AGRESİF B HÜCRELİ LENFOMALARDA TEDAVİ

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1 AGRESİF B HÜCRELİ LENFOMALARDA TEDAVİ Dr. Evren Özdemir Hacettepe Üniversitesi Onkoloji Hastanesi

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3 International Prognostic Index (IPI) Patients of all ages Age Performance status Lactate dehydrogenase (LDH) level Extranodal involvement Stage (Ann Arbor) Risk factors >60 years 2-4 Elevated >1 site III-IV Patients 60 years (age-adjusted) Performance status LDH Stage 2-4 Elevated III-IV Shipp, et al. N Engl J Med. 1993;329:987

4 Patients (%) IPI: Overall Survival by Risk Categories Among Patients With Aggressive NHL Treated With Chemotherapy Low Low-intermediate High-intermediate High Shipp, et al. N Engl J Med. 1993;329:987 Year

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7 RICOVER - 60 Study R-CHOP > CHOP R-CHOP x 6 + 2R = R-CHOP x 8 Pfreundschuh, et al. ASH 2005; Schubert, et al. ASH 2007

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9 Diffuse Large B-Cell Cell Lymphoma: At Least Three Diseases Germinal center B cell-like (GCB DLBCL) Activated B cell-like (ABC DLBCL) Primary Mediastinal B Cell Lymphoma (PMBL) Cell of Origin Germinal center B cell Post-germinal center B cell Thymic B cell Oncogenic Mechanisms BCL-2 translocation c-rel amplification Constitutive activation of NF-kB Chr. 9p24 amplification PDL1, PDL2 Clinical Outcome Favorable 59% 5-yr survival Poor 30% 5-yr survival Favorable 64% 5-yr survival Lossos IS, et al. JCO 2005; 23(26):

10 R-CHOP ile GCB DLBCL > ABC DLBCL R-CHOP ile GCB DLBCL de PFS ve OS ABC DLBCL den daha iyi 3 Yıllık genel sağkalım (OS 3 ) GCB DLBCL için %84 ABC DLBCL için %56 Gisselbrecht & Meunier, ASCO 2011 Lenz G et al, NEJM 2008; 359: 2313

11 High-Risk DLBCL treated with R-CHOP-like chemotherapy Subgroup aaipi=2 (<61 years) aaipi=3 (<61 years) Low-intermediate risk (ages 61-80) Intermediate-high risk (ages 61-80) High risk (ages 61-80) Very old cases (>80) ABC type myc breakpoint Double hit CNS involvement (ages18-60) CNS involvement (ages 61-80) Survival 90% (3 years) 70% (3 years) 71% (5 years) 55% (5 years) 52% (5 years) Median 2.2 years 56% (3 years) 32% (5 years) Median years Median 6.5 months Median 2.8 months Pfreundschuh, et al. ASCO 2011

12 R-CHOP-21 den daha iyi bir tedavi var mı? Mevcut rejimlerin uygulama sıklığının/doz yoğunluğunun artırılması Mevcut rejimlere yeni ajanlar eklenmesi Diğer rejimler Konsolidasyon/idame tedavileri Başlangıçta nakil (ilk remisyonda)

13 R-CHOP-21 den daha iyi bir tedavi var mı? Mevcut rejimlerin uygulama sıklığının/doz yoğunluğunun artırılması

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16 R-CHOP14 compared to R-CHOP21 in elderly patients with DLBCL: Final analysis of the LNH03-6B GELA study. R-CHOP-14 (n=304) R-CHOP-21 (n=296) LDH elevated 66% 71% Beta-2 elevated 43% 47% IPI % 78% Febrile neutropenia 21% 19% Grade III/IV anemia 22% 18% EFS 3 56% 60% PFS 3 60% 62% OS 3 69% 72% Delarue et al. ASCO 2012 # 8021

17 R-CHOP-21 den daha iyi bir tedavi var mı? Mevcut rejimlere yeni ajanlar eklenmesi

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21 Comparison of ER-CHOP intention-to-treat results with R-CHOP treated patients Phase 2 in newly diagnosed DLBCL R-CHOP x 6 + day 1 epratuzumab 360 mg/m 2 N = 107, 81 eligible Median age 62 IPI % No unexpected toxicity Micallef, et al. Blood 2011;118:

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23 R-CHOP + Lenalidomide (R2CHOP) initial therapy for aggressive B-cell lymphomas: phase I study R-CHOP-21 + lenalidomide days 1-10 (pegfilgrastim day 2) N = 24; Median age 65 (35-82) Lenalidomide 15 mg (N=3), 20 mg (N=3), or 25 mg (N=18) No DLT; no toxic death Grade IV neutropenia 67% (febrile neutropenia 4%) Grade IV thrombocytopenia 21% RR 100%, CR 77% Lenalidomide in DLBCL ABC > GCB (activity) Nowakowski GS, et al. Leukemia 2011

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25 R-CHOP-21 den daha iyi bir tedavi var mı? Diğer rejimler

