MODERN MANAGEMENT OF DLBCL. Ruth Pettengell St George s University of London

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1 MODERN MANAGEMENT OF DLBCL Ruth Pettengell St George s University of London

2 NHL OVERVIEW B T NHL 85% 15% Main B-cell lymphomas distribution DLBCL: The commonest subtype MALT 9% Follicular 29% Lymphoma Research Foundation. Understanding Non-Hodgkin Lymphoma Fourth edition; Image By Nephron (Own work) [CC BY-SA 3.0 (

3 New cases (%) DLBCL Presentation De novo or after transformation: follicular lymphoma, CLL/SLL 1 Incidence in Europe 3.8/ /year 2 Increases with age 3 Median age at diagnosis 64 years Risk factors 4 Family history Autoimmune disease HIV+ Hepatitis C Virus Percent of New Cases by Age Group: NHL SEER , All Races, Both Sexes Raut LS, et al., South Asian J Cancer Sant M, et al., Blood Tilly H, et al., Ann Oncol Morton LM, et al., J Natl Cancer Inst Monogr From the website of the National Cancer Institute ( Age

4 2016 REVISION OF THE WHO CLASSIFICATION DLBCL: Cell of Origin Common somatic mutations: inactivating mutations of TP53, genes in immunosurveillance (B2M, CD58), alterations in epigenetic regulators (CREBBP/EP300, KMT2D/C [MLL2/3], MEF2B), and oncogenic activation of BCL6. Biomarkers of GCB CD 10, BCL6, GCET1, LMO2. Frequently histone methyl transferase EZH2, BCL2 translocations, mutations in the cell motility regulator GNA13 Non GCB markers IRF4/MUM1, FOXP1. Frequently mutations in genes (MYD88, CD79A, CARD11,TNFAIP3) activating the B-cell receptor/toll-like receptor and NF-kB pathways DLBCL NOS Co expression of MYC and BCL2 (expression >50%) without gene aberrations, considered new prognostic marker (double-expressor lymphoma). Worse outcome than other DLBCL CD30 expression as new antibody-based therapies 1. Swerdlow SH, et al., Blood :

5 OS IMPORTANCE OF CELL-OF-ORIGIN MOLECULAR SUBTYPES GCB + CD10 + Bcl-6 + MUM1 Non-GCB Non-GCB GCB Hans classification DLBCL subgroup 5-Yr OS, % PMBL 64 GCB DLBCL 59 ABC DLBCL From NEJM 2002, Rosenwald A, et al., The Use of Molecular Profiling to Predict Survival after Chemotherapy for Diffuse Large-B-Cell Lymphoma; 346: Copyright (2002) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society; Rosenwald A, et al., J. Exp Med , copyright 2003, with permission from the Rockefeller University Press; Hans CP, et al., Blood 2004;103:

6 LUGANO CLASSIFICATION Staging 1 FDG PET-CT more sensitive than CT for detecting nodal and extra nodal disease in NHL (5 point Deauville score) Modified Ann Arbor classification Routine bone marrow biopsy (BMB) not required for most DLBCL 654 pts Sens:88.7%, Spec:99.8% 3.1% false negative (<20% BM involvement) 12.5% PET/CT +ve/-ve BMB End of Treatment PET/CT more accurate especially in CRu or PR and extranodal disease 1 Plan for minimum of 3 weeks preferably 6-8 weeks post chemo 2, 3 months postradiotherapy 3 1. Adams HJA, et al., EJNMMI 2014; 41: Juweid ME, et al., J Clin Onc 2007;21: Boellaard R, et al., Eur J Nuc Med Mol Imaging 2010;37:

7 Net survival Net survival DLBCL PROGNOSIS Overall Survival according to age and time period Events occur early :45 45:55 55:65 65:75 75: :45 45:55 55:65 65:75 75: Time since diagnosis (years) Time since diagnosis (years) 1. Monnereau A, et al., Survie des personnes atteintes de cancer en France Lymphomes diffus à grandes cellules. Études à partir des registres des cancers du réseau FRANCIM. 2. Monnereau A, et al., Lymphome diffus à grandes cellules B. Available on invs.santepubliquefrance.fr

8 CD20 MONOCLONAL ANTIBODIES Rituximab Specific anti-cd20 Pan-B cell marker Mature B-cells > 95% B-cell NHL DLBCL: CD20 staining Republished with permission of American Society of Hematology, from The clinical application of monoclonal antibodies in chronic lymphocytic leukemia, Jaglowski SM, et al., Blood 116(19): , copyright 2010; permission conveyed through Copyright Clearance Center, Inc.

