Antracicline liposomiali Antracicline liposomiali vsvsliposomiali liposomiali peghilatepeghilate nel MM: nel MM:
esperienze a confrontoesperienze a confronto
Stefania Stefania CiolliCiolliSODC di EmatologiaSODC di Ematologia
Azienda Azienda Ospedaliero-UniversitariaOspedaliero-Universitaria, Firenze, Firenze
MYOCET™ Polimero lineare doxorubicina citrato`
Precipitato gelatinoso doxorubicinasolfato di ammonio
Membrana liposomiale:Fosfatidil-colina e Colesterolo
Ø ~ 150 nm, captati -> SRE
Caelyx®
Superficie di poli-etilen-glicole (PEG)
Ø~ 80 nm, scarsamente captati ->SRE
DOXORUBICINA LIPOSOMIALE(liposomi convenzionali e liposomi peghilati)
Membrana liposomialeFosfatidil-colina di soia idrogenata, colesteroloe distearoil-fosfatidil-etanolammina
Non-PegylatedNon-Pegylated LiposomalLiposomal DoxorubicinDoxorubicin
< esposizione dei tessuti sani< esposizione dei tessuti sani
Tessuto normaleTessuto normale
LiposomaLiposomaconvenzconvenz..Liposoma
pegilato
EndotelioEndoteliosanosano
Tessuto tumorale
EndotelioEndoteliofenestratofenestrato
Liposomapegilato
LiposomaLiposomaconvenzconvenz..
> esposizione del > esposizione del txtx tumorale tumorale> nel midollo osseo> nel midollo osseo
““EscapeEscape”” MDR MDR ((LevineLevine AM AM etet al, JCO 2004; al, JCO 2004; TulpuleTulpule etet al, al, ClinClin LymphLymph Myeloma 2006) Myeloma 2006)
Minore tossicitàMinore tossicità Maggiore efficaciaMaggiore efficacia
Stealth® Liposome Localization in Human Tumors
Lungtumor
LiverSpleen
Bonemarrow
(Posterior view)
Harrington, et al.Clin Cancer Res. 2001.
Gamma Scintigraphy 24 and 48 Hours After Injection of Radio-labeledStealth® Liposomes
Con
cent
ratio
n (µ
M)
Time post-start infusion (hours)
Gabizon A et al. J Natl Cancer Inst 1989;81:1484–8
1,000
100
10
1
0.1
0.01
0.0010 24 48 72 96 120
Caelyx 50 mg/m2
Myocet 60 mg/m2
Doxorubicin 60 mg/m2
Concentrazioni plasmatiche medie didoxorubicina
(doxorubicina convenzionale vs Myocet vs Caelyx)
Table 3. Cardiac Safety of Nonpegylated Liposomal Doxorubicin
StudyNo. of
patients Treatment RR Median OS Cardiac safety
Harriset al
108 116 D-99 at a dose of 75mg/m2 every 3 weeks orconventionaldoxorubicin, 75 mg/m2
every 3 weeks
26%26%
16.0 vs20.0months
Cardiac events: 13% for D-99 vs. 29%for conventional doxorubicin (P =0.0001); CHF: 2% for D-99 vs. 8%for conventional doxorubicin (P =0.0001)
Batistet al
142 155 D-99 at a dose of 60mg/m2 + CP at a doseof 600 mg/m2 orconventionaldoxorubicin, 60 mg/m2
+ CP, 600 mg/m2
43%43%
19.0 mos16.0 mos
Cardiac events: 6% for D-99/CP vs.21% for conventional doxorubicin/CP(P = 0.0002); CHF: 0 patients with D-99/CP vs. 5 patients with conventionaldoxorubicin/CP (P = 0.02)
Shapiro et al
52 D-99 at a dose of 135mg/m2 + G-CSF, 5 /kg,every 21 days
46% 22.1 mos Cardiac events and CHF in 38% and13% of patients, respectively; 1 deathdue to cardiomyopathy at acumulative dose of 1035 mg/m2
Cardiac profiles of liposomal anthracyclinesTheodoulou M et al. Cancer 2004;100:2052-2063
Perche’ la doxo-liposomiale non pegilata (Myocet) ?