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32 R-ACVBP > R-CHOP in Younger Patients with Non-GC DLBCL in the GELA Trial LNH03-2B. GELA, NHL03-2B trial, cases with ages n= evaluable 107 cases on R-ACVBP 122 cases on R-CHOP For GCB population (n=101), EFS, PFS, OS = for R- ACVBP and R-CHOP For non-gcb population (n=128), R-ACVBP better than R-CHOP, EFS (p=0.02), PFS (p=0.007), OS (p=0.007) Molina et al. ASH 2011 # 2632

33 R-CHOP-21 den daha iyi bir tedavi var mı? Konsolidasyon/idame tedavileri

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36 R-CHOP-21 den daha iyi bir tedavi var mı? Başlangıçta nakil (ilk remisyonda)

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41 CORAL: Collaborative trial in Relapsed Aggressive Lymphoma Relapsed/ refractory DLBCL n = 396 R A N D O M I S E R-ICE x 3 R-DHAP x 3 PR, CR SD, PD off study Gisselbrecht et al. J Clin Oncol 2010; 28: Which salvage regimen is the best? ASCT BEAM R-DHAP = rituximab, dexamethasone, high-dose cytarabine, cisplatin R-ICE = rituximab, ifosfamide, carboplatin, etoposide R A N D O M I S E Rituximab 375 mg/m 2 q2mo x 6 Observation only Place of immunotherapy Post-transplantation?

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44 CORAL Study Final Report R-ICE x 3 (n=191) Rituximab (+), Every 2 months for 1 year (n=122) Relapsed / Refractory DLBCL, n=477 BEAM (n=242) R-DHAP x 3 (n=197) Rituximab ( ) (n=120) Gisselbrecht et al. ICML-11 Lugano # 75

45 CORAL Study Final Report Second Randomization Rituximab- Maintenance (n=122) Observation (n=120) p value EFS 3 54% 54% NS PFS 3 54% 57% NS OS 3 66% 69% NS Rituximab maintenance post-asct is not effective Rituximab maintenance post-asct is more effective in females than males: EFS 4 63% in females, 37% in males (p=0.01) Gisselbrecht et al. ICML-11 Lugano # 75

46 A multicenter phase II study of bendamustine with rituximab in patients with relapsed/refractory DLBCL Group n CR PR Median PFS All cases (37.3%) 15 (25.4%) 6.7 months Age (37.8%) 9 (24.3%) 6.3 months Age < (36.4%) 6 (27.3%) 6.7 months Ogura et al. ASCO 2012 # 8023

47 An update on gemcitabine, rituximab, and oxaliplatin in combination for relapsed/refractory NHLs 58 Cases with relapsed / refractory NHL DLBCL = 45 cases Prior rituximab yes = 38 cases, no = 20 cases Prior lines of therapy 1 Line = 33 cases 2 Lines = 12 cases 3 Lines = 8 cases 4 Lines = 5 cases CR = 15 (26%), PR = 18 (31%) Median PFS = 134 days Median OS = 296 days Crescentini et al. ASCO 2012 # 8084

48 Everolimus in Combination with Rituximab Induces CRs in Heavily Pretreated DLBCL Dana-Farber, R/R DLBCL, n=25 Stage III/IV at relapse = 76%, elevated LDH = 64% Median number of prior therapies = 4 Prior ASCT = 20% Everolimus 5mg (days 1-14) if tolerated everolimus 10mg (days 15-28); Rituximab (days 1,8,15,22 cycle 1) (day 1 cycles 2-6), repeated every 28 days upto 6 cycles Best ORR = 36% CR = 12%, PR = 24% Median PFS = 3.4 months, median OS = 8.6 months Barnes et al. ASH 2011 # 1635

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50 Novel Targeted Agents for DLBCL Derived from Gene Expression Profiling Studies* Drug GEP Subgroup Target Bortezomib ABC NF-κB Enzastaurin ABC; Fatal/Refractory PKCβ Bevacizumab Stromal-2 signature VEGF; angiogenesis Lenalidomide Stromal-2 signature; ABC Angiogenesis, NF-κB, pleiotropic Fostamatinib BCR-dependent; ABC Syk & BCR signaling; NF-κB via CARD 11 PCI BCR-dependent; ABC Syk & BCR signaling; NF-κB via CARD 11 CAL-101 Under investigation Associated with BCR signaling (PI 3 K-delta) Everolimus (RAD001) DCS4968q (anti-cd796 ADC) ABC Phase 1 Trial (Genentech) mtor (downstream from PI 3 K/AKT pathway) BCR signaling SMI of BCL6 1 BCR-dependent (pre-clinical) BCL6-dependnet DLBCL Friedberg et al. Clin Cancer Res 2011; 17:6115

51 BURKİTT LENFOMA - TEDAVİ -- En kısa sürede, kısa, sık ve yoğun, çoklu ajan immünokemoterapi rejimlerine başlanmalı, intratekal KT ile SSS profilaksisi verilmeli -- CHOP veya CHOP benzeri tedaviler inferior (OS %75 vs %22) -- Bu prensiplere uyan 3 majör tedavi kategorisi mevcut; -- Doz-yoğun, ardışık kemoterapi -- ALL-benzeri kemoterapi -- Yüksek doz kemoterapi ve otolog KİT konsolidasyonu ile biten kısa, doz-yoğun tedavi -- Faz II çalışmalar, karşılaştırmalı çalışma yok

