MODERN MANAGEMENT OF DLBCL

Ruth Pettengell St George’s University of London 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 2012. Fourth edition; Image By Nephron (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0) DLBCL

Presentation De novo or after transformation: follicular lymphoma, CLL/SLL1

Percent of New Cases by Age Group: NHL  Incidence in Europe SEER 18 2009-2013, All Races, Both Sexes5 2  3.8/100 000/year 30 3  Increases with age 24.3 25 21.5  Median age at diagnosis 64 years 21.0 20 4  Risk factors 15 12.7  Family history 9.4 10  Autoimmune disease Newcases (%) 5.7 5 3.7  HIV+ 1.6 0  Hepatitis C Virus+

1. Raut LS, et al., South Asian J Cancer 2014 2. Sant M, et al., Blood 2010 Age 3. Tilly H, et al., Ann Oncol 2015 4. Morton LM, et al., J Natl Cancer Inst Monogr 2014 5. From the website of the National Cancer Institute (https://www.cancer.gov) 2016 REVISION OF THE WHO CLASSIFICATION

DLBCL: Cell of Origin

 Common somatic mutations: inactivating mutations of TP53, genes in immuno- surveillance (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 -based therapies

1. Swerdlow SH, et al., Blood 2016 127:2375-2390 Hans CP, Rosenwald Copyright © (2002) Society. Reprinted Massachusetts Society;Medical Massachusetts with from Medical permission 2002, NEJMFrom Rosenwald A, MOLECULAR SUBTYPES MOLECULAR IMPORTANCEOF CELL et al., A, et al., Blood 2004;103:275 J. Exp Med Med 2003 198,851 et al., - 282

The Use of Molecular Profiling to Predict Survival after after The Chemotherapy to Use of Survival Predict Molecular Profiling for Large Diffuse OS 0.2 0.4 0.6 0.8 1.0 0 - 862. copyright 2003, with from Press;the Rockefeller permission University 0 2 4 - 6 OF - 8 ORIGIN 10 CD10 ABC DLBCL GCB DLBCL PMBL subgroup DLBCL – + Bcl Hans - GCB B - - 6 Cell Lymphoma; 346: 1937 – + 5 - Yr OS, OS, Yr classification 30 59 64 % MUM1 Non - GCB – + - 47. Non GCB - GCB LUGANO CLASSIFICATION

Staging1

 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 1  PET/CT more accurate especially in CRu or PR and extranodal disease 2  Plan for minimum of 3 weeks preferably 6-8 weeks post chemo , 3 months post- radiotherapy3

1. Adams HJA, et al., EJNMMI 2014; 41: 565-574 2. Juweid ME, et al., J Clin Onc 2007;21: 571-8 3. Boellaard R, et al., Eur J Nuc Med Mol Imaging 2010;37:181-200 DLBCL PROGNOSIS

Overall Survival according to age and time period Events occur early….

1989–20071 2005–20102

1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4

Net survival Net survival Net

15:45 15:45 0.2 45:55 0.2 45:55 55:65 55:65 65:75 65:75 75:++ 75:++ 0 0 0 2 4 6 8 10 0 1 2 3 4 5 Time since diagnosis (years) Time since diagnosis (years)

1. Monnereau A, et al., Survie des personnes atteintes de cancer en France 1989-2007. 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 CD20 MONOCLONAL

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):3705–14, copyright 2010; permission conveyed through Copyright Clearance Center, Inc. PROGNOSTIC SCORES

NCCN-IPI1 Score Age, y >40 to ≤60 1 IPI2 Score >60 to ≤75 2 >75 3 Age > 60 y ? LDH, normalised LDH > 1x normal ? >1 to ≤3 1 Stage III-IV 1 >3 2 > 1 extranodal lesion 1 Ann Arbor stage III-IV 1 Performance status ≥2 1 Extranodal disease* 1 IPI Score Performance status ≥2 1 IPI Score Overall survival2 1.00 L (0,1) 100 LI (2,3) 0.75 75 L (0,1) HI (4,5) LI (2) 0.50 50 HI (3)