Rispetto alla doxo-liposomiale pegilata
• concentrazione 1.44 > nei tessuti tumorali ricchi in RE (fegato,milza, midollo osseo)
• distribuzione sovrapponibile a livello cardiaco, polmonare e renale
• non si accumula a livello cutaneo e gastro-enterico minoretossicita’
• “escape” mdr phenotype
Rispetto alla doxorubicina convenzionale
• biodisponibilita’ equivalente, metabolismo ed escrezione piu’ lente
• Assenza di elevati picchi plasmatici dopo la somministrazione
• Tossicita’ modesta e reversibile in sede di iniezione
• concentrazione > nella milza (9 volte), nel midollo osseo (4.8 volte)
• concentrazione < a livello cardiaco (0.66)
• dose max 1280 mg/mq vs 450 mg/mq
Nonpegylated liposomal doxorubicin is highly active in patients with B and T/NKcell lymphomas with cardiac comorbidity or higher age.Heindel D, et al Ann Hematol. 2009 Jul 28. [Epub ahead of print]
Nonpegylated liposomal doxorubicin in the treatment of B-cell non-Hodgkin'slymphoma: where we stand. Visani G. Isidori A. Expert Rev Anticancer Ther. 2009Mar;9(3):357-63
Liposome-encapsulated doxorubicin in combination with cyclophosphamide,vincristine, prednisone and rituximab in patients with lymphoma and concurrentcardiac diseases or pre-treated with anthracyclines.Rigacci L. et al .Hematol.Oncol.2007;24(4):198-203
Liposome-encapsulated doxorubicin in combination with standard agents(cyclophosphamide, vincristine, prednisone)in patients with newly diagnosed AIDSrelated non-Hodgkins lymphoma:results of therapy and correlate of response.Levine AM eta. JCO 2004;22(13):2662-70
Liposomal doxorubicin: a review of its use in metastatic breast cancer andpotential in non-Hodgkins lymphomaDando TM et al. Am J Cancer 2005;4(3):193-206
LIPOSOMAL DOXORUBICIN IN HEMATOLOGY
Preclinical Rationale for CombiningPreclinical Rationale for CombiningMyocetMyocet + Bortezomib + Bortezomib
•• Interactions occur through multiple pathways toInteractions occur through multiple pathways toenhance anti-tumor efficacyenhance anti-tumor efficacy
–– Bortezomib abrogates anthracycline resistanceBortezomib abrogates anthracycline resistance
•• NF-kB NF-kB1,21,2, Bcl-2, P-glycoprotein, DNA damage, Bcl-2, P-glycoprotein, DNA damagerepairrepair33
–– Anthracyclines abrogate bortezomib resistanceAnthracyclines abrogate bortezomib resistance
•• Suppression of stress response protein MKP-1Suppression of stress response protein MKP-133
–– MyocetMyocet escape MDR escape MDR44
1Mark et al. Clin Cancer Res. 2003 2Mitsiades et al. Blood. 2003 3Small et al. Mol. Pharmacol. 4Tulpule et al, Clin Lymph Myeloma 2006
LIPOSOMAL DOXORUBICIN
IN MULTIPLE MYELOMA
Bortezomib and Liposomal Doxorubicin Are Highly Effective inObtaining the Best Possible Response before Autologous Transplant
for Multiple MyelomaBuda G. et al. Acta Haematol. 2009 Aug 29;122(1):39-41
The addition of liposomal doxorubicin to bortezomib,thalidomide and dexamethasone significantly improves
clinical outcome of advanced multiple myelomaCiolli S. et al. Br J Haemat 2008;141:814-19
Safety and efficacy of Liposomal doxorubicin added to low-doseBortezomib and Dexamethasone in R/R multiple myeloma
Aquino et al. EHA 2009
The addition of liposomal doxorubicin to bortezomib,thalidomide and dexamethasone significantly improves
clinical outcome of advanced multiple myelomaCiolli S. et al. Br J Haemat 2008;141:814-19
Studio di fase II monocentrico
confronta efficacia e tossicità del bortezomib/thalidomide/Dex (VTD)
vs
VTD plus liposomal doxorubicin (MyVTD)
In 2 gruppi di pazienti consecutivi e con analoghe caratteristiche arruolati dal
1. Gennaio 2004 (VTD)*2. Gennaio 2005 – Marzo 2007 (MyVTD)
*Low dose velcade, thalidomide and dexamethasone (LD-VTD): aneffective regimen for relapsed and refractory multiple myeloma patients.
