Hematolojide Yenilikler Dr.Burhan Ferhanoğlu Cerrahpaşa Tıp Fakültesi, İç Hastalıkları ABD, Hematoloji BD

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1 Hematolojide Yenilikler Dr.Burhan Ferhanoğlu Cerrahpaşa Tıp Fakültesi, İç Hastalıkları ABD, Hematoloji BD Febril Nötropeni Sempozyumu 27 Şubat 2010, Bilkent Otel

2 ASH 2009 DA GÖZEÇARPAN YENİLİKLER Agresif Lenfomada Yenilikler Multiple Myelom da Yenilikler Benign Hematolojide Yenilikler KLL de Yenilikler KML de Yenilikler İndolen Lenfomada Yenilikler

3 Agresif Lenfoma: Anlatım Planı DLBCL ilk seçenek tedavi GELA 10 yıllık takip sonuçları R-CHOP rejiminin optimize edilmesi Genç, yüksek riskli hasta tedavisi Kardiyak hastalarda Antrasiklin yerine Etoposid Nüks DLBCL tedavisi En iyi kurtarma rejimi CORAL çalışması

4 GELA LNH-98.5 çalışması,10 yıllık takip sonuçları (DBBHL da R-CHOP vs CHOP ) Endikasyon: İleri yaş, daha önce tedavi edilmemiş DBBHL. Çalışma: CHOP vs R-CHOP 10 yıllık takip sonuçları Coiffier et al. Blood : Abstract 3741.

5 10-year follow-up of the GELA LNH-98.5 study (R- CHOP vs CHOP in DLBCL): EFS Event-free rate R-CHOP 34% CHOP 19% p < Time (years) Coiffier et al. Blood : Abstract 3741.

6 10-year follow-up of the GELA LNH-98.5 study (R- CHOP vs CHOP in DLBCL): PFS 1.0 Progression-free survival rate R-CHOP 36.5% CHOP 20.0% p < Time (years) Coiffier et al. Blood : Abstract 3741.

7 10-year follow-up of the GELA LNH-98.5 study (R- CHOP vs CHOP in DLBCL): OS 1.0 Overall survival rate R-CHOP 43.5% CHOP 28.0% p < Time (years) Coiffier et al. Blood : Abstract 3741.

8 SWOG, 1993, NEJM

9 İleri yaş DBBHL da R-CHOP14 vs. R-CHOP21: LNH03-6B GELA Eligibility criteria: Diffuse large B-cell lymphoma Previously untreated Aged years Age-adjusted IPI 1-3 R A N D O M I Z E (n = 202) Primary endpoint : event-free survival Secondary endpoints: OS, PFS, DFS, ORR Median follow-up: 24 months R-CHOP21 CHOP21 x 8 cycles Rituximab x 8 cycles (n = 103) R-CHOP14 CHOP14 x 8 cycles Rituximab x 8 cycles (n = 98) Darbepoetin alfa Standard intervention for anemia Darbepoetin alfa Standard intervention for anemia Delarue et al. ASH 2009; abstract 406.

10 Event-free survival Median EFS : - 22 months (R-CHOP14) vs NR (R- CHOP21) 2-year EFS : - 48% (R-CHOP14) vs 61% (R-CHOP21)

11 Interim Results of R-CHOP14 vs. R-CHOP21 in Elderly Patients With DLBCL: LNH03-6B GELA Efficacy Response R-CHOP21 (n = 99) R-CHOP14 (n = 103) ORR 84% 81% CR/CRu 75% 67% P Value Event-Free Survival.1112 Median EFS Not reached 22 months 2-year EFS rate 61% 48% Progression-Free Survival.1186 Median PFS Not reached 23 months 2-year PFS rate 63% 49% 2-Year Disease-Free Survival NS 70% 57%.3991 Delarue et al. ASH 2009; abstract 406.

12 Interim Results of R-CHOP14 vs. R-CHOP21 in Elderly Patients With DLBCL: LNH03-6B GELA Adverse Events Hematologic R-CHOP21 R-CHOP14 Grade 3/4 neutropenia 69% 83% Grade 3/4 thrombocytopenia 22% 21% Grade 3/4 anemia 22% 26% Grade 3/4 leukopenia 73% 83% RBC transfusion 36% 50% Platelet transfusion 11% 15% Febrile neutropenia 19% 24% Nonhematologic Grade 3/4 mucositis 6% 11% Treatment-Related Deaths Due to Toxicity 4 pts 9 pts Delarue et al. ASH 2009; abstract 406.