H (>6) Survival (%) Survival 0.25 (%) Patients 25 H (4) NCCN-IPI 0 0 0 1 2 3 4 5 0 2 4 6 8 10

1. Zhou Z, et al., Blood 2014;123:827-842 2. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 1993;329:987–99 TREATMENT ALGORITHM FOR DLBCL

Aggressive non-Hodgkin Lymphoma

First-line treatment First Line

Cure First Relapse n=100 n=200

Transplant Eligible n=50 n=50 Transplant Ineligible

Second Line

Response to salvage No Response to n=25 therapy salvage therapy n=25 Proceed to ASCT

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;2011:498–505. 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;25:2997-3004. Reprinted with permission. © 2016, American Society of Clinical Oncology. All rights reserved ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL

First line treatment: R-CHOP (-like) Patients ≤ 60 years IPI low risk (aaIPI = 0) with bulk or IPI intermediate-high risk or IPI high risk (aaIPI = IPI low risk (aaIPI = 0) and no bulk IPI low-intermediate risk (aaIPI = 1) 2, 3) R-CHOP21 × 6–8 or R-CHOP14 × 6 with 8 R R-ACVBP and consolidation Consider more intensive regimens in selected R-CHOP21 × 6 or patients: R-CHOP21 × 6 + IF-RT on bulk R-CHOEP14 × 6 or R-CHOP or R-ACVBP plus ASCT Elderly > 60 years Fit, 60–80 years >80 years without cardiac dysfunction Unfit or frail or >60 years with cardiac dysfunction substitution with gemcitabine, R-CHOP21 × 6–8 (6 for IPI low risk) etoposide or liposomal doxorubicin or others: Attenuated regimens: or R-miniCHOP21 × 6 R-C(X)OP21 × 6 R-CHOP14 × 6 with 8 R or palliative care

Tilly H, et al., Ann Oncol 2015;26 Suppl 5:v116–2 YOUNG PATIENTS (<60 YEARS)

EFS PFS OS

0 24 48 72 96 120 0 24 48 72 96 120 0 24 48 72 96 120 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 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, 1013–22, copyright 2010 with permission from Elsevier 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;381:1817–26 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, 1858-1867, Copyright 2011, with permission from Elsevier ONGOING APPROACHES TO INTENSIFICATION CALBG R-CHOP vs. DA-EPOCH-R

R-CHOP R-EPOCH G4 neutropenia 90% 56% G4 thrombocytopenia 35% 6% G 3/4 FN 37% 19% G3 neuropathy Motor 8% Motor 1% Sensory 15% Sensory 3%

 524 patients, 2005 to 2013

 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%

 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 2016 128:469 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 relapse1 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 IPI2

1. Bernstein SH, et al., J Clin Oncol 2009;27(1):114-9 2. 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):3150–6. Reprinted with permission. © 2016 American Society of Clinical Oncology. All rights reserved. CAPITALISING ON BIOLOGIC INSIGHTS Cell cycle regulation If we can get the biomarkers right we p53 p16 can identify patients that may benefit p27 from intensification or specific Cyclin D2 targeted therapies 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 R-CHOP TREATED PATIENTS IN LUNENBURG Overall survival in Lunenburg analysis

BCL 2 BCL 6 1.00 1.00 0.75 0.75 0.50 0.50

Probability 0.25 0.25 0.00 0.00 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 No staining (0–5%) 5–25% 26–50% No staining Weak / Variable weak 51–75% >75% Strong / Variable strong

CD 5 Ki 67 1.00 1.00 0.75 0.75 0.50 0.50

Probability 0.25 0.25 0.00 0.00 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Years since treatment initiation Years since treatment initiation No staining 1–75% >75% 1–25% 26–50% 51–75% >75%