9 Survival (%) Patients (%) PROGNOSTIC SCORES NCCN-IPI 1 Score Age, y >40 to 60 1 >60 to 75 2 >75 3 LDH, normalised >1 to 3 1 >3 2 Ann Arbor stage III-IV 1 Extranodal disease * 1 Performance status 2 1 IPI Score NCCN-IPI L (0,1) LI (2,3) HI (4,5) H (>6) IPI 2 Score Age > 60 y? LDH > 1x normal? Stage III-IV 1 > 1 extranodal lesion 1 Performance status 2 1 IPI 0 Overall survival 2 Score L (0,1) LI (2) HI (3) H (4) Zhou Z, et al., Blood 2014;123: The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 1993;329:987 99

10 TREATMENT ALGORITHM FOR DLBCL Aggressive non-hodgkin Lymphoma First-line treatment First Line Cure n=200 First Relapse n=100 Transplant Eligible n=50 n=50 Transplant Ineligible Response to salvage No Response to n=25 therapy salvage therapy n=25 Proceed to ASCT Second Line Cure Not Cured Relapsed/Refractory n=25 n=50 Relapsed/Refractory n=10 n=15 Third Line 3rd line salvage ASCT=Autologous Stem cell transplantation n=90 Adapted from: Friedberg JW. Hematology Am Soc Hematol Educ Program. 2011;2011:

11 LIMITED STAGE DISEASE R-CHOP (3 cycles) plus RT prolonged follow-up PFS OS Stephens DM, et al., Continued Risk of Relapse Independent of Treatment Modality in Limited-Stage Diffuse Large B-Cell Lymphoma: Final and Long-Term Analysis of Southwest Oncology Group Study S8736. J Clin Oncol 2016;25: Reprinted with permission. 2016, American Society of Clinical Oncology. All rights reserved

12 ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL First line treatment: R-CHOP (-like) Patients 60 years IPI low risk (aaipi = 0) and no bulk R-CHOP21 6 Elderly > 60 years IPI low risk (aaipi = 0) with bulk or IPI low-intermediate risk (aaipi = 1) R-ACVBP and consolidation or R-CHOP IF-RT on bulk IPI intermediate-high risk or IPI high risk (aaipi = 2, 3) R-CHOP or R-CHOP14 6 with 8 R Consider more intensive regimens in selected patients: R-CHOEP14 6 or R-CHOP or R-ACVBP plus ASCT Fit, years >80 years without cardiac dysfunction Unfit or frail or >60 years with cardiac dysfunction R-CHOP (6 for IPI low risk) or R-CHOP14 6 with 8 R Attenuated regimens: R-miniCHOP21 6 Doxorubicin substitution with gemcitabine, etoposide or liposomal doxorubicin or others: R-C(X)OP21 6 or palliative care Tilly H, et al., Ann Oncol 2015;26 Suppl 5:v116 2

13 YOUNG PATIENTS (<60 YEARS) EFS PFS OS Months Median F/U 70 mo, No excess AEs in R group or second malignancies Reprinted from Lancet Oncol 12(11), Pfreundschuh M, et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-b-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group, , copyright 2010 with permission from Elsevier

14 DOSE DENSE CHEMOTHERAPY IN DLBCL R-CHOP14 vs. 21: no difference in outcome No subgroup identifies with better outcome Reprinted with permission from Elsevier. Cunningham D, et al., The Lancet, 2013;381:

15 DOSE INTENSIVE CHEMO IN DLBCL Improved outcome in R-ACVBP Arm EFS PFS RFS OS Reprinted from The Lancet, 378(9806), Recher C, et al., Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial, , Copyright 2011, with permission from Elsevier

