leucemia mieloide cronica: la terapia con imatinibfrancescapalandri.pdf · 2019-03-07 · leucemia...
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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.