Salles G, et al., Blood 2011;117:7070-7078 R-CHOP PLUS IBRUTINIB

 No difference according to cell of origin

 No dose dependant response

280mg 420mg 560mg Combined (n=7) (n=4) (n=21) (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 0 0 0 0 PD 0 0 0 0 NE 1(14%) 0 1(5%) 2(6%)

Younes A, et al., Lancet Oncology 2014 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):251–7. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved. 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 DLBCL, NOS BCL2 and/or BCL6R

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 2016 127:2375-2390 MYC AND DUAL TRANSLOCATION

MYC+- BCL2+ MYC+- IG loci+

Only MYC+- BCL2+ protein expression MYC+- IG loci+ predicts poor PFS predicts inferior PFS and OS (p<0.001) (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, Republished with permission of The American Society of Doxorubicin, , and Prednisone Hematology, from Blood, Copie-Bergman C, et al., 126(22):2466– J Clin Oncol 2012; 30:3452-3459. Reprinted with permission. 74, © 2015; permission conveyed through Copyright Clearance © 2012 American Society of Clinical Oncology. All rights reserved. Center, Inc IMPACT OF MYC STATUS IN DLBCL

R-CHOP (N=63) R-Hyper CVAD (N=38) 100 DA-EPOCH-R (N=57) Variable Risk factor p value R-CODOX-M/IVAC (N=41) Age ≥60 0.003 80 Other/multiple (N=24) ECOG PS 2-4 0.001 3 60 WBC ≥10 <0.001 Albumin <4 0.001 40 LDH >3x ULN 0.011

PFS (probability) PFS 20 B symptoms Present 0.019 Log rank p=0.0016 Extranodal disease >1 site 0.014 0 Ann Arbor Stage 3-4 0.001 0 25 50 75 100 125 Bone marrow involvement Positive <0.001 Time from diagnosis (months) CNS involvement Present <0.001 Multivariate analysis R-CHOP (N=100) WBC ≥103 0.05 R-Hyper CVAD (N=65) 100 LDH >3x ULN 0.05 DA-EPOCH-R (N=64) Ann Arbor Stage 3-4 0.014 80 R-CODOX-M/IVAC (N=42) Other/multiple (N=24) CNS involvement Present 0.011 60 Key points 40 DHL represents A subset of DHL patients may be cured, and some OS (probability) OS 20 an unmet patients may benefit from intensive induction Log rank p=0.119 0 medical need Further investigations into the roles of SCT and 0 25 50 75 100 125 novel agents are needed Time from diagnosis (months)

Petrich AM, et al., Blood. 2014;124(15):2354-61 GRAY ZONE LYMPHOMA (GZL)

Features intermediate between cHL and DLBCL

Retrospective analysis 100 pts GZL from 2001-2012

 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 NMGZL @median F/U 25 mo (8-209)

Evens AM, et al., Blood 2013, 22: Abstract 847 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 2016 127:2375-2390 ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL

First line treatment: R-CHOP (-like) Patients ≤ 60 years IPI low risk (aaIPI = 0) with bulk or IPI intermediate-high risk or IPI high risk (aaIPI = IPI low risk (aaIPI = 0) and no bulk IPI low-intermediate risk (aaIPI = 1) 2, 3) R-CHOP21 × 6–8 or R-CHOP14 × 6 with 8 R R-ACVBP and consolidation Consider more intensive regimens in selected R-CHOP21 × 6 or patients: R-CHOP21 × 6 + IF-RT on bulk R-CHOEP14 × 6 or R-CHOP or R-ACVBP plus ASCT Elderly > 60 years Fit, 60–80 years >80 years without cardiac dysfunction Unfit or frail or >60 years with cardiac dysfunction Doxorubicin substitution with gemcitabine, R-CHOP21 × 6–8 (6 for IPI low risk) etoposide or liposomal doxorubicin or others: Attenuated regimens: or R-miniCHOP21 × 6 R-C(X)OP21 × 6 R-CHOP14 × 6 with 8 R or palliative care