16 ONGOING APPROACHES TO INTENSIFICATION CALBG R-CHOP vs. DA-EPOCH-R 524 patients, 2005 to 2013 R-CHOP High-intermediate/high IPI (33.6%; 38.2%) Completed per protocol RCHOP 89% and R-EPOCH 83% disease progression on therapy was 2.6% and 1.7% R-EPOCH G4 neutropenia 90% 56% G4 thrombocytopenia 35% 6% G 3/4 FN 37% 19% G3 neuropathy Motor 8% Sensory 15% Motor 1% Sensory 3% Adverse side effects leading to treatment discontinuation were 1.7% and 5.6% No difference in EFS (HR 1.02 and p=0.89 at a median follow-up of 4.9 years) or OS (HR 1.19 and p=0.40 at median 5.0 years) Wilson W, et al., Blood :469

17 THE RISK OF CNS DISEASE IN PATIENTS WITH AGGRESSIVE B-CELL LYMPHOMA CNS relapse is early (median 5.4 mo from diagnosis, 0.2% isolated CNS relapse 1 N=1597 pts, median follow-up 4.2 y; median TT CNS rel 6.7 mo Low risk 0-1 factors; 2 year CNS relapse risk 0.8% Intermediate risk 2-3 factors; 2 year CNS relapse risk 3.9% High risk 4-6 factors; 2 y CNS relapse risk 12% Kidney/Adrenal involvement CNS relapse (2 year CNS risk BCCA 33%; 14% DSHNHL) Risk of CNS relapse according to the CNS IPI 2 1. Bernstein SH, et al., J Clin Oncol 2009;27(1): Schmitz N, et al., CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-cell Lymphoma Treated With R-CHOP, J Clin Oncol 2016;34(26): Reprinted with permission American Society of Clinical Oncology. All rights reserved.

18 CAPITALISING ON BIOLOGIC INSIGHTS If we can get the biomarkers right we can identify patients that may benefit from intensification or specific targeted therapies Cell cycle regulation p53 p16 p27 Cyclin D2 ki67 c-myc Apoptosis related Bcl-2 B-cell differentiation Bc-6 CD10 CD5 FoxP1 CD21 Adhesion Molecules ICAM-1 Microenvironment VEGF CD40 HIF-1a

19 Probability Probability R-CHOP TREATED PATIENTS IN LUNENBURG Overall survival in Lunenburg analysis 1.00 BCL BCL No staining (0 5%) 5 25% 26 50% 51 75% >75% No staining Weak / Variable weak Strong / Variable strong 1.00 CD Ki Years since treatment initiation No staining 1 75% >75% Years since treatment initiation 1 25% 26 50% 51 75% >75% Salles G, et al., Blood 2011;117:

20 R-CHOP PLUS IBRUTINIB No difference according to cell of origin No dose dependant response 280mg (n=7) 420mg (n=4) 560mg (n=21) Combined (n=32) ORR 6 (86%) 4 (100%) 20 (95%) 30 (94%) CR 5 (71%) 3 (75%) 15 (71%) 23 (72%) PR 1 (14%) 1 (25%) 5 (24%) 7 (22%) SD PD NE 1(14%) 0 1(5%) 2(6%) Younes A, et al., Lancet Oncology 2014

21 ABC PHENOTYPE AND R2-CHOP Can R2-CHOP overcome the adverse outcome of the ABC phenotype? R-CHOP R2-CHOP Nowakowski GS, et al., Lenalidomide Combined With R-CHOP Overcomes Negative Prognostic Impact of Non Germinal Center B-Cell Phenotype in Newly Diagnosed Diffuse Large B-Cell Lymphoma: A Phase II Study. J Clin Oncol 2015;33(3): Reprinted with permission American Society of Clinical Oncology. All rights reserved.

