:401-412

Avoids T315I

Ile315

Ponatinib

Imatinib

Ponatinib

Ponatinib in CML-CP (PACE)

• 267 pts Rx; 93% failed ≥2 TKI, 58% failed ≥3 TKI

Response Rate %Cytogenetic response 67MCyR 56CCyR 46

MMR 34MR4.5 15

• 91% MCyR sustained at 12 mos

Cortes. Blood 122: abst 650; 2013

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Months

Pro

ba

bil

ity

of

PF

S (

%)

0 6 12 18 24 30 360

10

20

30

40

50

60

70

80

90

100

R/I (N=203)

T315I (N=64)

Total (N=267)

No. at riskTotal

267 204 170 139 73 3 0

Months

Pro

ba

bil

ity

of

OS

(%

)

0 6 12 18 24 30 360

10

20

30

40

50

60

70

80

90

100

R/I (N=203)

T315I (N=64)

Total (N=267)

No. at riskTotal

267 242 225 210 162 29 0

Ponatinib Phase 2 Study. PFS and OS in CP-CML

Cortes. Blood 122: abst 650; 2013

• PFS at 2 years: 67% (median 29 months)

• OS at 2 years: 86% (median not reached)

Ponatinib Toxicities of Concern CML Therapy?

• Optimal dose: 30 vs. 45 mg daily?

• Incidence of toxicities of concern

–Pancreatitis 7%

–Skin rashes 40%; severe 4-7%

–Vasoocclusive disorders (cardiac, CNS, PAOD) 12%

–Hypertension 67%; severe 20%

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Response to Bosutinib 2nd Line Therapy

• Dual Src & Abl inhibitor, no effect over c-kit or PDGFR

• 286 pts with imatinib failure

• Median follow-up 24.8 mo (0.2-83.4 mo)

Response, %IM

resistant(n = 196)

IM intolerant(n = 90)

Total(n = 286)

CHR 86 84 86MCyR 59 61 59

CCyR 48 52 494-yr MCyR Dur 69 86 754-yr Transformation 5 2 44-yr Progression/Death 19 22 10• 40% remain on therapy

Brumendorf et al. Blood 2013; Asbtract #2723

Bosutinib in CML post imatinib failure PFS and survival

Cortes. Blood 118: 4567;2012

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Take Home Message – CML 2014 •Great therapy for CML•CGCR is endpoint of Rx = improves survival•Early response (3 months) predictive─ Should not change at 3 months─ Monitor at 6 months and decide

•Deeper molecular responses improve event-free survival− No impact on transformation or survival− No clear benefit for CMR (except

discontinuation?)•Excellent new drugs: ponatinib, bosutinib,

omacetaxine

Leukemia Questions?

• Pager: 713-404-3387

• Email: hkantarj@mdanderson.org