13 Genç, Agresif NHL da R-CHOEP14 vs.mega-choep Al nma kriterleri: Aggressive B-cell lymphoma Yaş: aaipi 2 and 3 R A N D O M I Z E R-CHOEP-14 (n = 91) CHOEP-14 (n = 15) - CLOSED MegaCHOEP (n = 16) - CLOSED R-MegaCHOEP (n = 94) Primary endpoint: Event-free survival Schmitz et al. ASH 2009; abstract 404.

14 DSHNHL R-MegaCHOEP study design after amendment 1 for CD20-pos. B-NHL PBSC PBSC PBSC mchoep I CYC 1500 ADR 70 VCR 2 ETO 600 PRD 500 mchoep II CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mchoep III CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mchoep IV CYC 6000 ADR 70 VCR 2 ETO 1480 PRD 500 R days CHOEP-14 CYC 750 ADR 50 VCR 2 ETO 300 PRD 500 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 PRD and VCR doses are absolute, all others are per m² Rituximab (375mg/m²)

15 DSHNHL MegaCHOEP Event-free survival p= R-CHOEP-14 R-MegaCHOEP Months

16 DSHNHL MegaCHOEP Progression-free survival p= R-CHOEP-14 R-MegaCHOEP Months

17 DSHNHL MegaCHOEP Overall survival p= R-CHOEP-14 R-MegaCHOEP Months

18 Antrasiklin kullanımına kontrendikasyonu olan hastalarda Antrasiklin yerine Etoposid kullanımı (R-CEOP): Retrospektif analiz Antrasiklin kontrendikasyon nedenleri: Kardiyak kontrendikasyon: 87% Daha önce antrasiklin kullanımı: 9% Median takip : 28 ay R-CEOP (n = 81) R-CHOP (n = 162) P Value Deaths 33 (41%) 48 (30%) - 5-Year Time to Progression 57% 62%.21 5-Year Overall Survival 49% 64%.02 5-Year Disease-Specific Survival 64% 68%.17 Moccia et al. ASH 2009; abstract 408.

19 Nüks DBBHL da R-ICE vs. R-DHAP ı takiben ASCT ve idame Rituximab veya observasyon (CORAL): Eligibility criteria: Relapsed/ r efractory, CD20+ DLBCL Aged 65 years R A N D O M I Z E R-ICE x 3 cycles R-DHAP x 3 cycles A S C T PR, CR SD, PD R A N D O M I Z E Maintenance Rituximab x 3 cycles Observation Off Study Gisselbrecht et al. ASH 2009; joint symposium.

20 56% 56% OVERALL SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT) 45% PROGRESSION-FREE SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT) 42% New Orleans ASH Dec 2009 Coral study C. Gisselbrecht

21 PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT) 62% 62% N=147 N=147 64% N=160 30% N=241 31% N=228 N=241 Orlando ASCO May 2009 / Coral study C. Gisselbrecht

22 DBBHL: Akılda kalması gerekenler R-CHOP: altın standard tedavi rejimidir Optimal CHOP (14 vs. 21) : CHOP 21 iyi. İlk seçenek tedavide yüksek doz + ASCT gereksiz. R-CHOP sonrası nüks ciddi problem. Yeni stratejilere gereksinim var: - allogeneik transplantasyon - Yeni ajanlar

23 ASH 2009 DA GÖZEÇARPAN YENİLİKLER Agresif Lenfomada Yenilikler Multiple Myelom da Yenilikler Benign Hematolojide Yenilikler KLL de Yenilikler KML de Yenilikler İndolen Lenfomada Yenilikler

24 Myeloma Tedavisinde Temel Yaklaşım TEDAVİ Kür şansı olan hasta grubu için tüm tedavi seçeneklerinin başlangıçta kullanılması. ya da Nükslerle seyreden myelomu kontrol etmek için tedavinin gerektiğinde devreye girmesi. Kronik Kontrol

25 Kronik Budama İle Kontrol

26 ASH 2009 dan Güncel Bilgiler M. Myelomda yaşam süresi uzuyor. FISH ve ISS in entegre olduğu prognostik model. Transplant adayı hastalarda ilk seçenek tedavi VD vs VAD sonrası OKIT VTD vs TD sonrası OKIT Post transplant Lenalidomid konsolidasyon tedavisi İleri yaş MM da ilk seçenek tedavi VMP vs VTD