22 2016 REVISION OF THE WHO CLASSIFICATION High-grade B-NHL, with MYC and BCL2 and/or BCL6 translocations New category: double-/triple-hit lymphomas (NOT FL or lymphoblastic lymphomas). Includes High-grade B-cell lymphoma, NOS, B-cell lymphoma, unclassifiable ± MYC and BCL2 or BCL6 translocations Morphology Blastoid BL DLBCL/BL DLBCL Phenotype and cytogenetics TdT+ TdT-, cyclin D1- Diagnosis B-LBL HGBL, NOS BL HGBL, with MYC and BCL2 and/or BCL6R DLBCL, NOS Orange arrows: BL phenotype + MYC rearrangement ( single hit ). Red arrows: MYC and BCL2 and/or BCL6 rearrangements ( double or triple hit ). MCLs, subtypes of LBCLs, nor Burkitt-like lymphoma with 11q aberration are indicated in this diagramme. Swerdlow SH, et al., Blood :

23 MYC AND DUAL TRANSLOCATION MYC + - BCL2 + MYC + - IG loci + Only MYC + - BCL2 + protein expression predicts inferior PFS and OS (p<0.001) MYC + - IG loci + predicts poor PFS (p=0.005) & OS (P=0.0006) independent from IPI or Hans Classifier Johnson NA, et al., Concurrent Expression of MYC and BCL2 in Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone J Clin Oncol 2012; 30: Reprinted with permission American Society of Clinical Oncology. All rights reserved. Republished with permission of The American Society of Hematology, from Blood, Copie-Bergman C, et al., 126(22): , 2015; permission conveyed through Copyright Clearance Center, Inc

24 OS (probability) PFS (probability) IMPACT OF MYC STATUS IN DLBCL Log rank p= R-CHOP (N=63) R-Hyper CVAD (N=38) DA-EPOCH-R (N=57) R-CODOX-M/IVAC (N=41) Other/multiple (N=24) Time from diagnosis (months) Log rank p=0.119 R-CHOP (N=100) R-Hyper CVAD (N=65) DA-EPOCH-R (N=64) R-CODOX-M/IVAC (N=42) Other/multiple (N=24) Time from diagnosis (months) DHL represents an unmet medical need Variable Risk factor p value Age ECOG PS WBC 10 3 <0.001 Albumin < LDH >3x ULN B symptoms Present Extranodal disease >1 site Ann Arbor Stage Bone marrow involvement Positive <0.001 CNS involvement Present <0.001 Multivariate analysis WBC LDH >3x ULN 0.05 Ann Arbor Stage CNS involvement Present Key points A subset of DHL patients may be cured, and some patients may benefit from intensive induction Further investigations into the roles of SCT and novel agents are needed Petrich AM, et al., Blood. 2014;124(15):

25 GRAY ZONE LYMPHOMA (GZL) Features intermediate between chl and DLBCL Retrospective analysis 100 pts GZL from M:F ratio was 1.5:1 44% mediastinal involvement (MGZL) Younger (37 vs. 50 years, P<0.0001) Stage I/II disease (77% vs. 17%, P=0.0001) Lower IPS (12% 3-7) and IPI scores (12% 3-5) compared with NMGZL (44% IPS 3-7, P=0.0002; and 33% IPI 3-5, P=0.0006) ORR 70%; CRR 58% no significant differences in RR based on treatment At 2y OS 84%, PFS 41% PFS or OS for MGZL did not differ from F/U 25 mo (8-209) Evens AM, et al., Blood 2013, 22: Abstract 847

26 2016 REVISION OF THE WHO CLASSIFICATION Large B-cell lymphoma with IRF4 rearrangement Localised disease, often involves cervical lymph nodes or Waldeyer ring Most common in children and young adults, resembles FL grade 3B or DLBCL Strong IRF4/MUM1 expression, usually with BCL6 and a high proliferative fraction. BCL2 and CD10 expressed in > 50%, with a minority CD5+ Good prognosis EBV+ DLBCL, NOS Newly recognised entity associated with iatrogenic immuno-suppression or age-related immuno-senescence Patients usually >50 years old and have a worse prognosis than Epstein-Barr virus negative (EBV2) tumours Does not include EBV + B-cell lymphomas that can be given a more specific diagnosis EBV + mucocutaneous ulcer 1. Swerdlow SH, et al., Blood :

