AGRESİF B HÜCRELİ LENFOMALARDA TEDAVİ

AGRESİF B HÜCRELİ LENFOMALARDA TEDAVİ Dr. Evren Özdemir Hacettepe Üniversitesi Onkoloji Hastanesi 20.04.2013

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

Patients (%) IPI: Overall Survival by Risk Categories Among Patients With Aggressive NHL Treated With Chemotherapy 100 75 50 25 Low Low-intermediate High-intermediate High 0 0 2 4 6 8 10 Shipp, et al. N Engl J Med. 1993;329:987 Year

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

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):6351-6357

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

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 0.21-1.5 years Median 6.5 months Median 2.8 months Pfreundschuh, et al. ASCO 2011

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)

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

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 3-5 72% 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

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

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 3-5 51% No unexpected toxicity Micallef, et al. Blood 2011;118:4053-4061

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

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

R-ACVBP > R-CHOP in Younger Patients with Non-GC DLBCL in the GELA Trial LNH03-2B. GELA, NHL03-2B trial, cases with ages 18-59 n=379 229 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

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

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

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; 28:4184 4190 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?

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

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

A multicenter phase II study of bendamustine with rituximab in patients with relapsed/refractory DLBCL Group n CR PR Median PFS All cases 59 22 (37.3%) 15 (25.4%) 6.7 months Age 65 37 14 (37.8%) 9 (24.3%) 6.3 months Age < 65 22 8 (36.4%) 6 (27.3%) 6.7 months Ogura et al. ASCO 2012 # 8023

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

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

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-32765 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

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

Erişkin Burkitt Lenfoma Faz II Çalışmaları N Median Yaş Rejim 2-yıllık DFS Kaynak 24 33 Kısa/doz yoğun/pediatrik NHL % 49 Hoelzer 1996 35 36 Kısa/doz yoğun/pediatrik NHL % 51 Hoelzer 1996 54 24 CODOX-M/IVAC % 89 Magrath 1996 (NCI) 48 58 Hyper-CVAD % 39 Thomas 1999 52 27 Modifiye CODOX-M/IVAC % 70 Mead 2002 92 47 Kısa/doz yoğun % 50 Rizzieri 2004 (CALGB) 14 47 Modifiye CODOX-M/IVAC % 71 Lacasce 2004 27 36 Kısa/doz yoğun/ BEAM-Otolog KİT % 81 Van Imhoff 2005 (HOVON) 31 46 R-Hyper-CVAD % 89 Thomas 2006 10 51 Kısa/doz yoğun % 72 Kujawski 2007

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

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

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

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

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

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

Salaverria I, et al. J Clin Oncol 29:1835-1843

Aukema SM, et al. Blood 2011;117(8):2319-2331

Phase II study of dose adjusted R-EPOCH in previously untreated BL and c-myc + DLBCL NCT01092182 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

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