Elias Jabbour, MDUniversity of Texas – M. D. AndersonCancer Center

CML and Imatinib Resistance: Which TKI and When?

CML and Imatinib Resistance: Which TKI and When?

Marcos de Lima, MD

Stem Cell Transplantation ProgramCase Western Reserve University

University Hospitals Seidman Cancer CenterCleveland - OH

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 et al; Blood 2009; 114: Abst# 1126

IRIS 8-Year Update

37%Unacceptable

Outcome

Deininger et al; Blood 2009; 114: Abst# 1126

5

IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos

Estimated rate at 60 months

n= 86 93%n= 73 81%

n= 350 97% p<0.001 p=0.20CCyRPCyRNo MCyR

Response at 12 months

% w

ithou

t AP

/BC

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

Rx aim: major CG response (Ph ≤ 35%)

Criteria for Failure and Suboptimal Response to Imatinib

Time (mo)

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

AnyLoss of CHR

Loss of CCgRMutation

CE

Loss of MMRMutation

Stable or improving

MMR

Baccarani. JCO 2009; 27: 6041-51

NCCN Treatment Recommendations3-Month Follow-up Therapy

BCR-ABL transcript levels ≤10% by QPCR International Scale (IS) or PCyR on bone marrow cytogenetics

BCR-ABL transcript levels >10% by QPCR using the IS or <PCyR on bone marrow cytogenetics

Continue same dose

of IM, DAS, or NIL

• Evaluate patient compliance and drug-drug interactions

• Mutational analysis

Monitor with QPCR every 3 mo

DAS 100 mg daily

NIL 400 mg BID

Evaluation and discussion of HSCT

Clinical trial

3-moevaluation

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Revised September 13, 2012.

No relapse

Relapse

Adherence Is the Most Important Factor Contributing to Molecular Responses

Marin D et al. J Clin Oncol. 2010;28(14):2381-2388.

Adherence monitored over a period of 3 months using a microelectronic monitoring device in the imatinib bottle cap. Patients were not aware of the device.

0.1

12Time Since Start of Imatinib Therapy (months)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0 6 18 24 30 36 42 48 54 60 66 72

Pro

babi

lity

of M

MR

Adherence >90% (n = 64) Adherence ≤90% (n = 23)

P<0.001

EFS by Response to IM at 6 and 12 Mos

0 12 24 36 48 60 72

Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Failure Suboptimal Optimal

p<0.0001

No.9

10240

Events (%)6 (67)5 (50)14 (6)

0 12 24 36 48 60 72

Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Failure Suboptimal Optimal

p<0.0001

No.1419

213

Evaluable (%)8 (57)3 (16)8 (4)

6 month response 12 month response

•281 pts; imatinib frontline (400mg in 73, 800mg in 208)•Suboptimal response at 6-12 months: 12-17% with

400mg, 1-4% with 800mg (p=0.002)

Alvarado. Cancer. 2009;115:3709-18.

MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS

Patients with MCyR have better OS than patients that do not

Landmark analysis at 6 mos

0 12 24 36 48 60 72

Cytogenetic response at 6 mos Total Dead P-value

Complete 201 5

Partial 39 1

Minor 10 3

Othersa 9 3

0.850.01

0.62

1.0

0.8

0.6

0.4

0.2

0

Prop

ortio

n al

ive

Months

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

MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS

Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos.

Landmark analysis at 12 mos

Prop

ortio

n PF

S

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72

Months

Cytogenetic response at 12 mos Total Failure P-value

Complete 214 7Partial 19 3Minor 5 2Others 8 5

0.02

0.2

0.22

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

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

Jabbour E et al. Blood. 2011.

Outcome by 12-Month Response in CML CP

• 848 pts randomized to IM 400mg, IM 800mg, or IM 400 + IFN

• Median FU: 40 months

12-month BCR-ABL/ABL (IS) N

PercentagePFS OS

<0.1% 341 99 990.1-1% 240 97 98>1% 267 94 93P value 0.0023 0.0011• Outcome independent of treatment arm

Hehlman et al. JCO 2011;29:1634-42

CCyR

Prob

abili

ty o

f sur

viva

l

Time from onset of imatinib therapy (years)

BCR-ABL/ABL<9.8% OS= 93.3%

BCR-ABL/ABL>9.8% OS= 54%

p<0.0001

Survival After Imatinib Therapy by Molecular Response Achieved at 3 Months

Marin et al, JCO 2011; [Epub ahead of print]