27 ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL First line treatment: R-CHOP (-like) Patients 60 years IPI low risk (aaipi = 0) and no bulk R-CHOP21 6 Elderly > 60 years IPI low risk (aaipi = 0) with bulk or IPI low-intermediate risk (aaipi = 1) R-ACVBP and consolidation or R-CHOP IF-RT on bulk IPI intermediate-high risk or IPI high risk (aaipi = 2, 3) R-CHOP or R-CHOP14 6 with 8 R Consider more intensive regimens in selected patients: R-CHOEP14 6 or R-CHOP or R-ACVBP plus ASCT Fit, years >80 years without cardiac dysfunction Unfit or frail or >60 years with cardiac dysfunction R-CHOP (6 for IPI low risk) or R-CHOP14 6 with 8 R Attenuated regimens: R-miniCHOP21 6 Doxorubicin substitution with gemcitabine, etoposide or liposomal doxorubicin or others: R-C(X)OP21 6 or palliative care Tilly H, et al., Annals of Oncology 2015

28 DLBCL IN THE OLDER PATIENT EFS RICOVER 60 N=1222 aged But PFS Only 26% >70y and 14% ECOG >1 1=6x CHOP14 2=8x CHOP14 3=6x R-CHOP14 the WINNER 4=8x RCHOP14 OS Reprinted from The Lancet, Oncology 9(2), Pfreudschuh M, et al., Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60), , Copyright 2008, with permission from Elsevier

29 DLBCL IN THE VERY ELDERLY R-miniCHOP (GELA) Single arm Phase II: pts aged 80y ECOG >2 48% N=149 Dose Day Rituximab 375 mg/m 2 1 Cyclophosphamide 400 mg/m 2 1 Vincristine 1mg 1 Doxorubicin 25 mg/m 2 1 Prednisolone 40 mg/m Reprinted from The Lancet Oncology, 12(5), Peyrade F, et al., Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial, , Copyright 2011, with permission from Elsevier

30 FRAIL PATIENT Symptom control Measurable quality of life Single agent chemotherapy Pulsed steroids Involvement of the multidisciplinary team early

31 OVERVIEW OF FIRST LINE DLBCL MANAGEMENT We are getting closer to understanding the distinct biology of the different subtypes of lymphomas R-CHOP remains the standard of care but likely to be R-CHOP+X in certain subgroups We are unlikely to make progress with on size fits all chemotherapy We need to better understand prognostic markers in DLBCL in order to better target therapies and trial design

32 Time to progression RELAPSED DLBCL DLBCL DLBCL PFS 2 Limited stage R-CHOP Rituximab-CHOP widely accepted 1 st line regimen All Advanced stage Cured Relapse Refractory 60% 30% 10% RR-DLBCL Time (years) Most relapses < 2 years after therapy 7% relapses > 5 years after therapy Usually symptomatic no place routine imaging Life expectancy (if left untreated): 3 4 months 3 1. Perry AR, et al., Ann Oncol Sehn L, et al., Blood 2015;125: Pfreundschuh M, et al., Lancet Oncol 2006

33 REL/REF DLBCL: A HETEROGENOUS POPULATION OS according to response or time to failure after diagnosis n=7400 patients years old Coiffier B. Ann Oncol 2008;Suppl 4:iv [oral communication; ICML Lugano 2008, abstract 001]. Courtesy of Dr Coiffier

34 TREATMENT ALGORITHM FOR DLBCL Aggressive non-hodgkin Lymphoma First-line treatment First Line Cure n=200 First Relapse n=100 Transplant Eligible n=50 n=50 Transplant Ineligible Response to salvage No Response to n=25 therapy salvage therapy n=25 Proceed to ASCT Second Line Cure Not Cured Relapsed/Refractory n=25 n=50 Relapsed/Refractory n=10 n=15 Third Line 3rd line salvage ASCT=Autologous Stem cell transplantation n=90 Adapted from: Friedberg JW. Hematology Am Soc Hematol Educ Program. 2011;2011:

35 FACTORS TO CONSIDER IN TREATMENT DECISIONS Subtype and histology Comorbidities GCB vs. ABC? Double hit vs. myc-negative Neuropathy, diabetes Renal or liver failure Heart, lung, liver disease Previous therapies, responses and duration of response Functional status, Frailty Comprehensive Geriatric assessment Charlson Comorbidity Index Patient preferences (side effects, hospitalisation)

