Antracicline liposomiali vs liposomiali peghilate nel MM: esperienze a confronto

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1 Antracicline liposomiali vs liposomiali peghilate nel MM: esperienze a confronto Stefania Ciolli SODC di Ematologia Azienda Ospedaliero-Universitaria,, Firenze

2 DOXORUBICINA LIPOSOMIALE (liposomi convenzionali e liposomi peghilati) MYOCET Polimero lineare doxorubicina citrato` Membrana liposomiale: Fosfatidil-colina e Colesterolo Ø ~ 150 nm, captati -> SRE Precipitato gelatinoso doxorubicina solfato di ammonio Caelyx Membrana liposomiale Fosfatidil-colina di soia idrogenata, colesterolo e distearoil-fosfatidil-etanolammina Superficie di poli-etilen-glicole (PEG) Ø~ 80 nm, scarsamente captati ->SRE

3 Non-Pegylated Liposomal Doxorubicin Liposoma pegilato Liposoma convenz. Liposoma pegilato Liposoma convenz. Endotelio sano Tessuto normale < esposizione dei tessuti sani Endotelio fenestrato Tessuto tumorale > esposizione del tx tumorale > nel midollo osseo Escape MDR (Levine AM et al, JCO 2004; Tulpule et al, Clin Lymph Myeloma 2006) Minore tossicità Maggiore efficacia

4 Stealth Liposome Localization in Human Tumors Gamma Scintigraphy 24 and 48 Hours After Injection of Radio-labeled Stealth Liposomes (Posterior view) Lung tumor Spleen Liver Bone marrow Harrington, et al. Clin Cancer Res

5 Concentrazioni plasmatiche medie di doxorubicina (doxorubicina convenzionale vs Myocet vs Caelyx) 1,000 Caelyx 50 mg/m 2 Concentration (µm) Myocet 60 mg/m 2 Doxorubicin 60 mg/m Time post-start infusion (hours) Gabizon A et al. J Natl Cancer Inst 1989;81:1484 8

6 Table 3. Cardiac Safety of Nonpegylated Liposomal Doxorubicin Study Harris et al Batist et al Shapir o et al No. of patients Treatment RR Median OS Cardiac safety D-99 at a dose of 75 26% mg/m 2 every 3 weeks or 26% conventional doxorubicin, 75 mg/m 2 every 3 weeks D-99 at a dose of 60 43% mg/m 2 + CP at a dose 43% of 600 mg/m 2 or conventional doxorubicin, 60 mg/m 2 + CP, 600 mg/m 2 52 D-99 at a dose of 135 mg/m 2 + G-CSF, 5 /kg, every 21 days 16.0 vs20.0 months 19.0 mos 16.0 mos Cardiac events: 13% for D-99 vs. 29% for conventional doxorubicin (P = ); CHF: 2% for D-99 vs. 8% for conventional doxorubicin (P = ) Cardiac events: 6% for D-99/CP vs. 21% for conventional doxorubicin/cp (P = ); CHF: 0 patients with D- 99/CP vs. 5 patients with conventional doxorubicin/cp (P = 0.02) 46% 22.1 mos Cardiac events and CHF in 38% and 13% of patients, respectively; 1 death due to cardiomyopathy at a cumulative dose of 1035 mg/m 2 Cardiac profiles of liposomal anthracyclines Theodoulou M et al. Cancer 2004;100:

7 Perche la doxo-liposomiale non pegilata (Myocet)? 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 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 minore tossicita escape mdr phenotype

8 LIPOSOMAL DOXORUBICIN IN HEMATOLOGY Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone)in patients with newly diagnosed AIDS related non-hodgkins lymphoma:results of therapy and correlate of response. Levine AM eta. JCO 2004;22(13): Liposomal doxorubicin: a review of its use in metastatic breast cancer and potential in non-hodgkins lymphoma Dando TM et al. Am J Cancer 2005;4(3): Liposome-encapsulated doxorubicin in combination with cyclophosphamide, vincristine, prednisone and rituximab in patients with lymphoma and concurrent cardiac diseases or pre-treated with anthracyclines. Rigacci L. et al.hematol.oncol.2007;24(4): Nonpegylated liposomal doxorubicin in the treatment of B-cell non-hodgkin's lymphoma: where we stand. Visani G. Isidori A. Expert Rev Anticancer Ther Mar;9(3): Nonpegylated liposomal doxorubicin is highly active in patients with B and T/NK cell lymphomas with cardiac comorbidity or higher age. Heindel D, et al Ann Hematol Jul 28. [Epub ahead of print]