27 Multiple Myelomda Genel Sağkalımın Uzaması Yeni tedavilerin etkisi Genel Sağkalım Tedavi Periyodu Medyan OS Son 10 yılda 45 ay >10 yıl öncesi 30 ay p < Hastalar (%) yaş (60 vs 33 ay) > 65 yaş (32 vs 26 ay) Zaman (ay) Kumar SK, et al. Blood. 2008;111:

28 Multiple Myelomda Kromozomal Anormalliklerin Sağkalıma Etkisi IMWG Analizi, 9897 hasta Genetik Anormallikler Positif Negatif Toplam % Any CA Hipodiploidi Hiperdiploidi Del 13 FISH Analizi t(4;14) Del 13 Del 17 t(14;16) t(11;14) % 9.5% 16% 12.7% 12.6% 43% 8% 2.7% 19% Avet-Loisseau et al., ASH 09, abstract 743

29 New ISS and FISH Staging System 100% Overall survival by ISS and t(4;14) or del17 by FISH P-values: a v b<0.0001, a v c<0.0001, b v c< % 52% 32% 80% 60% 40% 20% 0% HIGH LOW INT Years from start of treatment 4-year Deaths/N estimate a ISS I or ISS II and Normal FISH 193/610 76% (72,79) b ISS I and Abnormal FISH/ISS III and Normal FISH 140/252 52% (45,58) c ISS II or ISS III and Abnormal FISH 146/196 32% (26,39) Herve Avet Loiseau et al, ASH 2009

30 Transplant Adayı Hastalar için İlk Seçenek Tedavi

31 MMda Indüksiyon Tedavisi Olarak Bortezomib/Dexametazon (VD) vs. VAD VD VD q 21 gün,, x 4 DCEP 2 VAD DCEP 2 VAD q 28 gün,, x 4 28-günde bir MEL ASCT Eğer < VGPR 2. ASCT veya RIC allo VD: bortezomib 1.3 mg/m 2, dexamethasone 40 mg VAD: vincristine 0.4 mg/m 2, doxorubicin 9 mg/m 2, dexamethasone 40 mg DCEP: dexamethasone 40 mg, days 1-4; cyclophosphamide 15 mg/m 2 ; etoposide 400 mg/m 2, cisplatin 10 mg/m 2 Harousseau et al. ASH 2009; abstract 353.

32 İndüksiyon Tedavisi Olarak VD vs. VAD: Etkinlik En iyi yanıt VD (n = 223) VAD (n = 218) p ncr (%) Indüksiyon 15% 7%.003 Post -ASCT I Post -ASCT 2 35% 39% 18% 32% <.0001 <.0001 VGPR (%) Indüksiyon 39% 16% <.0001 Post -ASCT I Post- ASCT 2 54% 68% 57% 47% <.0003 <.0001 Harousseau et al. ASH 2009; abstract 353.

33 n = 480 R A N D O M I Z E Bortezomib/Thalidomid/Dexametazon (VTD) vs. Thalidomid/Dexametazon (TD) Yeni tanı MM da Çift ASCT 65 yaş VTD Bortezomib 1.3 mg/m 2 days 1,4, 8, 11 Thalidomide mg/day s 1-63 Dexametazon 320 mg/cycle 3 x 21-gün siklus TD PBSC toplama CTX Thalidomid 200 mg/gün 1-63 Dexametazon 320 mg/siklus Transplantasyon MEL200 x 2 Bortezomib 1.3 mg/m 2 gün 1, 8, 15, 22 Thalidomide 100 mg/gün, days 1-70 Dexametazon 320 mg/siklus 2 x 35-gün siklus Thalidomid 100 mg/gün, gün 1-70 Dexametazon 320 mg/siklus Birincil sonlanım noktası: CR/n CR indüksiyondan 3 siklus sonra Cavo et al. ASH 2009; abstract 351.

34 İndüksiyonda VTD vs. TD ASCT: Etkinlilik Etkinlilik* VTD (n = 241) TD (n = 239) P Değeri İndüksiyon Çift ASCT Konsolidasyon ORR ncr VGPR ncr VGPR ncr VGPR 92% 26% 61% 52% 79% 59% 82% 79% 9% 28% 41% 64% 43% 67% <.0001 <.0001 < PFS 30 month 76% 58%.009 OS Şimdiye kadar aynı.6 n = 236 (VTD) ve n = 238 (TD) Cavo et al. ASH 2009; abstract 351.