36 ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL First relapse/progress Eligible for transplant Platinum-based chemotherapy regimens (i.e. R-DHAP, R-ICE, RGDP) as salvage treatment For chemosensitive patients: R-HDCT with ASCT as remission consolidation Consider allogeneic transplantation in patients relapsed after R- HDCT with ASCT Not eligible for transplant Platinum- and/or gemcitabinebased regimens Clinical trials with novel drugs or in patients with poor-risk factors at relapse R, rituximab; HDCT, high-dose chemotherapy; ASCT, autologous stem-cell transplantation; DHAP, cisplatin, cytarabine, dexamethasone; ICE, ifosfamide, carboplatin, etoposide; GDP, cisplatin, gemcitabine, dexamethasone Tilly H, et al., Annals of Oncology 2015

37 RR-DLBCL: ELIGIBLE FOR HDCT-ASCT CORAL no 50% 3-yr EFS 30% Maintenance no benefit Event-free survival by duration of response and prior rituximab Standard salvage regimen does not overcome poor prognosis of early relapse Gisselbrecht C, et al., Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era. J Clin Oncol 2010;28(27): Reprinted with permission American Society of Clinical Oncology. All rights reserved

38 BIO-CORAL: GCB VS. NON-GCB (BY IHC) Outcome by Cell of Origin Cell of origin remains a major and independent factor in RR-DLBC Response to R-DHAP: better in GCB-like DLBCL Thieblemont C, et al., The Germinal Center/Activated B-Cell Subclassification Has a Prognostic Impact for Response to Salvage Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Bio-CORAL Study. J Clin Oncol 2011;29 (31) : Reprinted with permission American Society of Clinical Oncology. All rights reserved

39 BIO-CORAL: MYC TRANSLOCATION Progression free survival Overall survival Time (months) 18% 42% MYC p= Time (months) MYC- MYC- 29% MYC % p= MYC positive 17% R-DHAP/R-ICE no difference Cuccuini W, et al., Blood 2012;119(20):

40 CORAL: PREDICTIVE VALUE OF PET-CT PRE TRANSPLANT FDG-PET - FDG-PET+ P-value N= BEAM ORR (CR) 60 (53) 30(5) RR CT 98% (CI %) 50% (CI 37-63%) 3y 40% 16% < y 43% 28% 3y 66% 49% <0.007 FDG-PET + pts transplanted EFS p=0.03, PFS and OS p=ns Factors affecting RR, EFS and PFS in multivariate analysis were early relapse/refractory < 12 months and PET+ve following induction Trneny M, et al., Blood : Abstract 881

41 WHO SHOULD BE CONSIDERED FOR AN ALLO-SCT DLBCL Failing R-Chemo Auto SCT REMAINS the standard therapy However high risk of failure in some patients: High secondary aaipi Time to relapse < 12 months PET+ve post salvage Myc+? ABC subtype? Double Hit lymphomas? Clinical studies required to assess efficacy of allosct in this setting

42 TREATMENT ALGORITHM FOR DLBCL Aggressive non-hodgkin Lymphoma First-line treatment First Line Cure n=200 First Relapse n=100 Transplant Eligible n=50 n=50 Transplant Ineligible Response to salvage No Response to n=25 therapy salvage therapy n=25 Proceed to ASCT Second Line Cure Not Cured Relapsed/Refractory n=25 n=50 Relapsed/Refractory n=10 n=15 Third Line 3rd line salvage ASCT=Autologous Stem cell transplantation n=90 Adapted from: Friedberg JW. Hematology Am Soc Hematol Educ Program. 2011;2011:

43 RR-DLBCL PATIENTS INELIGIBLE FOR ASCT Which assessment criteria? 1,2 Patients with severe concomitant medical or psychiatric illness Active central nervous system involvement HIV seropositivity Bilirubin level>2 mg/dl Creatinin level>1.5 mg/dl LVEF*<50% FEV** in 1 sec <50% and/or carbon monoxide diffusion test <50% * Low cardiac ejection fraction ** Forced expiratory volume 1. Majhail NS, et al., Biol Blood Marrow Transplant Rodriguez J, et al., Ann Oncol 2004