9 Preclinical Rationale for Combining Myocet + Bortezomib Interactions occur through multiple pathways to enhance anti-tumor efficacy Bortezomib abrogates anthracycline resistance NF-kB 1,2, Bcl-2, P-glycoprotein, DNA damage repair 3 Anthracyclines abrogate bortezomib resistance Suppression of stress response protein MKP-1 3 Myocet escape MDR 4 1 Mark et al. Clin Cancer Res Mitsiades et al. Blood Small et al. Mol. Pharmacol. 4Tulpule et al, Clin Lymph Myeloma 2006

10 LIPOSOMAL DOXORUBICIN IN MULTIPLE MYELOMA The addition of liposomal doxorubicin to bortezomib, thalidomide and dexamethasone significantly improves clinical outcome of advanced multiple myeloma Ciolli S. et al. Br J Haemat 2008;141: Bortezomib and Liposomal Doxorubicin Are Highly Effective in Obtaining the Best Possible Response before Autologous Transplant for Multiple Myeloma Buda G. et al. Acta Haematol Aug 29;122(1):39-41 Safety and efficacy of Liposomal doxorubicin added to low-dose Bortezomib and Dexamethasone in R/R multiple myeloma Aquino et al. EHA 2009

11 The addition of liposomal doxorubicin to bortezomib, thalidomide and dexamethasone significantly improves clinical outcome of advanced multiple myeloma Ciolli S. et al. Br J Haemat 2008;141: 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): an effective regimen for relapsed and refractory multiple myeloma patients. Ciolli et al. Leukemia Lymphoma 2006;47:171-73

12 SCHEMA DI TERAPIA 1h dopo Velcade VELCADE 1 mg/m 2 e.v. gg 1-4, 8-11 MYOCET 50 mg/m 2 in 250cc di s.f. o glucosata in 1h al g4 DESAMETAZONE 24 mg gg 1-2, 4-5,8-9,11-12 MYOCET 30 mg/m 2 nei pazienti di eta >75aa (THALIDOMIDE 100 mg/die + coumadin ) Terapia da ripetersi al 28 giorno massima tox ematologica attesa al giorno 14 consentito l impiego di fattori di crescita (G.CSF, EPO) valutazione della risposta dopo ogni ciclo: malattia progressiva off study i rispondenti proseguono fino alla max risposta e per un massimo di 6 cicli

13 Ciolli S. et al. Br J Haemat 2008;141:814-19

14 Table II: treatment results VT#28 MyVTD#42 P value total (%) total (%) CR/nCR 6 (21) 22 (52) 0.01 PR 4 (14) 9 (21) n.s. MR 4 (14) 3 (7) n.s. ORR 14 (50) 34 (81) TTP, months PFS, months OS, months 13 not reached 0.04 Median time to the first evidence of response was 2 vs 1.5 months (P = n.s.) Ciolli S. et al. Br J Haemat 2008;141:814-19

15 Treatment results in particular subset of patients Patients CR/nCR PR MR Stem cell transplant 7 VTD 10 MyVTD Impaired renal funcion 3 VTD 4 MyVTD Extramedullary disease 1 VTD 5 MyVTD Antracycline refractory 0 VTD 8 MyVTD Previous BOR 0 VTD MyVTD Six patients underwent peripheral stem cell collection 1 died before transplant because of disease progression 5 were transplanted

16 By regression logistic model, considering Myocet, thalidomide, International Prognostic Scoring System (ISS), age number of previous therapy lines as covariates Myocet (P = 0.01) the number of previous therapy lines (P = 0.02) retained a significance for the achievement of CR or ncr.

17 Table III. Selected adverse events of clinical interest Ciolli S. et al. Br J Haemat 2008;141:814-19

18 Ciolli S. et al. Br J Haemat 2008;141:814-19

19 Ciolli S. et al. Br J Haemat 2008;141:814-19

20 Bortezomib + CAELYX vs Bortezomib Monotherapy: : Study Design Study Design Relapsed or refractory MM Phase III, multicenter (123 participating centers) Eligibility 2+ lines of therapy Bortezomib-naïve ECOG 0-1 Stratify β 2 microglobulin ( ( 2.5, > 2.5 but 5.5, > 5.5) R A N D O M I Z A T I O N Response vs progression to prior treatment Orlowski et al. J Clin Oncol. 2007;25: N = 646 Bortezomib 1.3 mg/m 2 days 1, 4, 8, 11 every 21 days Treat until progression, unacceptable toxicity or max. of 8 cycles (unless disease still responding) Bortezomib as above + CAELYX 30 mg/m 2 on day 4 Primary endpoint: TTP Secondary: OS, ORR, safety

21 Response Rate Total (CR + ncr + PR) CR ncr Bortezomib (n = 322) CAELYX + Bortezomib (n = 324) P-value 41% 44%.43 2% 8% 4% 9% PR 39% 40% CR + VGPR 19% 27%.0157 Duration of response 7.0 months ( ) 10.2 months ( ).0008 Orlowski et al. J Clin Oncol. 2007;25:

