GIMEMA CML WP 42° CONGRESSO NAZIONALE SIE Società Italiana di Ematologia Milano, 18-21 ottobre 2009 Francesca Palandri Dipartimento di Ematologia e Oncologia “L. e A. Seràgnoli” Bologna University Hospital Leucemia Mieloide Cronica: la terapia con imatinib
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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
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
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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
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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
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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)
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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
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GIMEMA CML WP
COMBINATIONTHERAPIES
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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
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GIMEMA CML WPGIMEMA CML 011- IM + PegIFN-αin de-novo CP-CML
Identificare l’ANTIGENE TUMORALESPECIFICO più appropriato
Rompere la TOLLERANZAIMMUNOLOGICA al tumore
VACCINOTERAPIA
P 210TARGET “TUMORE-SPECIFICO”
P 210IMMUNOGENICO GRAZIE A
SEQUENZA AMINOACIDICA “UNICA”
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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)
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
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
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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.”
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GIMEMA CML WPIN REPLY TO “CARDIOTOXICITY OF THE CANCERTHERAPEUTIC AGENT IMATINIB MESYLATE”Nature Medicine 2007; 13: 13-16
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
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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
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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
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GIMEMA CML WP
Imatinib andPlasma level testing
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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
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GIMEMA CML WPImatinib Trough Levels IS AN INDEPENDENTPROGNOSTIC FACTOR FOR CCgR