44 ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL First relapse/progress Eligible for transplant Platinum-based chemotherapy regimens (i.e. R-DHAP, R-ICE, RGDP) as salvage treatment For chemosensitive patients: R-HDCT with ASCT as remission consolidation Consider allogeneic transplantation in patients relapsed after R- HDCT with ASCT Not eligible for transplant Platinum- and/or gemcitabinebased regimens Clinical trials with novel drugs or in patients with poor-risk factors at relapse R, rituximab; HDCT, high-dose chemotherapy; ASCT, autologous stem-cell transplantation; DHAP, cisplatin, cytarabine, dexamethasone; ICE, ifosfamide, carboplatin, etoposide; GDP, cisplatin, gemcitabine, dexamethasone Tilly H, et al., Annals of Oncology 2015

45 SECOND LINE THERAPY: TRANSPLANT INELIGIBLE No standard Regimen PECC prednisone, etoposide, chlorambucil, lomustin +/- R CEPP cyclophosphamide, etoposide, prednisone, procarbazine +/- R CEOP cyclophosphamide, etoposide, vincristine, prednisone +/- R GDP gemcitabine, dexamethasone, carboplatin +/- R GemOX gemcitabine, oxaliplatin +/- R Lenalidomide +/- R Bendamustine +/- R Palliative RT Gisselbrecht C, et al., Br J Haematol 2008

46 % R-GEMOX IN RR DLBCL PATIENTS Phase II multicenter study 49 patients (median age: 69 years) with refractory (n=6) or relapsing (n=43) DLBCL Prior treatment included rituximab in 31 (63%) and autologous transplantation in 17 (35%) patients IPI at enrollment was >2 in 34 patients (71%) Primary endpoint: ORR after four cycles of treatment OS and PFS in patients treated with R-GemOx OS PFS Months Mounier N, et al., Haematologica 2013

47 TREATMENT ALGORITHM FOR DLBCL Aggressive non-hodgkin Lymphoma First-line treatment First Line Cure n=200 First Relapse n=100 Transplant Eligible n=50 n=50 Transplant Ineligible Response to salvage No Response to n=25 therapy salvage therapy n=25 Proceed to ASCT Second Line Cure Not Cured Relapsed/Refractory n=25 n=50 Relapsed/Refractory n=10 n=15 Third Line 3rd line salvage ASCT=Autologous Stem cell transplantation n=90 Adapted from: Friedberg JW. Hematology Am Soc Hematol Educ Program. 2011;2011:

48 ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL > 2nd relapse/progress Eligible for transplant Allogeneic transplantation Clinical trials with novel drugs Not eligible for transplant Clinical trials with novel drugs Palliative care Tilly H, et al., Annals of Oncology 2015

49 Probability >2 ND RELAPSE DLBCL PATIENTS ELIGIBLE FOR ALLO-SCT Patients eligible for a second transplant: very limited number N=101 patients Over 10 years in EU by EBMT (European Group for Blood and Marrow Transplantation) Time after Allo-SCT (months) Van Kampen RJ, et al., Allogeneic Stem-Cell Transplantation As Salvage Therapy for Patients With Diffuse Large B-Cell Non-Hodgkin's Lymphoma Relapsing After an Autologous Stem-Cell Transplantation: An Analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 2011;29(10): Reprinted with permission. (Year of publication being used) American Society of Clinical Oncology. All rights reserved.

50 SINGLE-AGENT THERAPY IN R/R NHL OR DLBCL (NOT A COMPARATIVE TRIAL) Ref Regimen Type of lymphoma No. of patients No. of previous lines chemo PFS (months) TTP*, EFS**, median time from last treatment, FFS CR/CRu (%) 1 Gemcitabine R/R a-nhl for responders* Rituximab R/R a-nhl ** Lenalidomide R/R a-nhl R/R a-dlbcl Lenalidomide R/R a-nhl Bendamustine R/R a-nhl Ibrutinib (ABC) DLBCL ABC DLBCL Bortezomib R/R NHL (excl. MCL) % at 6 months*** Oxaliplatin R/R NHL R/R a-nhl Pixantrone R/R a-nhl ***Patients % CR=Complete Response; CRu=Complete Response Unconfirmed; DLBCL=Diffuse Large B-Cell Lymphoma; OR=Overall Response; R/R= Relapsed/Refractory; 1. Fossa SD, et al., J Clin Oncol. 1999;17(12): Rothe A, et al., Haematologica 2004;89(7): Witzig TE, et al., Ann Oncol. 2011;22 (7): Wiernik PH, et al., Lenalidomide Monotherapy in Relapsed or Refractory Aggressive Non-Hodgkin s Lymphoma (2008), J Clin Oncol. 5.Weidmann E, et al., Ann Oncol. 2002;13(8): Wilson WH, et al., Nat Med. 2015;21(8): Goy A, et al., J Clin Oncol. 2005;23(4): Oki M, et al., Cancer. 2005;15;104(4): Pettengell R, et al., Lancet Oncol. 2012;13(7): OR (%)