22 Selected Adverse Events of Interest Bortezomib (n = 318) Total Grade 3/4 CAELYX + Bortezomib (n = 318) Total Grade 3/4 Peripheral neuropathy 39% 9% 35% 4% Febrile neutropenia 2% 2% 3% 3% Bleeding/hemorrhage 9% 1% 14% 4% Thromboembolic events 1% 1% 1% 1% Cardiac events 7% 3% 10% 2% Alopecia 1% 0 2% 0 Orlowski et al. J Clin Oncol. 2007;25:

23 Bortezomib and Liposomal Doxorubicin Are Highly Effective in Obtaining the Best Possible Response before Autologous Transplant for Multiple Myeloma Buda G. et al. Acta Haematol Aug 29;122(1):39-41 My-VD: V 1.3 mg/m 2 +Dex 24 mg standard schedule, Myocet 30 mg/m 2 d4 (1 h after V) 52 MM patients 16 with less than VGPR after 4 cycles ThaDD Response to My-VD (4 cycles) ORR 87.5% successful PBSC collection ASCT Response after ASCT at 13.5 months median age 52, ISS II 12 (75%) 5 PR, 9 SD, 2 PD ORR 87.5% 6 ncr, 4 VGPR, 4 PR, 2 SD 12/15 (80%) 12 6 ncr, 5 VGPR, 1 PR 9/12 (75%) alive and disease free Overall toxicity neutropenia 12.5% thrombocytopenia 25% fatigue 25% PNP 25%

24 Safety and efficacy of Liposomal doxorubicin added to low-dose Bortezomib and Dexamethasone in R/R multiple myeloma Aquino et al. EHA patients Velcade 1 mg/m 2 + Dex 20 mg standard schedule +Myocet 50 mg/m 2 d4 (30 mg >75 yrs) No DVT or cardiac toxicity, all outpatients ORR 86% PR 12 VGPR 5 ncr 3 Median PFS for VGPR was 8 months (+6-20 months)

25 ThaDD-V Offidani et al, EHA 2009 Thalidomide 100 mg/die Desametasone 20 mg giorni 1,2-4,5-8,9-11,12 Caelyx 30 mg/m 2 giorno 4 Velcade 1.3 mg/m 2 giorni 1, 4, 8, 11 X 6 consolidation Maintenance : Thalidomide 50 mg/die Thalidomide 50mg/die Desametasone 20 mg giorni 1-4 Velcade 1 mg/m2 giorni 1, 8, Desametasone 20 mg giorni 1,2-8,9 X 3 X 3 My-VTD Ciolli et al, BJH 2008 My-VTD Thalidomide 100 mg/die Desametasone 24 mg giorni 1,2-4,5-8,9-11,12 Myocet 50 mg/m 2 (30 mg >75yr) giorno 4 Velcade 1.0 mg/m 2 giorni 1, 4, 8, 11 X 6

26 ThaDD-V vs My-VTD: : caratteristiche pazienti Caratteristiche Età mediana ISS II-III Insuff.. renale Citogenetica sfavorevole Linee terapia precedente: 1 Precedente thalidomide Precedente bortezomib Precedente trapianto Anthracycline refractory Primary refractory 2 ThaDD-V (40 pts) 62 (31-83) 31 (74) 6 (14) 12/28 (29) 28( 70) 12 (30) 21 (52.5) 6 (15) 21 (52.5) na na My-VTD (42 pts) 63 (35-81) 32 (76) 4 (9.5) na 3 (1-6) 27 (64) 6 (14) 10 (24) 8(19%) 19(45%)

27 ThaDD-V vs My-VTD: : eventi avversi grado 3-4 Side effect neutropenia piastrinopenia Infezioni (1 fatale) alopecia emorragia TVP neuropatia PPE Skin rash diarrea stanchezza Eventi cardiaci ThaDD-V (40 pts) 5% 17% 10% 0 0 5% 12% 0 2% 5% 7% 0 My-VTD (42 pts) 24% 29% 7% 16% 5% 2% 2%

28 ThaDD-V vs My-VTD: outcomes Outcomes PR VGPR CR ThaDD-V (40 pts) 85 % 67.5 % 35% My-VTD (42 pts) 74% na 52% Follow-up mediano (mesi) PFS OS 23 Not reached 15 Not reached

29 Considerazioni conclusive efficacia della associazione Myocet & VTD: una > ORR ed un maggior numero di risposte ottimali con impatto significativo sulla PFS tossicità: ematologica > rispetto al VTD ma di breve durata extraematologica modesta e gestibile la maggior parte dei pazienti trattati in sede ambulatoriale risposta ottenibile anche in pazienti refrattari alla doxorubicina convenzionale non è compromessa la PBSC ed il successivo trapianto