Ciolli et al. Leukemia Lymphoma 2006;47:171-73
SCHEMA DI TERAPIA
VELCADE 1 mg/m2 e.v. gg 1-4, 8-11
MYOCET 50 mg/m2 in 250cc di s.f. o glucosata in 1h al g4
DESAMETAZONE 24 mg gg 1-2, 4-5,8-9,11-12
(THALIDOMIDE 100 mg/die + coumadin )
MYOCET 30 mg/m2 nei pazienti di eta’>75aa
Terapia da ripetersi al 28°giorno
1h dopo Velcade
massima tox ematologica attesa al giorno 14
consentito l’impiego di fattori di crescita (G.CSF, EPO)
valutazione della risposta dopo ogni ciclo:
malattia progressivaoff study
i rispondenti proseguono fino alla max risposta e per un massimo di 6 cicli
Ciolli S. et al. Br J Haemat 2008;141:814-19
0.001158PFS, months
0.011911TTP, months
0.04not reached13OS, months
0.00934 (81)14 (50)ORR
n.s.3 (7)4 (14)MR
n.s.9 (21)4 (14)PR
0.0122 (52)6 (21)CR/nCR
P valueMyVTD#42total (%)
VT#28total (%)
Table II: treatment results
Ciolli S. et al. Br J Haemat 2008;141:814-19
Median time to the first evidence of response was 2 vs 1.5 months (P = n.s.)
Six patients underwent peripheral stem cell collection 1 died before transplant because of disease progression 5 were transplanted
Treatment results in particular subset of patients
0140 VTD8 MyVTD
Antracyclinerefractory
1
3
1
2
PR
020 VTD6 MyVTD
Previous BOR
031 VTD5 MyVTD
Extramedullarydisease
133 VTD4 MyVTD
Impaired renalfuncion
077 VTD10 MyVTD
Stem celltransplant
MRCR/nCRPatients
By regression logistic model, considering
Myocet,
thalidomide,
International Prognostic Scoring System (ISS), as covariates
age
number of previous therapy lines
• Myocet (P = 0.01)
• the number of previous therapy lines (P = 0.02) retained asignificance for the achievement of CR or nCR.
Table III. Selected adverse events of clinical interest
Ciolli S. et al. Br J Haemat 2008;141:814-19
Ciolli S. et al. Br J Haemat 2008;141:814-19
Ciolli S. et al. Br J Haemat 2008;141:814-19
Bortezomib + CAELYX Bortezomib + CAELYX vsvs Bortezomib BortezomibMonotherapyMonotherapy: Study Design: Study Design
Bortezomib 1.3 mg/mBortezomib 1.3 mg/m22 days 1, 4, days 1, 4,8, 11 every 21 days8, 11 every 21 days
Bortezomib as above +Bortezomib as above +CAELYX 30 mg/mCAELYX 30 mg/m22 on day 4 on day 4
StudyStudy Design DesignRelapsedRelapsed oror refractoryrefractory MM MMPhase III, Phase III, multicentermulticenter (123 (123
participatingparticipating centerscenters))EligibilityEligibility2+ 2+ lineslines of of therapytherapyBortezomib-naïveBortezomib-naïveECOG 0-1ECOG 0-1
RANDOMIZATION
N = 646N = 646
Treat until progression, unacceptableTreat until progression, unacceptabletoxicity or max. of 8 cycles (unless diseasetoxicity or max. of 8 cycles (unless diseasestill responding)still responding)
Orlowski et al. J Clin Oncol. 2007;25:3892-3901.
