GIMEMA CML WP

42° CONGRESSO NAZIONALE SIESocietà Italiana di Ematologia

Milano, 18-21 ottobre 2009

Francesca PalandriDipartimento di Ematologia e Oncologia “L. e A. Seràgnoli”

Bologna University Hospital

Leucemia Mieloide Cronica:

la terapia con imatinib

2

GIMEMA CML WP

Imatinib standard dose:IRIS 7-year update

3

GIMEMA CML WPIRIS Protocol: Study Design

IFN-a +

Ara-C

Imatinib

Crossover for:• Lack of response• Loss of response• Intolerance of treatment• Reluctance to continue IFN

Crossover

RANDOMIZE

n = 553

n = 553

O’BRIEN et al, NEJM, 2003

4

GIMEMA CML WP

All randomized to imatinib(n= 553; 100%)

Discontinued study imatinib* (n = 221; 40%)

Still receiving study imatinib (n = 332; 60%)

In CCR(n = 317; 97%)

No CCR(n = 15; 3%)

Safety(5%)

Efficacy(15%)

Other(22%)

Alive(40%)

Dead(60%)

Alive(63%)

Dead(37%)

Alive(84%)

Dead(16%)

*Patients may have continued imatinib off study.

Hochhaus A et al,Leukemia 2009

IRIS: 7-year update

Cumulative

CCgR rate:

456/553 (82%)164 alive patients (30%)

formally off protocol

5

GIMEMA CML WPIRIS- Molecular Response

BCR-ABL% (International Scale)

Months from imatinib start

≤0.1% (MMolR) ≤0.01%

0

10

20

30

40

50

60

70

80

90

100

% o

f ava

ilabl

e sa

mpl

es

0 3 6 9 12 15 18 21 24 30 36 42 48 54 60 66 72 78 84

O’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186

6

GIMEMA CML WPOverall Survival (ITT Principle)

86%

Survival: deaths associated with CMLOverall Survival

% a

live

0

10

20

30

40

50

60

70

80

90

100

Months Since Randomization0 12 24 36 48 60 72 84 96

94%

O’BRIEN et al, ASH 2008, Blood 2008; 112(11): 76, Abstract 186

7

GIMEMA CML WP

Imatinib standard dose:Indipendent analyses

8

GIMEMA CML WP

38 (12-85)Median follow-up, mos59 (29%)Low Sokal86 (42%)Intermediate Sokal59 (29%)High Sokal

204Patients number

80 (39%)MMolR

159 (78%)CCgR

201 (98%)CHR

no of patients (%)

OS 83%

PFS 82%

EFS* 63%

•Event: death, progression to AP/BC, loss ofCHR/MCgR, IM discontinuation for AE/ failure to

achieve a PCgR

De Lavallade et al, JCO 2008; 26: 3358-3363

9

GIMEMA CML WP

0%

20%

40%

60%

80%

100%

Complete cytogenetic response rate

6 mos 12 mos 18 mos

68%79% 79%

OS: 93%

PFS: 92%

FFS: 82%

EFS: 74%

Failures: no CHR at 6 mos, no CgR at 6 mos, no PCgR at 12 mos, no CCgR at 18 mos,loss CHR or CCgR, progression to accelerated/blastic phase and death.

Events: failures, off-treatment for toxicity, refusal and lost to follow-up.

GIMEMA CML WP:analysis of 553 Early Chronic Phase patients accruedbetween 2004 and 2007 in 3 multicentric studies

10

GIMEMA CML WP

Beyond imatinib standarddose:

room for improvementswith higher doses?

11

GIMEMA CML WP

The issue is complex and probably it cannot be applied, or pursued, inall patients irrespective of

1) Response2) Tolerance3) Blood level testing data

Rational for higher doses of IM1) Responses to 800mg after failure to 400mg

2) Chronic phase: Response correlates with actual dose intensity

3) Accelerated phase 600 mg (vs 400 mg): improved response rate,survival and EFS

4) Some mechanisms of resistance may be overcome by higher dose

Imatinib dose optimization

12

GIMEMA CML WPTyrosine Kinase Inhibitor Optimizationand Selectivity (TOPS) study

PFS, OS

Imatinib 400 mg

N=319 pts Imatinib 800 mg

MMR at 12 months

N=157 pts

Random 2:1N=476

Total 5 years

Accrual: June 2005 – December 2006

Follow-up: 12 months

Cortes et al., JCO 2009, in press

13

GIMEMA CML WP“TOPS” study: IM 400 mg vs 800 mg

17%34%

40%46%

0%

20%

40%

60%

80%

100%

400 mg 800 mg 400 mg 800 mg

6 mos 12 mos

MMolR

p 0.0002p NS

45%

57% 66%70%

0%

20%

40%

60%

80%

100%

400 mg 800 mg 400 mg 800 mg

6 mos 12 mos

CCgR

p 0.015 p NS

By 12 months, CCgRand MMR rates

were comparablebetween 400 and 800

mg/day arms

14

GIMEMA CML WP

Imatinib 400mg

FAILURES• Lack of CHR at 6 months• Less than minor CyR at 6 months• Less than Partial CyR at 12 months• Loss of CHR • Loss of CCyR