Tilly H, et al., Annals of Oncology 2015 DLBCL IN THE OLDER PATIENT EFS

RICOVER 60

N=1222 aged 61-81 PFS But

Only 26% >70y and 14% ECOG >1

1=6x CHOP14 2=8x CHOP14 OS 3=6x R-CHOP14 – the WINNER 4=8x RCHOP14

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), 105–16, Copyright 2008, with permission from Elsevier 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/m2 1 Cyclophosphamide 400 mg/m2 1 Vincristine 1mg 1 Doxorubicin 25 mg/m2 1 Prednisolone 40 mg/m2 1-5

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, 460–8., Copyright 2011, with permission from Elsevier FRAIL PATIENT

 Symptom control

 Measurable quality of life

 Single agent chemotherapy

 Pulsed steroids

 Involvement of the multidisciplinary team early 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 RELAPSED DLBCL

DLBCL PFS2 1.0 DLBCL Limited stage 0.8

Rituximab-CHOP 0.6 All R-CHOP widely accepted st 1 Advanced stage 1 line regimen 0.4

Time to progression to Time 0.2 Cured Relapse Refractory 0.0 ≈ 60% ≈ 30% ≈ 10% 0 2 4 6 8 10 Time (years) RR-DLBCL  Most relapses < 2 years after therapy

 7% relapses > 5 years after therapy

 Usually symptomatic → no place routine imaging 3  Life expectancy (if left untreated): ≈ 3–4 months

1. Perry AR, et al., Ann Oncol 1998 2. Sehn L, et al., Blood 2015;125:22–32 3. Pfreundschuh M, et al., Lancet Oncol 2006 REL/REF DLBCL: A HETEROGENOUS POPULATION OS according to response or time to failure after diagnosis

n=7400 patients 18–80 years old

Coiffier B. Ann Oncol 2008;Suppl 4:iv31–296 [oral communication; ICML Lugano 2008, abstract 001]. Courtesy of Dr Coiffier TREATMENT ALGORITHM FOR DLBCL

Aggressive non-Hodgkin Lymphoma

First-line treatment First Line

Cure First Relapse n=100 n=200

Transplant Eligible n=50 n=50 Transplant Ineligible

Second Line

Response to salvage No Response to n=25 therapy salvage therapy n=25 Proceed to ASCT

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;2011:498–505. FACTORS TO CONSIDER IN TREATMENT DECISIONS

Subtype and histology

 GCB vs. ABC?

 Double hit vs. myc-negative Comorbidities

 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) ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL

First relapse/progress Eligible for transplant Not 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 Platinum- and/or gemcitabine- consolidation based regimens Consider allogeneic transplantation in patients relapsed after R- Clinical trials with novel drugs HDCT with ASCT 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 RR-DLBCL: ELIGIBLE FOR HDCT-ASCT no ∆ 50% 3-yr EFS 30% CORAL

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):4184–90. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved 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) :4079–87. Reprinted with permission. © 2011 American Society of Clinical Oncology. All rights reserved BIO-CORAL: MYC TRANSLOCATION

Progression free survival Overall survival

1.0 1.0

0.8 0.8

0.6 0.6 MYC- MYC- 62% 42% 0.4 0.4 29% p=0.0113 18% p=0.0322 0.2 0.2 MYC+ MYC+ 0.0 0.0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Time (months) Time (months)

MYC positive 17% R-DHAP/R-ICE no difference

Cuccuini W, et al., Blood 2012;119(20):4619–24 CORAL: PREDICTIVE VALUE OF PET-CT PRE TRANSPLANT

FDG-PET - FDG-PET+ P-value N=123 61 62 BEAM 50 26 ORR (CR) 60 (53) 30(5) RR CT 98% 50% (CI 91-100%) (CI 37-63%) EFS @ 3y 40% 16% <0.0001 PFS @ 3y 43% 28% OS @ 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 2009 114: Abstract 881 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 Clinical studies required to assess efficacy of  Myc+? alloSCT in this setting  ABC subtype?