• Optimal PCR value determined by Receiver operating characteristic (ROC) curve

CML IV: Long-Term Impact of Response at 3 Months

•1223 pts randomized to imatinib 400, imatinib + IFN, imatinib + ara-C, imatinib 800

•3 month analysis: PCR in 692 pts, cytogenetics in 460

•3 mo transcript levels predictive of achievement of CCyR and MMR

% 5-year outcome

Cytogenetics (% Ph+)

Molecular [BCR-ABL/ABL (IS)]

≤35% >35% ≤10% >10%PFS 94 87 93 87OS 95 87 95 87

Hanfstein et al. ASH 2011; Abstract #783

OS by Response to TKI at 3 Months at MDACC

Naqvi et al. ASH 2011; Abstract #3784

EFS by Response to TKI at 3 Months at MDACC

Naqvi et al. ASH 2011; Abstract #3784

Failure On Imatinib And Strategies

Imatinib Failure Imatinib

Second Generation

TKI

• Ph 100% at 6 mos _ +

• Ph ≥ 35% at 12 mos + +

• No CGCR in yr 2 + +

• CG relapse + +• Hematologic relapse

_ +

Imatinib Dose Escalations

% 2-yrResistance1,2 No. % CG CR TFS OSCytogenetic 63 52 80 90Hematologic 21 5 51 67

• Similar results from IRIS 3

1Kantarjian Blood 101:473, 2003 2Jabbour Blood 113:2154, 2008 3Kantarjian Cancer 115:551, 2008

2nd Generation TKI in CMLParameter Dasatinib Nilotinib BosutinibPotency (fold vs IM) 325 30 20-50Target Src & Abl Abl Src & ABLBCR-ABL binding Active + Inactive Inactive IntermediateResistant mutations T315I T315I T315IMutations with intermediate sensitivity

E255K/V, V299L, F317L

E255K/V, Y253F/H, Q252H, F359V

E255V/K,V299L, F317L

Standard dose (CP) 100mg QD 400mg BID 500mg QDGrade 3-4 neutropenia & thrombocytopenia 33% / 22% 31% / 33% 12% / 21%

Other notable toxicities Pleural effusion, bleeding

Bilirubin, lipase elevation Diarrhea, rash

C-kit inhibition (vs imatinib) Increased Similar None

PDGFR inhibition (vs imatinib) Increased Similar None

Clinical activity Highly active Highly active Highly active

Phase II Studies of Dasatinib After Imatinib Failure

ResponsePercent by Disease Stage

CPn=387

APn=174

MyBPn=109

LyBPn=48

ALLn=46

Hematologic 91 64 50 39 49 CHR 91 50 26 29 35 NEL - 14 7 6 7Cytogenetic 62 40 47 58 62 Complete 53 33 27 46 54 Partial 9 7 7 6 2

Blood 110:abst 470 and 734, 2007.

Baccarani. Blood 112:abst 450, 2008

Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib Failure

% Parameter

100mgQD

N=166

50mgBID

N=166

140mgQD

N=163

70mgBID

N=167MCyR 63 61 63 61CGCR 50 50 50 5424-months PFS 80 76 75 76Neutropenia, G3-4 35 47 44 45Thrombocytopenia, G3-4 23 36 41 38Pleural effusion, G3-4 2 4 5 5Interruption 58 66 69 71Reduction 33 45 54 57

Shah. Blood 112:abst 3225, 2008

Phase II Studies of Nilotinib After Imatinib Failure

Response

PercentageCP

n =321AP

n =137MyBPn =106

LyBPn =30

•HR 77 54 24 20CHR 76 26 12 13

•CytogeneticMajor 59 31 38 50Complete 44 19 28 33

Blood 112:abst 3229, 3238, 2008.