RANDOMIZE

Imatinib 800mg

Primary Endpoint: CCgR at 1 year

15

GIMEMA CML WP

6 mos 12 mos

52%50%

64%

58%

0%

20%

40%

60%

80%

100%

400 mg 800 mg 400 mg 800 mg

CCgR

p NS p NS

42%

32%

49%

41%

0%

20%

40%

60%

80%

100%

400 mg 800 mg 400 mg 800 mg

6 mos 12 mos

MMolR

p NS p NS

91%73%

20%0%

20%

40%

60%

80%

100%

700-800 699-400 <400

HIGH DOSE ARMCCgR according to average daily

dose

ELN “CML022” study

CCyR rates appeared to berelated to the actual dose

16

GIMEMA CML WP

Beyond imatinib alone:room for improvements

with combinationtherapies?

17

GIMEMA CML WPGIMEMA CML 011- IM+PegIFN-αin 76 ECP-CML

Cytogenetic response rate(5 yrs)

0%

20%

40%

60%

80%

100%

87%

10%

Partial Complete

0 12 24 36 48 60 720

20

40

60

80

100

months

prog

ress

ion-

free

sur

viva

l95%

0 12 24 36 48 60 720

20

40

60

80

100

months

over

all s

urvi

val 96%

18

GIMEMA CML WP

0%

5%

15%

25%

35%

45%

12 mos 18 mos 24 mos 36 mos

1st cohort

2nd cohort

3rd cohort

41%

18%

13%3%

GIMEMA CML 011 –Compliance to PegIFN-α

19

GIMEMA CML WPFrench “SPIRIT” trial636 ECP patients

Randomization1:1:1:1

Study initiation:Sept 2003

Courtesy of dr. F. Guilhot

Imatinib 400 mg

Imatinib 600 mg

Imatinib 400 mg + Ara-C

Imatinib 400 mg + PegIFN

20

GIMEMA CML WPSPIRIT: Major Molecular Responseat 18 months (ITT)

6252 53

41

0102030405060708090

100

18 monthsIM

+ IFN

IM 60

0

IM + AraC

IM 40

0

P=0.0001

62%

41%

Courtesy of dr. F. Guilhot 1 . Guilhot F, et al. Bood (ASH Annual Meeting Abstracts) 112:183, 2008

46% of the patientsdiscontinued IFN

during the first year

21

GIMEMA CML WP

Imatinibn=336

alloSCTn=84

Failure

R

Imatinib 800 mgn=350

Imatinib after IFNan=131

Imatinib + IFNan=362

Imatinib + AraCn=158

German CML Study IV

Courtesy of dr. R. Helhhman

No significantdifferences betweentreatment arms for

CCgR, MMolRand PFS

Median follow-up: 45 months

Hehlmann R. Haematologica 2009; 94:193

22

GIMEMA CML WP

Beyond imatinib:room for therapydiscontinuation?

23

GIMEMA CML WP

Molecular relapsein 36 pts

Courtesy dr. P Rousselot

Median follow-up: 4 mos (1-20)

15/34 (44%) LCP21/36 (58%) ECP

The STop IMatinib (“STIM”) study

24

GIMEMA CML WPSUMMARY1. IM 400 mg daily in early chronic phase CML:

CHR ≥ 95%

CCgR 75-90%

MMolR 50-70%

7-yrs PFS 85-90%

7-yrs OS 90-95%

2. IM 800 mg: cytogenetic and molecular responses more rapid, but nodifferences at 1 year. Limited compliance.

3. IM in combination/rotation with other agents is investigational. Thefeasibility of the combination with IFN-alpha seems to be limited.