52 Erişkin Burkitt Lenfoma Faz II Çalışmaları N Median Yaş Rejim 2-yıllık DFS Kaynak Kısa/doz yoğun/pediatrik NHL % 49 Hoelzer Kısa/doz yoğun/pediatrik NHL % 51 Hoelzer CODOX-M/IVAC % 89 Magrath 1996 (NCI) Hyper-CVAD % 39 Thomas Modifiye CODOX-M/IVAC % 70 Mead Kısa/doz yoğun % 50 Rizzieri 2004 (CALGB) Modifiye CODOX-M/IVAC % 71 Lacasce Kısa/doz yoğun/ BEAM-Otolog KİT % 81 Van Imhoff 2005 (HOVON) R-Hyper-CVAD % 89 Thomas Kısa/doz yoğun % 72 Kujawski 2007

53 The incorporation of rituximab and liposomal doxorubicin into CODOX-m/IVAC for untreated Burkitt lymphoma (BL): Final results of a prospective multicenter phase II study After cycle 2 ORR 100%, CR 78% After cycle 3/4 ORR 100%, CR 100% Median follow-up was 24 months PFS 2 was 86% OS 2 was 86% Evens, et al. ASCO 2012 # 8080

54 Hyper-CVAD and Rituximab for De Novo Burkitt Lymphoma/Leukemia MDACC, newly diagnosed BL (n=30) or B-ALL (n=27), non-hiv, median age 44 Rituximab on days: 1 & 8 of Hyper-CVAD 1 & 8 of MTX/Ara-C Every 21 days R-Hyper- CVAD, n=57 Hyper-CVAD, n=48 CR 43/47 (92%) 41 (85%) OS 5 74% 50% R R R R R R R R Thomas et al, Cancer 2006;106:1659 H-CVAD M/A H-CVAD M/A H-CVAD M/A H-CVAD M/A IT IT IT IT IT IT IT IT IT IT IT IT IT IT IT IT Thomas et al. ASH 2011 # 2698

55 Burkitt Lenfoma ve myc Pozitif DLBCL İlk Basamak Tedavisinde DA-EPOCH-R Tedavi edilmemiş, 12 yaşın üzerindeki 31 Burkitt lenfoma olgusu HIV negatif = 20, HIV pozitif = 11 Tüm olgular IT MTX profilaksisi almış CR=30, CRu=1, ORR=%100 EFS 5 =%97, OS 5 =%100 Dunleavy, et al. ICML-11 Lugano # 71

56 Long-Term Outcome of Cases with Lymphoblastic Lymphoma After Hyper-CVAD Variants MDACC 49 Cases Median follow-up was 80 months (~60%) Current scheme: Hyper-CVAD x 8 Nelarabine 650mg/m2 daily for 5 days x 2 Cases in each variant 5-Year CR Duration OS 5 C 21 69% 63% AI 11 70% 55% No AI 17 78% 79% C: Classic Hyper-CVAD, AI: Modified hyper-cvad with anthracyclin intensification, No AI: Modified hyper- CVAD without anthracyclin intensification Thomas et al. ASH 2010 # 2831

57 Other Aggressive B-Cell Lymphomas in the WHO Classification Burkitt(BL)/DLBCL and MYC MYC: BL 100% MYC: double-hit 100% MYC: DLBCL 8-10% MYC: Plasmablastic 50% B-UNC/BL/DLBCL MYC/BCL-2/BCL-6( ) More CNS relapses Bone marrow involvement common MYC positives & negatives do the same with DA-EPOCH-R regimen Jaffe, et al. ASH 2011

58 R-CHOP and MYC rearranged DLBCL EFS 35 (14%) with MYC rearrangements 19 also had t(14;18) 3 also had BCL6 OS 7 triple hit Therefore most MYC+ are double or triple hit Barrans et al. JCO 2010

59 Salaverria I, et al. J Clin Oncol 29:

60 Aukema SM, et al. Blood 2011;117(8):

61 Phase II study of dose adjusted R-EPOCH in previously untreated BL and c-myc + DLBCL NCT Inclusion criteria Burkitt lymphoma or B-cell lymphoma, unclassifiable, with features intermediate between Diffuse Large B- cell lymphoma and Burkitt Lymphoma c-myc + DLBCL c-myc+ plasmablastic lymphoma

62 Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP x 6-8 R-CHOP x 3 + IFRT IPI High Risk: High dose chemotherapy followed by autologous stem cell transplantation in CR1 Relapsed DLBCL: Salvage chemotherapy (if chemo. sensitive) followed by autologous stem cell transplantation Mantle Cell Lymphoma (MCL) Front-line aggressive regimen: R-HyperCVAD, etc. Autologous stem cell transplantation in CR1 Relapsed MCL: RIC Burkitt/Lymphoblastic Lymphoma/Double hit/gray zone High-dose sequential regimens: R-HyperCVAD, R-CODOX- M/IVAC, ALL-like regimens Autologous stem cell transplantation in CR1