Nilotinib in Chronic Phase CML Post Imatinib Failure

• 321 pts; nilotinib 400 mg BID; median FU 19 mos; median nilotinib 788 mg/D; median days off 20

• Outcome Percent- CGCR 46- MMR 28 (56% of CGCR)- 24-mos PFS 64- 24-mos OS 87

Kantarjian. Blood 114:abst 1129; 2009

Nilotinib in CML Chronic Phase. Survival and PFS

0

10

20

30

40

50

60

70

80

90

100

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

Time in mos

84%

73%64%

95% 91% 88%

Kantarjian. Blood 112:abst 3238, 2008

% P

rogr

essi

on-fr

ee s

urvi

val

Bosutinib in CML-CP post imatinib failure

• 288 pts Rx with bosutinib 500 mg/D: Imatinib resistant 200; intolerant 88

• Parameter Percent -CHR 86

-MCyR 53 -CCyR 41 -MMR if CCyR 64 -2-yr PFS 79 2-yr OS 92

• Side effects: diarrhea 9%, rash 9% Cortes. Blood 118: 4567;2012

Response to Bosutinib 3rd Line Therapy• Dual Src & Abl inhibitor, no effect over c-kit or

PDGFR• 118 pts who failed imatinib (600mg) & dasatinib

or nilotinib

Response, %

IM + D resistant(n = 37)

IM + D intolerant(n = 50)

IM + NI resistant(n = 27)

CHR 50 80 77MCyR 31 30 32

CCyR 14 28 27PCyR 17 2 8

MMR 3 35 112-yr PFS 22 61 502-yr OS 66 85 100IM, imatinib; D, dasatinib; NI, nilotinib.

Khoury. Blood 119:3403;2012

2nd Generation TKI in CML CP Post-Imatinib Resistance

ResponsePercentage

Dasatinib Nilotinib BosutinibFU (mo) >24 >24 24*

CHR 89 77 86MCyR 59 56 54CCyR 44 41 41

24 mo PFS** 80% 64% 79%24 mo OS** 91% 87% 92%* Median** All patients

Shah et al. Haematologica 2010; 95: 232-40Kantarjian et al. Blood 2011; 117: 1141-45

Cortes et al. Blood 2011; 118; 4567-76

2nd-Generation TKI in CML CP Post- Imatinib Failure

Toxicity Dasatinib Nilotinib BosutinibPleural effusion ++ - -Liver + + +

Transaminases + + ++Bilirubin - ++ -

Rash + + ++Diarrhea - - ++Lipase - (+) ++ -Glucose - ++ -Hypophosphatemia ++ ++ +Bleeding + - -QTc ++ ++ -

2nd-Generation TKI in CML CP Post- Imatinib Failure

Toxicity Dasatinib Nilotinib Bosutinib

Anemia 13 11 13

Neutropenia 35 31 18

Thrombocytopenia 23 30 24

Shah et al. Haematologica 2010; 95: 232-40Kantarjian et al. Blood 2011; 117: 1141-45

Cortes et al. Blood 2011; 118; 4567-76

Better Outcome on Dasatinib with Earlier Intervention

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

• Status at IM Failure No.Percentage

CCyR MMR

Loss of MCyR 151 72 60

Loss of CHR & MCyR 33 42 29

Loss of CHR (never MCyR) 109 26 26

Quintás-Cardama. Cancer 115: 2912-21, 2009

Dasatinib Early InterventionEFS & OS

Quintás-Cardama. Cancer 115: 2912-21, 2009

Event-Free Survival Overall Survival

Time to intervene: Loss of MCyR

Prognosis with 2nd TKIs. Survival•Adverse factors: PS ≥1 and lack of CyR to imatinib

Jabbour. Blood 117: 1822-7, 2011

No MCyR (27)

MCyR (59)

0

0.2

0.4

0.6

0.8

1

0 12 24 36Months on second TKI

PFS

(%)

PFS and Response to 2nd TKI

Response @ 12 mo

% AP/BP/Death/CHR loss Next Year

MCyR 3%

No MCyR 17%

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

Tam. Blood 112: 516-8, 2008

p = 0.003

Optimal Response to 2nd TKIs. Survival

3-year survival (%)Parameter Event-free OverallCCyR by 3 months Yes 74 98

No 43 79

How Do You Choose The Second Generation TKIs

• Disease characteristics- AP/BP: favor dasatinib (?) and combinations- chronic: see below

• Mutations-T315I → none- nilotinib IC50 > 150nM → avoid- dasatinib IC50 > 3nM → avoid

• Patient Hx- Hypertension, CHF, lung problems, COPD → avoid dasatinib, consider bosutinib/nilotinib- Severe diabetes, pancreatitis Hx, atherosclerosis → avoid nilotinib, consider bosutinib/dasatinib - QTc problems → be cautious with all (?)