25

GIMEMA CML WP OPEN ISSUES

1. Imatinib is not always a “magic bullet”D/C IMATINIB FOR FAILURE 15 - 20%D/C IMATINIB FOR TOXICITY 8 - 10%MMolR RATE 40 - 90%

2. Imatinib and “Quality of Life”

3. Imatinib and safe procreation

4. Imatinib and “CURE”

26

GIMEMA CML WP

Department of Hematology “L. and A. Seràgnoli”Bologna University Hospital

Thank you!GIMEMA CML WP

Scientific CommiteeMichele Baccarani (Bologna)

Giuliana Alimena (Roma)Renato Fanin (Udine)

Francesco Frassoni (Genova)Giovanni Martinelli (Bologna)Gianantonio Rosti (Bologna)Domenico Russo (Brescia)Giuseppe Saglio (Torino) Giorgina Specchia (Bari)

27

GIMEMA CML WP

BACK-UP

28

GIMEMA CML WPIRIS: 7-year update Annual Event Rates

Event Loss of CHRLoss of MCRAP/BCDeath

AP/BC

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7Year

% W

ith E

vent

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

AP/BC3.3

7.5

4.8

1.71.5

2.8

1.60.9 0.8

0.30.50

2.0

0.4

*

0

1

2

3

4

5

6

7

8

1 2 3 4 5 6 7Year

% W

ith E

vent

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

AP/BC3.3

7.5

4.8

1.71.5

2.8

1.60.9 0.8

0.30.50

2.0

0.4

*

All patients

7

31

2

1

01

23

4567

89

10

1st 2nd 3rd 4th 5th

>24 months (n = 33)>12- _24 months (n = 50)_12 months (n = 373)

Num

ber P

rogr

essi

ng A

fter C

CR

Year After Achievement of CCR

Time to CCR

7

31

2

1

01

23

4567

89

10

1st 2nd 3rd 4th 5th

>24 months (n = 33)>12- _24 months (n = 50)_12 months (n = 373)

Num

ber P

rogr

essi

ng A

fter C

CR

Year After Achievement of CCR

Time to CCRCCgR patients

EFS at 7 years:81%

PFS at 7 years:93%

29

GIMEMA CML WP

559 Early Chronic Phase patients accrued betweenJan 2004 and Apr 2007 in 3 multicentric studies:

• CML/021, phase II 82 pts imatinib 800 mg in intermediate Sokal risk

• CML/022, phase III, randomized 112 pts imatinib 400 vs 800 mg in high Sokal risk

• CML/023, observational 365 pts imatinib 400 mg, all risks

GIMEMA CML WP: ITT ANALYSIS

30

GIMEMA CML WPELN “CML022” study:IM 400 mg vs 800 mg in high risk pts

27%

17%

5%

5%

400(n. 108)

8%Withdrawals

8%Adverse events

15%Failures

31%Total

800(n. 108)

Treatment discontinuation in the first year

12%6%<350

31%6%350-399

57%25%400-599

NA25%600-799

NA28%800 mg

400mg800 mg

Average daily dose

53%

31

GIMEMA CML WPEvaluating Response in CML

11

Num

ber o

f leu

kem

ic c

ells

1012

106

108

1010

102

104

3 log reduction

Limits of detection

4 log reductionMolecularresponse(Q-PCR)

CCR (CG)

MCR Cytogeneticresponse

CCR (FISH)