35 Phase III IFM : Post-ASCT Lenalidomid İdame ve Konsolidasyonu N = 614 İlk Basamak ASCT < 65 yaş Lenalidomide 25 mg/gün 1-21 günler/ay 2 ay 6 ay No PD Konsolidasyon Lenalidomide 25 mg/gün 1-21 günler/ay 2 ay İdame Lenalidomide mg/d Nükse kadar Placebo Nükse kadar Birincil sonlanım noktası: PFS Attal et al., ASH 09; abstract 529

36 Phase III IFM : Post-ASCT Lenalidomid Konsolidasyon ve İdame uygulanmas. Konsolidasyon Faz n n 1. Analizi Konsolidasyon sırasında değerlendirme (n = 361) Konsolidasyon sonrası yanıt Düzelme: CR, IFnCR VG PR / PR Değişiklik olmayan PD CR IF- (n = 16 [4%]) ncr (n = 63 [18%]) VGPR (n = 129 [36%]) NA PR/SD (n = 153 [42%]) / Konsolidasyon Sonrası Yanıt (n = 361) Pre Post P CR, IF- VG PR 4% 58% 13% 70% <.0001 <.0001 Attal et al., ASH 09; abstract 529

37 Yaşlılar için İlk Seçenek Tedavi

38 Yeni Tanı Konmuş MM lı Yaşlı Hastalarda Bortezomib/Melphalan/Prednisone(VMP) vs. Bortezomib/Thalidomide/Prednisone (VTP) YAŞ > 65 R A N D O M I Z E n = 260 VMP x 6 Bortezomib* 1.3 mg/m 2 ; d1,8,15,22 Melphalan 9 mg/m 2 ;d 1-4 Prednisone 60 mg/m 2 ; d1-4 1 x 6-hafta siklus(* Btz, iki haftada bir) 5 x 5-Hafta siklus VTP x 6 Bortezomib* 1.3 mg/m 2 ; d1,8,15,22 Thalidomide 100 mg/d Prednisone 60 mg/m 2 ; days 1-4 İdame Bortezomib 1.3 mg/m 2 ; d1, 4, 8,11, q 3 ay Prednisone 50 mg q.o.d; Thalidomide, 50 mg/d VP VT İdame VP VT Mateos et al. ASH 2009; abstract 3.

39 Yeni Tanı MM Yaşlı Hastalarda VMP vs. VTP : Etkinlilik Mateos et al. ASH 2009; abstract 3.

40 4 Grup için PFS Karşılaştırması Mateos, et al: ASH 2009

41 MM da yaşam süresi uzuyor. Multipl Myelom Sitogenetik ile ISS verilerini kombine eden prognostik veriler önemli. Transplant adayı genç hastalarda yeni ajanların yanıt oranını arttırması yaşam süresine önemli katkıda bulunuyor. Post transplant Lenalidomid konsolidasyon ve idame tedavi sonuçları beklenmeli. İleri yaş MM da tedavi maliyetine karşılık yararlanım (yaşam süresinde uzama) henüz düşük oranda.

42 Benign Hematolojide Yenilikler Trombopoetin reseptör uyarıcı ajanların ITP de etkinliği Dabigatran ın VTE de etkinliği

43 Thrombopoietin reseptor uyarıcı ajanlar Romiplostim 2 yeni-fda onaylı ajan TPO yu aktive edici ve hücre içi sinyal uyarıcı

44 Thrombopoietin Reseptor (TPO-R) Agonistleri: Temel Farklılıklar Sınıflandırma TPO-R bağlanma alanı Romiplostim Peptibody Ligand bağlanma alanı Eltrombopag Peptit olmayan küçük molekül Transmembran alan Yeni ajanlarla ilgili önemli bir konu etpo homoloji yok yok uzun vadede güvenliliktir. Dağıtım S.C. Oral Dozajlama Haftada bir Günde bir Onay durumu ABD ve Australya ABD Endikasyon Kortikosteroidlere, İmmünglobulünlere ve Splenektomiye yetersiz yanıt vermiş kronik ITPli hastalar Kortikosteroidlere, İmmünglobulünlere ve Splenektomiye yetersiz yanıt vermiş kronik ITPli hastalar Bussel et al. N Engl J Med. 2006;355: Jenkins et al. Blood. 2007;109:

45 ITP li Hastalarda Romiplostim vs Standart Medikal Tedavi Olarak Randomizasyon Sonrası Tedavi Yanıtsızlık ve Splenektomi Oranı David J Kuter, MD, DPhil et al. Abstract #679 Massachusetts General Hospital, Boston, MA

46 ITP li Hastalarda Romiplostim vs Standart Medikal Tedavi Olarak Randomizasyon Sonrası Tedavi Yanıtsızlık ve Splenektomi Oranı Platelet count < /L R A N D O M I Z E 2:1 Romiplostim 3 mg/kg/week s.c. 52 weeks Dose adjustments based on platelet count (n=157) Standard of Care 52 weeks Investigator s choice (n=77) 6-Month Safety Follow-up Kuter et al. ASH 2009; abstract 679.

