54th ash annual meeting and exposition december 8-11, 2012, convention center atlanta
TRANSCRIPT
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54th ASH Annual Meeting and Exposition
December 8-11, 2012, Convention Center Atlanta
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American Society of Hematology (ASH) Annual Meeting 2012
22.000 Teilnehmer
Georgia Convention Center, Atlanta USA360.000 m2 (Fußballfeld 7.000 m2)
638 Berichte (Präsentationen) zum Myelom
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• Arry-520 (Kinesin Spindle Protein Inhibitor) PR20%• Circularly permutated TRAIL (CPT) PR30%, Pro-apoptotic receptor agonist, Bejing Sunbio Biotech Co.• MLN9708 (oraler Proteasomhemmer)• Dinaciclib (Hemmer der CDK5)• Tabalumab (anti-BAFF AK)• Daratumumab (anti-CD38 AK)• Elotuzumab (anti-CS1 AK)• Lorvotuzumab Mertansine (anti-CD56 AK + DM1)• BHQ880 (anti-DKK1 AK)• CAR T-cells
Die großen Themen
1.
2.
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Bailar and Smith: „Progress against cancer?“Vergleich Alters-adaptierte Mortalitätsrate 1950-82New England Journal of Medicine, Mai 1986
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„How to use new biology to guide therapy in multiple myeloma“ Morgan & Kaiser, ASH Educational 2012
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„Old agents“ Melphalan (Alkeran®), Prednisone, Dexamethason, Cyclophosphamid (Endoxan®), Doxorubicin, Cisplatin, Interferon- u.a.
„New agents“ ThalidomideBortezomib (Velcade®) Lenalidomide (Revlimid®)
Bendamustin (Levact®) – erstmals 1963 synthetisiert liposomales Doxorubicin
„New new agents“Carfilzomib (Kyprolis®) irreversibler Proteasomhemmer FDA-Zulassung 20. Juli 2012Pomalidomide (Pomalyst®) immunomodulatorische SubstanzFDA-Zulassung 8. Feb. 2013
Future agents………….
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Late braking abstract 6Dimopoulos et al.
Pomalidomide + low-dose Dex vs. high-dose Dex(Pomalidomide 4mg Tag 1-21 eines 28 Tage Zyklus)
Relapsiert/refraktäres Myelom (Durchschnitt 5 Vortherapien)302 Pat. Pom.-Arm 153 Pat. Ko.-Arm (R 2:1)
Verbesserung Ansprechrate (21 vs. 3%)Verbesserung PFS (3,6 vs. 1,8 Mo.) und OS (NR vs. 7,8 Mo.)
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Jagannath et al., Abstract 450Leleu et al., Abstract 2961Pom/Dex bei relapsiert/refraktären Myelom Phase II30% Ansprechrate
Usmani et al., Abstract 4083; Richardson et al., Abstract 4053 Pom zeigt Aktivität bei Hochrisiko-Erkrankung
Palumbo et al., Abstract 446Pom/Cyclophosphamid/Dex bei relapsiert/refraktären Myelom Phase II
Richardson et al., Abstract 727Pom/Bortezomib/Dex bei relapsiert/refraktären Myelom Phase I
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0
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4000
6000
8000
10000
12000
1 2 3 4 5 6 7 8 9 10
Fr.lambda
TPU
Fr.kappa
INDUKTION ERHALTUNG
Myelom ErstlinientherapieInterferon-alphaPrednisolonThalidomid
KONS.
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Induktionstherapie
Stammzellsammlung
Hochdosistherapie +ASCT
Konsolidierungstherapie
Erhaltungstherapie
First Line Therapie Patienten bis 65 Jahre
Konzept verzögerte Tx
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Vel/DexRev/DexThal/Dex
VDT (Vel/Dex/Thal)RVD (Rev/Vel/Dex)VCD (Vel/Cyc/Dex)
VTDC (Vel/Thal/Dex/Cyc)VDCR (Vel/Dex/Cyc/Rev)
Wie viele Partner sind genug?