CHR Hematologic response

32

GIMEMA CML WP

Late chronic phase

Accelerated/blast phase

33

GIMEMA CML WPGIMEMA CML 002: Imatinibin Late Chronic Phase CML

Palandri et al, GIMEMA CML WP, JCO 2008

0 10 20 30 40 50 60 70 800

102030405060708090

100

Months from IM start

OS

/ PFS

OSPFS

90%

0 12 24 36 48 60 720

102030405060708090

100early

late

Months from IM startPa

tient

s in

CC

gR

34

GIMEMA CML WPGIMEMA CML 003: Imatinib 600mg in Accelerated/blast Phase

29 (26%)27 (29%)Chemotherapy prior to IM

18 (16%)36 (39%)PS at IM start =2

21 (22%)20 (22%)ACA at IM start

58 (26-82)55 (18-88)Median age at IM start

70/4159/33Male/female

11192Number of patients

Accelerated phaseBlast crisis

35

GIMEMA CML WPGIMEMA 003 - Overall survival

0 12 24 36 48 60 720

102030405060708090

100

no HR

HR

months from IM start

over

all s

urvi

val

0 12 24 36 48 60 720

102030405060708090

100

MCgRno MCgR

months from IM start

over

all s

urvi

val

BC patients

0 12 24 36 48 60 72 84 960

102030405060708090

100

months from IM start

over

all s

urvi

val

0 12 24 36 48 60 72 84 960

102030405060708090

100

months from IM start

over

all s

urvi

val

AP patients

36

GIMEMA CML WP

DOSE ISSUE

37

GIMEMA CML WPImatinib high dose: rationale

1. Dose-response in preclinical models

2. Phase I: No MTD, dose-response correlation

3. Responses to 800mg after failure to 400mg

4. Accelerated phase 600 mg (vs 400 mg): improved response rate,

survival and EFS

5. Chronic phase: Response correlates with actual dose intensity,

plasma levels

6. Improved long-term outcome with early responses

7. Some mechanisms of resistance may be overcome by higher dose

38

GIMEMA CML WP

No CHR No PCgR No CCgR No MMolRIM 600 mg

Dose escalation to 800 mg

3 months 6 months 9 months 12 months

Accrual: October 2002- August 2003

No. of patients: 103

Therapeutic Intensification in DE- novo Leukaemia (TIDEL STUDY)Australasian Leukaemia and Lymphoma Group

39

GIMEMA CML WPTIDEL STUDY – response rate

“ Patients able to dose escalate and those remaining on 600 mg achieved superiorresponses to patients receiving 600 mg.

Superior responses achieved in patients able to tolerate imatinib at 600 mgsuggests that early dose intensity may be critical to optimise response in CP-CML”

p N.S.

0%

20%

40%

60%

80%

100%

12 mos 24 mos

CCgR

69%

88%80%

90%IR

IS

TID

EL

IRIS

TID

EL

MMolR

12 mos 24 mos

40%

47%55%

73%

IRIS

TID

EL

IRIS

TID

EL

p .001p .002

40

GIMEMA CML WP

4%1%8%87%

98%2%1%

656 months

30

3%90%

Minimal/absentMinorPCgRCCgR

98%//

2%

81%19%

//

CHRPHRABP

4372No Observed12 months3 months

Study 021 - Sokal Intermediate RiskIM 800 mg (72 pts)

41

GIMEMA CML WPComparison

NA

NA

48%

46%

90%

87%

91%

GIMEMA800 mg(021)

NA72%60%55%24 months

NA28%7%4%PCR undetectable

43% m960%25%39%12 months

31%39%5%21%6 monthsMMR

NA95%75%68%12 months

80%82%55%52%6 months

NA95%80%82%OverallCCyR

TIDEL600 mg

Houston800 mg

Houston400 mg

IRIS400 mg

42

GIMEMA CML WP

COMBINATIONTHERAPIES

43

GIMEMA CML WPGIMEMA CML 0408

IM 400 mgOAD

NILO 400 mgBID

IM 400 mgOAD >

24 months “CORE” > 36 months “EXTENSION”

NILO 400 mgBID

3-days wash out

44

GIMEMA CML WPGIMEMA CML 011- IM + PegIFN-αin de-novo CP-CML

60 (40-68)Median follow-up ofliving patients,mos, (range)

10 (0.5-49)Median time onpegIFNα, mos(range)

47 (18-68)Median age atdiagnosis, yrs,(range)

44 (58%)32 (42%)

All patients(76)

Male, no. (%)Female, no. (%)

1st cohort (27 patients)50 µg/week

2nd cohort (18 patients)100 µg/week

3rd cohort (31 patients)150 µg/week

45

GIMEMA CML WP

vaccino antitumorale “IDEALE”

induce una risposta immune sistemica “ATTIVA”

distrugge specificatamente cellule tumorali disseminate

da origine ad una memoriaimmunologica persistente

OSTACOLI

Identificare l’ANTIGENE TUMORALESPECIFICO più appropriato

Rompere la TOLLERANZAIMMUNOLOGICA al tumore

VACCINOTERAPIA

P 210TARGET “TUMORE-SPECIFICO”

P 210IMMUNOGENICO GRAZIE A

SEQUENZA AMINOACIDICA “UNICA”

46

GIMEMA CML WP

CRITERI DI INCLUSIONE

diagnosi di LMC b3a2 almeno 1 di HLA A3, A11, B8, DR11, DR1 o DR4 Risposta citogenetica maggiore o completa STABILE da almeno 6 mesi durante trattamento convenzionale (IFN-α o IMATINIB)

CMLVAX100: STUDIO DI FASE II

DOSE VACCINO 5 PEPTIDI: 100µg/peptide (500µg/iniezione)QS-21: 100µgGM-CSF: 50µg/m2

PIANO DITRATTAMENTO

6 vaccinazioni ogni 2 settimane(IMMUNIZAZIONE)

+“richiami” ogni 4-6 mesi dal termine

(MANTENIMENTO)

47

GIMEMA CML WP

23 patients with various degrees of cytogenetically and/ormolecularly defined MRD persisting after a median time of 2 yearsof imatinib treatment entered the vaccination protocol

15/23 (65%) pts measurably reduced their levels of residualdisease after immunization (6 vaccinations)