47 ITP li Hastalarda Romiplostim vs Standart Medikal Tedavi Olarak Randomizasyon Sonrası Tedavi Yanıtsızlık ve Splenektomi Oranı Incidence of Splenectomy Romiplostim (n = 157) Standard of Care (n = 77) 14 (9%) 28 (36%) OR 0.17 (95% CI, ); P <.0001 Time to Splenectomy HR 0.05 (95% CI, ); P <.0001 Incidence of Treatment Failure 18 (12%) 23 (30%) OR 0.31 (95% CI, ); P =.0005 Time to Treatment Failure HR 0.31 (95% CI, ): P =.017 The efficacy of romiplostim is significantly grater than that of SOC in both primary endpoints analyses. Kuter et al. ASH 2009; abstract 679.

48 ITP li Hastalarda Romiplostim vs Standart Medikal Tedavi Olarak Randomizasyon Sonrası Tedavi Yanıtsızlık ve Splenektomi Oranı Adverse Events Romiplostim (n = 154) Standard of Care (n = 75) Any treatment related 82 (53%) 29 (39%) Serious treatment related 7 (5%) 6 (8%) Deaths (none treatment related) 1 (1%) 5 (8%) Bleeding Events 4% 5% Grade 3 0.1% 0.3% Thrombotic Events 0.2% 0.1% No bone marrow reticulin or neutralizing antibodies to romiplostim or TPO were detected. Kuter et al. ASH 2009; abstract 679.

49 Akut VTE Tedavisi

50 Venöz Tromboemboli Tedavisinde Dabigatran Etexilate vs Warfarin Department of Medicine, McMaster University, Hamilton, ON, Canada, Sam Schulman, et al. Abstract #1

51 RE-COVER Faz III Çalışması:Akut VTE Tedavisinde Dabigatran vs Warfarin Parenteral anticoagulant After mean 9 days (5-11) n=2539 R A N D O M I Z E 1:1 Dabigatran n=1274 Warfarin n=1265 Dabigatran 150 mg b.i.d. 6 ay Warfarin dose adjusted 6 ay Schulman et al. ASH 2009; abstract 1. Schulman et al. N Engl J Med 2009; 361:

52 RE-COVER Faz III Çalışması: Akut VTE Tedavisinde Dabigatran vs Warfarin VTE or Related Death (Primary Endpoint) Dabigatran (n = 1274) Warfarin (n = 1265) HR (95% CI) During the study period 30 (2%) 27 (2%) 1.10 ( ) During the study period plus 30 days of follow-up Secondary Endpoints 34 (3%) 32 (2.5%) 1.05 ( ) Symptomatic DVT 16 (1%) 18 (1%) 0.87 ( ) Symptomatic nonfatal PE 13 (1%) 7 (< 1%) 1.85 ( ) Death related to VTE 1 (<1%) 3 (< 1%) 0.33 ( ) All deaths 21 (2%) 21 (2%) ) Schulman et al. ASH 2009; abstract 1. Schulman et al. N Engl J Med 2009; 361:

53 RE-COVER Faz III Çalışması: Akut VTE Tedavisinde Dabigatran vs Warfarin Dabigatran (n = 1274) Warfarin (n = 1265) Major Bleeding Event 20 (2%) 24 (2%) HR (95% CI) 0.82 ( ) Fatal event 1 1 NR Bleeding into critical organs 1 9 NR Resulting in decreased Hb or need for blood transfusions Major or Clinically Relevant Nonmajor Bleeding Event 20 (2%) 18 (1%) NR 71 (6%) 111 (9%) Any Bleeding Event 205 (16%) 227 (22%) 0.63 ( ) 0.71 ( ) Schulman et al. ASH 2009; abstract 1. Schulman et al. N Engl J Med 2009; 361:

54 RE-COVER Faz III Çalışması: Akut VTE Tedavisinde Dabigatran vs Warfarin: Sonuç Sabit günlük dozda direkt trombin inhibitörü olan dabigatran etexilat akut VTE tedavisinde warfarin kadar etkili ve güvenlidir. Bu veri antikoagülan tedavisinde devrim niteliğinde bir yeniliğe işaret etmektedir.