51 RITUXIMAB AND OTHER SALVAGE REGIMENS FOR RR-DLBCL PATIENTS Regimen Disease status n ORR/CR Survival Reference R-GEM High grade B-NHL (64-78 years) 7 71%/29% Median PFS and OS, 10 and 11 months, Wenger et al R-GEMOX Aggressive NH 46 74%/72% 2-year EFS 43%, 2-year OS 66% El Gnaoui et al R-GIFOX Aggressive NHL 13 77%/54% Median FFS 80% Corazzelli et al GaRD Aggressive NHL 19 79%/42% Cabanillas et al GaRD Aggressive B-NH 22 55%/27% Smith et al R + Bendamustine DLBCL 34 20%/12% PFS 0-3 months Rigacci et al R + E DLBCL 15 47%/33% (CR/CRu) Median PFS 6 months Strauss et al R-CMD DLBCL (65 79 years) 30 74%/57% (CR/CRu) 2-year OS 45%, PFS 37% Niitsu et al R-TTP Aggressive NHL 71 (32 primary refractory) 70%25% primary Median DR 21 months Younes et al R-TTP B-cell lymphoma 10 60%/30% Canales et al DLBCL R-ADOX (heavily pre-treated) 20 70%/25% Median OS 11 months Woehrer et al CMD: irinotecan, mitoxantrone, dexamethasone; TTP: paclitaxel, topotecan; E: epratuzumab

52 PD1/PD-L1 IN DLBCL PD-L1 + and mpd-l1 + expression in DLBCL were 11% and 15.3%, respectively More frequent in non-gcb type and EBV + PD-L1 + DLBCL had inferior OS (p=0.0009) Anti PD1: nivolumab, pembrolizumab, avelumab Anti PD-L1: durvalumab, atezoluimumab Nivolumab ORR DLBCL 36% (n=11, median DOR 22 weeks) Kiyasu J, et al., Blood Nov 5; 126(19): Lesokhin AM, et al., J Clin Oncol 2016;34:2698

53 GCB ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC Change in tumour SPD (%) Subject #, DLBCL subtype BTK INHIBITION IN DLBCL ONO/GS-4509 in 17 DLBCL pts (A) Waterfall plot by dose (B) by CT imaging 80 mg 160 mg 320 mg 480 mg 600 mg 240 mg bid *Ongoing patients. Walter HS, et al., Blood 2016;127:411 9 Subject #, DLBCL subtype Plasmablastic Plasmablastic MLBCL ABC ABC GCB ABC ABC GCB ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC ABC * * Duration of treatment (weeks)

54 OVERVIEW REL/REF DLBCL Relapsed DLBCL Poor prognosis Clinical trials and palliation Intensive Salvage Therapy AutoSCT remains the standard of care Salvage induction and relapse prevention require improvement Role of allosct in selected high risk patients? Checkpoint inhibition Relapse after AutoSCT Clinical Trials and palliation AlloSCT (including cord and haplo donors) should be actively considered Checkpoint inhibition Refractory Outcomes poor with all approaches including novel therapies

55 CONCLUSIONS DLBCL is the most common NHL Outcome of DLBCL improved with addition of rituximab to CHOP Patients who fail R-CHOP have a dismal outcome Selectivity of targeted agents underlines the importance of molecular subtyping at relapse Plethora of new agents, but studies generally include very few patients with DLBCL Novel therapies are warranted

56 THANK YOU!