6/23 (26%) pts achieved a CMR after immunization

Clinical responses were durable and tended to improve further afterboosts of vaccine

CMLVAX100 peptide vaccine: summary clinical results

48

GIMEMA CML WP

IM SAFETY

49

GIMEMA CML WPIRIS SAEs in Years 6 and 7

No unique, previously unreported AEs attributed to imatinib observed overthe past 24 monthsIn years 6 and 7, 13 SAEs with suspected relationship to imatinib werereported:• Congestive Heart Failure (n=3): all of the patients had pre-existing

cardiac disease prior to study entry• Second malignancy (n=3)*• Myositis (n=1); elevated CK (n=1); multiple sclerosis (n=1)• Pancreatitis (n=1); vomiting (n=1)• Renal failure (n=1)• Dermatitis (n=1)

*With >400,000 patient years of estimated imatinib exposure, the analysis ofclinical safety data from clinical trials and spontaneous reports did not provideevidence for an increased incidence of malignancies for patients treated withimatinib compared to that of the general population

50

GIMEMA CML WP

The issue of cardiotoxicity

KERKELA et al, NATURE MEDICINE 2006; 12:908-916

“…Here we report ten individuals whodeveloped severe congestive heart failurewhile on imatinib and we show that imatinib-treated mice develop left ventricularcontractile dysfunction.”

51

GIMEMA CML WPIN REPLY TO “CARDIOTOXICITY OF THE CANCERTHERAPEUTIC AGENT IMATINIB MESYLATE”Nature Medicine 2007; 13: 13-16

0.110.557*63801276ATALLAH et al

M.D. ANDERSON

<0.04<0.120**2383833ROSTI et al

GIMEMA CML WP

0.42

<0.97

0.51

% OF

PTS

0.1319147704539TOTAL

<0.240412103GAMBACORTI et al

MILANO

0.211255952327HATFIELD et al

NOVARTIS

% OF YEARS

PTS EXPOSURE

NO.

CHF

YEARS PTS

EXPOSURE

NO. OF

PTS

0.110.557*63801276ATALLAH et al

M.D. ANDERSON

<0.04<0.120**2383833ROSTI et al

GIMEMA CML WP

0.42

<0.97

0.51

% OF

PTS

0.1319147704539TOTAL

<0.240412103GAMBACORTI et al

MILANO

0.211255952327HATFIELD et al

NOVARTIS

% OF YEARS

PTS EXPOSURE

NO.

CHF

YEARS PTS

EXPOSURE

NO. OF

PTS

*22 RECORDED, 7 CONFIRMED ** 3 CASES OF MYOCARDIAL INFA RCTUS

52

GIMEMA CML WP

Imatinib andpregnancy

53

GIMEMA CML WPCurrent Recommendations

Data still not conclusive BUT estimated risk of foetalabnormalities 7-10%

It is currently advised to avoid imatinib in pregnancy unlessabsolutely essential.

Women of child-bearing age receiving imatinib should takeadequate contraceptive measures.

In case of accidental pregnancy , a risk-benefit evaluation onan individual basis

54

GIMEMA CML WPExposure To ImatinibDuring Pregnancy

Imatinib is teratogenic, embryotoxic (notgenotoxic) and causes increased rates of postimplantation lossClinical trials excluded pregnant womenMost pregnancies are unplannedInsufficient data available yet“Specific” pharmacovigilance requested

55

GIMEMA CML WP

Outcome known for 128/180 (63%)

10

6.7

19.5

35

(%) of totaln=180

14.418SpontaneousAbortion

9.612Foetal Abnormality

2835ElectiveTermination*

5063Normal Live Infant

(%) with knownoutcome n=125

Totalnumber

Pregnancyoutcome

* Includes 3 terminated following identification of fetal abnormalities

56

GIMEMA CML WP

Imatinib andPlasma level testing

57

GIMEMA CML WP

0 500 1000 1500 2000

010

2030

40

Imatinib Trough Level in ng/mL (Day 29)

Num

ber o

f Pat

ient

s

Quartile 1<647 ng/mL

N=87

Quartiles 2 and 3≥647-1170 ng/mL

N=178

Quartile 4>1170 ng/mL

N=86

DISTRIBUTION OF IMATINIB TROUGH LEVELS(N = 351) (IRIS STUDY)

Larson R. et al, Blood. 2008;111:4022-4028

58

GIMEMA CML WPImatinib Trough Levels IS AN INDEPENDENTPROGNOSTIC FACTOR FOR CCgR

N=297 N=54

p=0.004 by Wilcoxon test

1009±544812±409

Larson R. et al, Blood. 2008; 110, 11.