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