Primary endpoint: TTPPrimary endpoint: TTPSecondary: OS, ORR, safetySecondary: OS, ORR, safety
StratifyStratifyββ22microglobulin (microglobulin (≤≤ 2.5, 2.5,
> 2.5 > 2.5 butbut ≤≤ 5.5, > 5.5) 5.5, > 5.5)Response Response vsvs progressionprogression to to priorprior treatmenttreatment
Response RateResponse Rate
BortezomibBortezomib(n = 322)(n = 322)
CAELYX +CAELYX +BortezomibBortezomib(n = 324)(n = 324)
P-valueP-value
TotalTotal(CR + (CR + nCRnCR + PR) + PR) 41%41% 44%44% .43.43
CRCRnCRnCR
2%2%8%8%
4%4%9%9%
PRPR 39%39% 40%40%
CR + VGPR CR + VGPR 19%19% 27%27% .0157.0157
Duration ofDuration ofresponseresponse
7.0 months7.0 months(5.9-8.3)(5.9-8.3)
10.2 months10.2 months(10.2-12.9)(10.2-12.9) .0008.0008
Orlowski et al. J Clin Oncol. 2007;25:3892-3901.
Selected Adverse Events of Interest
BortezomibBortezomib(n = 318)(n = 318)
CAELYX +CAELYX +BortezomibBortezomib
(n = 318)(n = 318)
TotalTotal GradeGrade3/43/4 TotalTotal Grade 3/4Grade 3/4
Peripheral neuropathyPeripheral neuropathy 39%39% 9%9% 35%35% 4%4%
Febrile neutropeniaFebrile neutropenia 2%2% 2%2% 3%3% 3%3%
Bleeding/hemorrhageBleeding/hemorrhage 9%9% 1%1% 14%14% 4%4%ThromboembolicThromboemboliceventsevents 1%1% 1%1% 1%1% 1%1%
Cardiac eventsCardiac events 7%7% 3%3% 10%10% 2%2%
AlopeciaAlopecia 1%1% 00 2%2% 00
Orlowski et al. J Clin Oncol. 2007;25:3892-3901.
Bortezomib and Liposomal Doxorubicin Are Highly Effective inObtaining the Best Possible Response before Autologous Transplant
for Multiple MyelomaBuda G. et al. Acta Haematol. 2009 Aug 29;122(1):39-41
6 nCR, 5 VGPR, 1 PRResponse after ASCT
12ASCT
ORR 87.5%6 ≥ nCR , 4 VGPR, 4 PR , 2 SD
Response to My-VD (4 cycles)ORR 87.5%
12/15 (80%)successful PBSC collection
9/12 (75%) alive and disease free at 13.5 months
median age 52, ISS ≥ II 12 (75%)
5 PR, 9 SD, 2 PD
52 MM patients16 with less than VGPR after4 cycles ThaDD
My-VD: V 1.3 mg/m2 +Dex 24 mg standard schedule, Myocet 30 mg/m2 d4 (1 h after V)
Overall toxicity• neutropenia 12.5%
• thrombocytopenia 25%
• fatigue 25%
• PNP 25%
Safety and efficacy of Liposomal doxorubicin added to low-doseBortezomib and Dexamethasone in R/R multiple myeloma
Aquino et al. EHA 2009
14 patients Velcade 1 mg/m2 + Dex 20 mg standard schedule +Myocet 50 mg/m2 d4 (30 mg >75 yrs)
ORR 86%
≥ PR 12
≥ VGPR 5
≥ nCR 3
Median PFS for ≥ VGPR was 8 months (+6 -20 months)
No DVT or cardiac toxicity, all outpatients
ThalidomideThalidomide 100 mg/die 100 mg/die
Desametasone 20 mg giorniDesametasone 20 mg giorni1,2 - 4,5 - 8,9 - 11,121,2 - 4,5 - 8,9 - 11,12
CaelyxCaelyx 30 mg/m 30 mg/m22 giorno 4 giorno 4
VelcadeVelcade 1.3 mg/m 1.3 mg/m22
giorni 1, 4, 8, 11 giorni 1, 4, 8, 11
My-VTDMy-VTD CiolliCiolli etet al , BJH 2008 al , BJH 2008