Ponatinib Phase 2 Study - PACE Response Characteristics CP-CML

• 93% failed ≥2 TKI, 58% failed ≥3 TKIResponse Rate, n (%) N=267Any Cytogenetic Response 180 (67)

MCyR 149 (56) CCyR 124 (46)MMR 91 (34) MR4.5 39 (15)BCR-ABL ≤10% at 3 months, n/N(%) 142/240 (59) 1 prior approved TKI 14/16 (88)Median Time to Response*, months [range]MCyR 2.8 [1.6 – 11.3]MMR 5.5 [1.8 – 19.2]• 91% MCyR sustained at 12 months (K-M)Cortes J, et al. Blood. 2012;120: Abstract 163.

Ponatinib Phase 2 Study - PACE Response by Baseline Mutation CP-CML

Baseline Mutations in at Least 2 Patients (Excluding T315I)P-Loop Non P-Loop

Num

ber o

f Pat

ient

s

MCyRCP-CMLN=267n/N (%)

R/I, no mutation 66/136 (49)

R/I, any non-T315I mutation

38/67 (57)

T315I mutation 45/64 (70)

Cortes J, et al. Blood. 2012;120: Abstract 163.

Ponatinib Phase 2 Study - PACE Response in Advanced Phase

n (%)

AP-CML N=83

BP-CML N=62 Ph+ ALLN=32Myeloid

N=52Lymphoid

N=10MaHR* 47 (57) 15 (29) 4 (40) 13 (41)

Any CyR** 46 (55) 19 (37) 5 (50) 15 (47)

MCyR 32 (39) 10 (19) 4 (40) 15 (47)

CCyR 20 (24) 8 (15) 3 (30) 12 (38)

MMR# 13 (16) N/A N/A N/A*MaHR = primary endpoint; 14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR assessment counted as non-responders **CCyR + PCyR + minor CyR + minimal CyR#MMR was assessed on the International Scale using peripheral blood; Patients missing a valid baseline MMR assessment , or who met the criteria for MMR at baseline, were counted as non-responders

Kantarjian HM, et al. Blood. 2012;120: Abstract 915.

Omacetaxine for CML CP After Failure to ≥2 TKI

• 122 pts with CML CP (n=81) or AP (n=41) with ≥2 prior TKI

• Omacetaxine 1.25 mg/m2 BID x14d, then x7d

Response, % CPN=81

APN=41

Primary endpoint MCyR 20% MaHR 27%CCyR 10% CHR 24%

Median duration, mo 17.7 9Median PFS, mo 9.6 4.7Median OS, mo 33.9 16• 11 pts (9 CP, 2 AP) ongoing response• Median 35 cycles over median 39 months• Median response duration: 14 mo CP, 24 mo AP

Kantarjian HM, et al. Blood. 2012;120: Abstract 2767.

Allo SCT. Second or Third Salvage?• Imatinib failure in AP, BP: use new TKI as bridge to MRD, then

alloSCT ASAP• T315I mutation in any CML phase: use AP 24534, other T315I

inhibitors, HHT, HU, others as bridge to MRD, then allo SCT ASAP

• Imatinib failure in CP: – if IC50 , clonal evolution, or no major CG in 12 mos allo

SCT (risk should also be reasonable: young, good match)– If not TKI until failure• Age 70 yrs or if poor match: may decide to forgo curative

allo SCT option for several years of CML control; • Young patient (?) • Financial considerations

Monitoring Patients with CML While on TKI Therapy

• Adequate monitoring required to optimize outcome / Not too much, not too little

• CCyR is associated with survival benefit• MMR is associated with durable CCyR and may

therefore decrease probability of relapse• CMR offers hope for treatment discontinuation

(clinical trials only) • Results should be interpreted in the context of

alternative options

• Not failure criterion / QPCR in CCyR

CML in 2013• Imatinib,nilotinib,dasatinib are standard

frontline Rx (except p190 CML)• Dose optimization and adequate

monitoring• Sub-optimal response dose imatinib (400mg → 800mg)– New TKI

• Failure– Dasatinib, nilotinib, bosutinib– Allogeneic SCT

• T315I: ponatinib, omacetaxine

Questions?

ejabbour@mdanderson.org

Marcos.delima@uhhospitals.org