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First Line Therapie Patienten bis 65 JahreInduktionstherapie
VADThal/Dex VGPR (vor Tx) > VAD Vel/Dex ORR, CR, PFS > VADVel/Thal/Dex (VTD) CR, PFS > Thal/DexVTDC (C=Endoxan)Rev/DexVel + Rev/Dex
Autologe Tx MEL 200
MEL140 + TBI: schlechte ErgebnisseMEL 140 + Busulfan: venookklusive Erkrankung
Konsolidierungs-/Erhaltungsstrategien
Velcade basierte Konsolidierung (z.B. VTD: Molecular response)Velcade basierte Maintenance (z.B. HOVON-65/GMMG-HD4)Thalidomid PFS OS?Revlimid basierte Erhaltung PFS OS? Zweitmalignome
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Universitätsklinikum Heidelberg, Institut für Humangenetik
Die bunte Genetik des multiplen Myeloms
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Moreau et al., Abstract 598
Prognostischer Score IFM2005-01 Studie (VAD vs. Vel/Dex Induktion gefolgt von HD und ASCT)
High LDHISS 3t(4;14) oder 17p del
Score 0 – kein RisikofaktorScore 1 – 1 RisikofaktorScore 2 – hohe LDH und ISS 3Score 3 - t(4;14) oder 17p del und hohe LDH oder ISS 3
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ISS 3, high LDH and t(4;14) and/or del(17p) as a prognostic index for OS
Score: 0
Score: 1
Score: 2
Score: 3
Moreau et al. ASH 2012 (Abstract 598), oral presentation
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Carfilzomib
Epoxyketon-basierterProteasomhemmer
ORR 24% bei r/r Patienten(Siegel et al., Blood 2012)
Keine Dosisadaptierung beiRenaler Dysfunktion
Wenig behandlungsinduziertePolyneuropathie (14%)
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Abstract 333Sonneveld et al.
Carfilzomib + Thalidomid + Dexamethason(Carfilzomib 20/27 od. 20/36 mg/m2 Tag 1,2, 8,9 15,16
eines 28 Tage Zyklus)
Patienten mit neu-diagnostiziertem Myelom bis 65 Jahre4 Zyklen vor 4 Zyklen nach Transplantation
40 Patienten evaluierbar
90% ORRCR 18% nach Induktion 25% nach HD+ASCT 35% nach Konsolidierung
Tumor-Lyse Syndrom 5%PN Grad 2/3 17%
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Mikhael et al., Abstract 445
Carfilzomib + Thalidomid + Dexamethason (CYCLONE)
27 Patienten evaluierbar
Nach 4 ZyklenORR 96%CR 29%
Korde et al., Abstract 732
Carfilzomib + Lenalidomid + Dexamethason (CRd) Neudiagnostizierte Patienten
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Attal et al., New Engl.J.Med., Mai 2012 McCarthy et al., New Engl.J.Med., Mai 2012
Lenalidomide Maintenance Therapie nach HDT + ASCT
18 Mo. 18 Mo.
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McCarthy et al., New Engl.J.Med., Mai 2012
Sekundärmalignome (zweite Krebserkrankung) unter Maintenance
8% LEN vs. 3% Plazebo(Attal et al.: 8% vs. 4%)
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• Arry-520 (Kinesin Spindle Protein Inhibitor) PR20%• Circularly permutated TRAIL (CPT) PR30%, Pro-apoptotic receptor agonist, Bejing Sunbio Biotech Co.• MLN9708 (oraler Proteasomhemmer)• Dinaciclib (Hemmer der CDK5)• Tabalumab (anti-BAFF AK)• Daratumumab (anti-CD38 AK)• Elotuzumab (anti-CS1 AK)• Lorvotuzumab Mertansine (anti-CD56 AK + DM1)• BHQ880 (anti-DKK1 AK)• CAR T-cells
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Lehners et al., Abstract 4040
BRAF V600E Mutation
• 6/310 (2%) der untersuchten Myelompatienten
• Schlechte Prognose?
• 4/6 Patienten: extramedulläre Manifestation
• 1 Patient Vemurafenib: partielle Remission
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Van de Donk et al., Leukemia 2012
??
?
Antikörper Therapie beim Myelom
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Richardson et al., Abstract 202
Elotuzumab + Lenalidomid/DexamethasonE = AK gegen CS1, ein Glykoprotein an der Zellmembranvon MyelomzellenE Tag 1,8,15,22 eines 28 Tage Zyklus73 Patienten mit r/r Myelom (1-3 Vortherapien)
ORR 84%PFS 25 Monate
ELOQUENT 1 & 2 Studie
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Lorvotuzumab
CD56 Berdeja et al., Abstract 728LM + Len/DexLM Tag 1,8,15 eines 28 Tage Zyklus44 Patienten (relapsiert/refraktär) CD56+MTD 75mg/m2
Polyneuropathie!Tumor-Lyse Syndrom 2 PatientenORR 59% (2 Patienten CR)
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Girl’s Last Hope, Altered Immune Cells Beat Leukemia
ASH 2013 Ernest Beutler Lecture and Prize, 10.12. 2012Dr. June, Perelman School of Medicine, Univ. of Pennsylvania, PhiladelphiaCAR T-cells in der Behandlung der CLL und pädiatrischen ALL
9.12. 2012
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Chimeric antigen receptor T-cells„CAR“ T-cells
„Cytokine-release“ SyndromTNF-, IL-6Behandlung mit EtanerceptTocilizumab
MyelomMögliche Targets:CD44, BCMAAbstract 949, 937
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Danke für Ihre Aufmerksamkeit!