55 Kronik Lenfositik Lösemi (KLL): Yenilikler R-FC vs FC KLL de yaşam süresi avantajı sağlayan ilk çalışma. Ofatumumab- FC: KLL de etkin bir alternatif

56 Daha önce tedavi almamış ileri evre KLL de Fludarabin (F), Siklofosfamid (C) ve Rituksimab (R) Tedavisi Yaşam Süresini Olumlu Etkiliyor. Faz III Alman KLL Grubu Çalışması Hallek M, Fingerle-Rowson G, Fink A-M, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris Cappio F, Seymour J, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner C-M, Eichhorst BF, Staib P, Boettcher S, Ritgen M, Stilgenbauer S, Mendila M, Kneba M, Döhner H, Fischer K on behalf of an international group of investigators and of the German CLL Study Group (GCLLSG). Hallek et al. ASH 2009; abstract 535.

57 Phase III CLL8 Trial of FC With or Without Rituximab in Previously Untreated CLL: Study Design Key eligibility criteria: Untreated active CLL CIRS score 6 Creatinine clearance 70 ml/min R A N D O M I Z E (n = 817) Fludarabine 25 mg/m 2, days 1-3 Cyclophosphamide 250 mg/m 2, days 1-3 q 28 days 6 cycles Fludarabine 25 mg/m 2, days 1-3 Cyclophosphamide 250 mg/m 2, days 1-3 Rituximab 500 mg/m 2, day 1 (375-mg/m 2 initial dose) q 28 days 6 cycles F O L L O W - U P Updated results of the 2nd analysis Median observation time 37.7 ay. Hallek et al. ASH 2008; abstract 325. Hallek et al. ASH 2009; abstract 535.

58 Phase III CLL8 Trial of FC With or Without Rituximab in Previously Untreated CLL: Efficacy FCR (n = 388) FC (n = 371) HR P Value ORR 95% 88% NA <.01 CR 44% 22% NA <.01 PR 51% 67% NA NA SD 4% 8% NA <.01 Median PFS 3-Year OS 51.8 ay (n = 401) 87% (n = 408) 32.8 ay (n = 389) 82.5% (n = 409) < Median observation time: 37.7 ay FCR significantly improved the CR rate in the patients with del(11q), del(13q), trisomy 12, and unmutated IGHV (P <.001) but not in those with del(17p) (P =.3). The patients achieving a CR had the longest survival. Hallek et al. ASH 2009; abstract 535.

59 Phase III CLL8 Trial of FC With or Without Rituximab in Previously Untreated CLL: Grade 3/4 AEs FCR (n = 408) FC (n = 409) P Value Any 76.5% 63% <.0001 Hematologic 56% 40% <.0001 Neutropenia 34% 21% <.0001 Leukocytopenia 24% 12% <.0001 Thrombocytopenia 7% 11%.07 Infection 25.5% 21.5%.18 Tumor Lysis Syndrome 0.2% 0.5%.55 Cytokine release syndrome 0 0.2%.32 Treatment-related mortality: 2% in both arms Hallek et al. ASH 2009; abstract 535.

60 Progression-free survival Median observation time 25.5 ay Median PFS: FCR: 51.8 ay FC: 32.8 ay (N=790 Hazard ratio 0.563, ranges , p<0.001) FCR FC PFS rate 3 yrs post randomization: FCR: 64.9% FC: 44.7% P<0.001

61 Overall survival FC FCR Overall survival 3 years post randomization: FCR: 87.2% FC: 82.5% n=817, HR 0.664, p=0.012 At 3 years post randomization: FCR: 12.8% have died FC: 17.5% have died

62 Rate of complete remissions in different genetic subgroups (S. Stilgenbauer) n CR (%) FC (%) FCR (%) Δ p All patients x < q single x < q x < Trisomy x < p n.a. 0.3 None x 0.27 IGHV mut x < IGHV unmut x < 0.001