 “Double Hit” lymphomas? TREATMENT ALGORITHM FOR DLBCL

Aggressive non-Hodgkin Lymphoma

First-line treatment First Line

Cure First Relapse n=100 n=200

Transplant Eligible n=50 n=50 Transplant Ineligible

Second Line

Response to salvage No Response to n=25 therapy salvage therapy n=25 Proceed to ASCT

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;2011:498–505. RR-DLBCL PATIENTS INELIGIBLE FOR ASCT

1,2  Which assessment criteria?

 Patients with severe  Bilirubin level>2 mg/dL

concomitant medical or  Creatinin level>1.5 mg/dl psychiatric illness  LVEF*<50%  Active central nervous  FEV** in 1 sec <50% system involvement and/or carbon monoxide  HIV seropositivity diffusion test <50%

* Low cardiac ejection fraction ** Forced expiratory volume

1. Majhail NS, et al., Biol Blood Marrow Transplant 2015 2. Rodriguez J, et al., Ann Oncol 2004 ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL

First relapse/progress Eligible for transplant Not 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 Platinum- and/or gemcitabine- consolidation based regimens Consider allogeneic transplantation in patients relapsed after R- Clinical trials with novel drugs HDCT with ASCT 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 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 R-GEMOX IN RR DLBCL PATIENTS

 Phase II multicenter study OS and PFS in patients treated

 49 patients (median age: 69 with R-GemOx years) with refractory (n=6) 1.0 or relapsing (n=43) DLBCL 0.8  Prior treatment included rituximab in 31 (63%) and 0.6

autologous transplantation % 0.4 in 17 (35%) patients OS 0.2  IPI at enrollment was >2 PFS in 34 patients (71%) 0.0

 Primary endpoint: ORR after four 0 12 24 36 48 60 72 84 cycles of treatment Months

Mounier N, et al., Haematologica 2013 TREATMENT ALGORITHM FOR DLBCL

Aggressive non-Hodgkin Lymphoma

First-line treatment First Line

Cure First Relapse n=100 n=200

Transplant Eligible n=50 n=50 Transplant Ineligible

Second Line

Response to salvage No Response to n=25 therapy salvage therapy n=25 Proceed to ASCT

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;2011:498–505. ESMO CLINICAL PRACTICE GUIDELINES: RECOMMENDED TREATMENT STRATEGIES IN DLBCL

> 2nd relapse/progress Eligible for transplant Not eligible for transplant Allogeneic transplantation Clinical trials with novel drugs Clinical trials with novel drugs Palliative care

Tilly H, et al., Annals of Oncology 2015 >2ND 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) Probability

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):1342–8. Reprinted with permission. © (Year of publication being used) American Society of Clinical Oncology. All rights reserved. SINGLE-AGENT THERAPY IN R/R NHL OR DLBCL (NOT A COMPARATIVE TRIAL)

Ref Regimen Type of lymphoma No. of No. of previous PFS (months) CR/CRu OR TTP*, EFS**, median time patients lines chemo from last treatment†, FFS‡ (%) (%) 1 Gemcitabine R/R a-NHL 30 1-3 6 for responders* 0 20 2 Rituximab R/R a-NHL 21 ≥ 1 3.8** 5 38 3 Lenalidomide R/R a-NHL 217 3 3.7 13 35 R/R a-DLBCL 108 3 2.7 7 28 4 Lenalidomide R/R a-NHL 49 4 4.0 12 35 5 Bendamustine R/R a-NHL 18 2 3.5 17 44 6 Ibrutinib (ABC) DLBCL 80 3 1.6 10 25 ABC DLBCL 38 3 2.0 16 37 7 Bortezomib R/R NHL (excl. MCL) 21 4 36% at 6 months*** 5 19 8 Oxaliplatin R/R NHL 30 1-3 3† 7 27 R/R a-NHL 22 1-3 2.1‡ 9 32 9 Pixantrone R/R a-NHL 70 3 5.3 20 37