ThalidomideThalidomide 100 mg/die 100 mg/die
Desametasone 24 mg giorni 1,2 - 4,5 - 8,9 - 11,12Desametasone 24 mg giorni 1,2 - 4,5 - 8,9 - 11,12
MyocetMyocet 50 mg/m 50 mg/m22 ( (30 mg >75yr)30 mg >75yr) giorno 4giorno 4
VelcadeVelcade 1.0 mg/m 1.0 mg/m22 giorni 1, 4, 8, 11 giorni 1, 4, 8, 11
ThalidomideThalidomide 50mg/ 50mg/diedie
Desametasone 20 mg giorniDesametasone 20 mg giorni1-41-4
X 3
VelcadeVelcade 1 mg/m2 1 mg/m2 giorni 1, 8, giorni 1, 8, DesametasoneDesametasone 20 mg 20 mggiorni 1,2 - 8,9giorni 1,2 - 8,9
X 3
ThaDD-VThaDD-V OffidaniOffidani etet al, EHA 2009 al, EHA 2009
X 6
cons
olid
atio
n
Maintenance : Thalidomide 50 mg/die
X 6
ThaDD-VThaDD-V vsvs My-VTDMy-VTD: caratteristiche pazienti: caratteristiche pazienti
ThaDD-VThaDD-V
(40 (40 ptspts))
62 (31-83)62 (31-83)
31 (74)31 (74)
6 (14)6 (14)
12/28 (29)12/28 (29)
28( 70)28( 70)
12 (30)12 (30)
2121 (52.5) (52.5)
6 (15)6 (15)
21 (52.5)21 (52.5)
nana
nana
CaratteristicheCaratteristiche
Età medianaEtà mediana
ISS II-IIIISS II-III
InsuffInsuff. renale. renale
Citogenetica sfavorevoleCitogenetica sfavorevole
Linee terapia precedente: 1Linee terapia precedente: 1
≥≥22
Precedente Precedente thalidomidethalidomide
Precedente bortezomibPrecedente bortezomib
Precedente trapiantoPrecedente trapianto
Anthracycline Anthracycline refractoryrefractory
PrimaryPrimary refractoryrefractory
My-VTDMy-VTD
(42 (42 ptspts))
63 (35-81)63 (35-81)
32 (76)32 (76)
4 (9.5)4 (9.5)
nana
3 (1-6)3 (1-6)
27 (64)27 (64)
6 (14)6 (14)
10 (24)10 (24)
8(19%)8(19%)19(45%)19(45%)
07%stanchezza00Eventi cardiaci
05%diarrea02%Skin rash00PPE
2%12%neuropatia2%5%TVP5%0emorragia
16%0alopecia7%10%Infezioni (1 fatale)
29%17%piastrinopenia24%5%neutropenianeutropenia
My-VTD(42 pts)
ThaDD-V(40 pts)
Side effect
ThaDD-VThaDD-V vsvs My-VTDMy-VTD: eventi avversi grado 3-4: eventi avversi grado 3-4
ThaDD-VThaDD-V(40 (40 ptspts))
85 %85 % 67.5 % 67.5 %
35%35%
2525
2323NotNot reachedreached
OutcomesOutcomes
≥≥ PR PR≥≥ VGPRVGPR ≥≥ CRCR
Follow-up mediano (mesi)Follow-up mediano (mesi) PFS PFS
OSOS
My-VTDMy-VTD(42 (42 ptspts))
74%74%nana
52%52%
1818
1515NotNot reachedreached
ThaDD-VThaDD-V vsvs My-VTDMy-VTD: : outcomesoutcomes
Considerazioni conclusiveConsiderazioni conclusive• efficacia della associazione Myocet & VTD:
una > ORR ed un maggior numero di risposte ottimali con impattosignificativo sulla PFS
• tossicità: ematologica > rispetto al VTD ma di breve durata
extraematologica modesta e gestibile la maggior parte dei pazienti trattati insede ambulatoriale
• risposta ottenibile anche in pazienti refrattari alladoxorubicina convenzionale
• non è compromessa la PBSC ed il successivo trapianto