63 Overall survival and cytogenetic abnormalities according to the hierarchical model 3-yr OS* None: 86.9% 12q+: 85.8% 11q-: 82.6% 13q-: 89.1% 17p-: 36.5% * Bold letters: p< yr OS* None: 83.8% 12q+: 95.8% 11q-: 93.7% 13q-: 94.9% 17p-: 38.1%

64 GCLLSG CLL8 MRD analysis: Levels in peripheral blood 2 months post-therapy Böttcher et al., ASH 2008

65 Ofatumumab fully human anti-cd20 (to small and large loops) Human IgG 1 antibody Novel membrane-proximal epitope encompassing small & large loops Induces ADCC* Induces strong and rapid CDC - Triggered at low CD20 expression - Relatively insensitive to complement regulatory proteins - Active against rituximab - resistant cells including CLL * ADCC: Antibody dependent cell-mediated cytotoxicity CDC: Complement dependent cytotoxicity Wierda et al. ASH 2009; abstract 207.

66 Randomized Phase II Trial of 2 Doses of Ofatumumab Plus Fludarabine/Cyclophosphamide in Previously Untreated CLL: Study Design R A N D O M I Z E Ofatumumab 300 mg I.V., day 1 (cycle 1) 500 mg I.V., day 1 (cycles 2-6) Fludarabine 25 mg/m 2 I.V., days 1-3 Cyclophosphamide 250 mg/m 2 I.V., days 1-3 q 4 weeks 6 cycles Ofatumumab 300 mg I.V., day 1 (cycle 1) 1000 mg I.V., day 1 (cycles 2-6) Fludarabine 25 mg/m 2 I.V., days 1-3 Cyclophosphamide 250 mg/m 2 I.V., days 1-3 q 4 weeks 6 cycles Wierda et al. ASH 2009; abstract 207.

67 Randomized Phase II Trial of 2 Doses of Ofatumumab Plus Fludarabine/Cyclophosphamide in Previously Untreated CLL: Efficacy Ofatumumab 500 mg (n = 31) Ofatumumab 1000 mg (n = 30) ORR 24 (77%) 22 (73%) CR* 10 (32%) 15 (50%) npr 1 (3%) 1 (3%) PR 13 (42%) 6 (20%) SD 3 (10%) 2 (7%) * Primary endpoint Responses were observed in patients with unmutated IgV H, del (17p), and del (11q). Median PFS and OS were not reached. Wierda et al. ASH 2009; abstract 207.

68 KLL: Anafikir FC ye Rituksimab ilave edilmesi İleri Evre Semptomatik KLL Hastalarında, Yanıt Oranını, Progresyonsuz Yaşamı ve Yaşam Süresini Uzatmaktadır. CR Elde Edilen Hastalar Daha Uzun Yaşamaktadır. MRD Statüsü Yaşam Süresini Belirleyen Önemli Bir Kriterdir. Ofatumumab, Rituksimab alternatifi bir monoklonal antikor izlenimi vermektedir.

69 KML de Yenilikler

70 Imatinib in Newly Diagnosed CML-CP: 8-Year Follow-up of the IRIS Study 553 patients were randomized to receive imatinib: 8-year OS: 85% 8-year EFS: 81% Freedom from progression to AP/BC at 8 years: 92% 457 (83%) achieved CCyR: 82 (18%) lost CCyR. 15 (3%) progressed to AP/BC. Patients with minor to partial CyR at 3 ay and those with PCyR at 6 and 12 ay were more likely to achieve a stable CCyR than have an event 8-year MMR rate: 86% No patients with MMR at 12 ay progressed to AP/BC. No new safety signals identified: SAE profile was similar to that reported previously. Deininger et al. ASH 2009; abstract 1126.

71 Phase III ENESTnd Trial of Nilotinib vs. Imatinib in Newly Diagnosed CML-CP: Efficacy Nilotinib 300 mg b.i.d. (n = 282) Nilotinib 400 mg b.i.d. (n = 281) Imatinib 400 mg/day (n = 283) MMR at 12 ay Primary endpoint: MMR at 12 ay Follow-up: 5 years 44% 43% P <.0001 a P <.0001 a 22% High-risk Sokal score 41% 32% 17% CCyR at 12 ay Progression to AP/BC a Compared with the imatinib arm 80% 78% P <.0001 a P =.0005 a 65% 2 (< 1%) 1 (< 1%) 11 (4%) P =.0095 a P =.0037 a Saglio et al. ASH 2009; abstract LBA-1.

72 Phase III ENESTnd Trial of Nilotinib vs. Imatinib in Newly Diagnosed CML-CP: Grade 3/4 Adverse Events Nilotinib 300 mg b.i.d. (n = 279) Nilotinib 400 mg b.i.d. (n = 277) Imatinib 400 mg/day (n = 280) Neutropenia 12% 10% 20% Thrombocytopenia 10% 12% 9% Anemia 3% 3% 5% Nausea < 1% 1% 0 Diarrhea < 1% 0 1% Rash < 1% 3% 1% Grade 3/4 fluid retention AEs were rarely observed in any treatment arm (< 1%). Grade 3/4 lab abnormalities were < 10% in all treatment arms. No patients showed an absolute QTcF interval of > 500 ms. No decrease from baseline in mean LVEF was observed during treatment in any arm. Saglio et al. ASH 2009; abstract LBA-1.

73 KML: Anafikir Kronik faz KML de Imatinib ile 8 yıllık takip sonuçları ilacın etkinliği ve güvenliliğini teyit etmiştir. Nilotinib ve Dasatinib ilk seçenek tedavi sonuçları umut vermektedir.

74 İndolen Lenfomalarda Yenilikler

75 İndolen Lenfomalarda Yenilikler Bendamustin Rituksimab kombinasyonu ilk seçenek FL de çok etkin GA101 umut veren monoklonal antikor

76 Bendamustine Chemical structure ClH 2 C Bendamustine ClH 2 C N N COOH Carboxylic acid Nitrogen mustard N Benzimidazole ring Cl Cyclophosphamide CH 3 N NH 2 N Cl N O O P N H Cl N HOCH O 2 Cladribine OH N

77 Phase III Study of First-line Bendamustine/Rituximab (B-R) vs R-CHOP in Indolent NHL: Final Results B-R Key Eligibility Criteria: CD20 + FL (grade 1/2), MCL, MZL, WM, SLL, other LPL Stage III/IV No prior therapy R A N D O M IZ E Gün R-CHOP Age 18 years Gün Rituximab Bendamustine CHOP Rummel et al. ASH 2009; abstract 405.

78 Progression free survival B-R vs R-CHOP Probability p = 0,11 B-R B-R CHOP-R R-CHOP months Rummel et al 2008

79 Phase III Study of First-line Bendamustine/Rituximab (B-R) vs R-CHOP in Indolent NHL: Efficacy B-R (n = 260) R-CHOP (n = 253) P Value HR Overall Response Rate 93% 91% Complete response 40% 30%.0262 Median Progression-Free Survival Median Time to Next Treatment 54.9 months Not reached 34.8 months months Rummel et al. ASH 2009; abstract 405.

80 Phase III Study of First-line Bendamustine/Rituximab (B-R) vs R-CHOP in Indolent NHL: Safety B-R (n = 1450) Cycles R-CHOP (n = 1408) Grade 3/4 Leukocytopenia 12% 38% Grade 3/4 Neutropenia 11% 46.5% G-CSF Administered 4% 20% Infectious Complications (All Grades) B-R (n = 260) Number of Patients R-CHOP (n = 253) Skin (Erythema, All Grades) Allergic Skin Reactions (All Grades) Rummel et al. ASH 2009; abstract 405.

81 GA101: mechanisms of action type I versus type II antibodies Increased direct cell death Unique type II epitope & elbow-hinge modification Increased ADCC via increased affinity to the 'ADCC receptor' FcgRIIIA Effector cell B cell CD20 Lower CDC activity Due to recognition of type II epitope FcgRIIIa Complement

82 GA101: prior clinical experience Salles G et al. (ASH 2009) Phase I study -CD20+ NHL with no available therapy of higher priority -Dose escalation 3 x 3 design -GA101 infused days 1, 8, 22, then Q3 weeks for 9 infusions -Flat doses between 50 mg to 2000 mg Results -21 heavily pretreated patients -No dose limiting toxicity, well-tolerated -Overall response rate 43% (5 CR/CRu, 4 PR) -Five patients with ongoing response (duration 11 to 21+ mos)

83 İndolen Lenfomalar: Anafikir İlk seçenek Bendamustin- Rituksimab kombinasyonları dikkat çekici Nüks FL da GA-101 sonuçları heyecan verici

84 Hematolojide Yenilikler Dr.Burhan Ferhanoğlu Cerrahpaşa Tıp Fakültesi, İç Hastalıkları ABD, Hematoloji BD Febril Nötropeni Sempozyumu 27 Şubat 2010, Bilkent Otel