***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):3786-3792. 2. Rothe A, et al., Haematologica 2004;89(7):875-876. 3. Witzig TE, et al., Ann Oncol. 2011;22 (7):1622-1627. 4 .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):1285-1289. 6.Wilson WH, et al., Nat Med. 2015;21(8):922-6. 7. Goy A, et al., J Clin Oncol. 2005;23(4):667-675. 8.Oki M, et al., Cancer. 2005;15;104(4):781-7. 9. Pettengell R, et al., Lancet Oncol. 2012;13(7):696-706. RITUXIMAB AND OTHER SALVAGE REGIMENS FOR RR-DLBCL PATIENTS

Regimen Disease status n ORR/CR Survival Reference High grade B-NHL Median PFS and OS, R-GEM 7 71%/29% Wenger et al. 2005 (64-78 years) 10 and 11 months, 2-year EFS 43%, R-GEMOX Aggressive NH 46 74%/72% El Gnaoui et al. 2007 2-year OS 66% R-GIFOX Aggressive NHL 13 77%/54% Median FFS 80% Corazzelli et al. 2006 GaRD Aggressive NHL 19 79%/42% Cabanillas et al. 2006 GaRD Aggressive B-NH 22 55%/27% Smith et al. 2006 R + DLBCL 34 20%/12% PFS 0-3 months Rigacci et al. 2012 Bendamustine

47%/33% Median PFS 6 months R + E DLBCL 15 Strauss et al. 2006 (CR/CRu) DLBCL 74%/57% 2-year OS 45%, R-CMD 30 Niitsu et al. 2006 (65–79 years) (CR/CRu) PFS 37% 71 (32 primary 70%25% R-TTP Aggressive NHL Median DR 21 months Younes et al. 2005 refractory) primary R-TTP B-cell lymphoma 10 60%/30% Canales et al. 2005 DLBCL R-ADOX 20 70%/25% Median OS 11 months Woehrer et al. 2005 (heavily pre-treated)

CMD: irinotecan, mitoxantrone, dexamethasone; TTP: paclitaxel, topotecan; E: epratuzumab 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. 2015 Nov 5; 126(19): 2193–2201 Lesokhin AM, et al., J Clin Oncol 2016;34:2698 BTK INHIBITION IN DLBCL

101108 Plasma- 101123 blastic  ONO/GS-4509 in 17 DLBCL pts 101130 MLBCL 101144 ABC (A) Waterfall plot by dose 101152 ABC 101157 GCB (B) by CT imaging 101159 ABC 101167 ABC 102140 GCB 80 mg 160 mg 320 mg 102145 ABC 103119 ABC 480 mg 600 mg 240 mg bid 103132 ABC 103134 ABC 103149 ABC 103153 ABC 103155 ABC 40 201120 ABC 201121 ABC 20 201122 ABC 201131 ABC 201146 ABC -20 201147 ABC 201148 ABC -40 subtype #, DLBCL Subject 201151 ABC -60 201168 ABC 201171 ABC * -80 202124 ABC *

202135 ABC Change in tumour (%) tumour in SPD Change

- 202137 ABC

blastic 202150 ABC Plasma 202158 ABC

202169 ABC

113 ABC 113

119 ABC 119

108 108

169 ABC 169 ABC 148 ABC 167 ABC 168 ABC 122 ABC 123 ABC 146 ABC 144 ABC 159 ABC 120 ABC 132 ABC 124 ABC 171

140 140 GCB

-

-

-

------

- 203113 ABC -

203133 ABC

203

103

101

202 201 101 201 201 101 202 101 101 201 103 202 201 102 203143 ABC Subject #, DLBCL subtype 0 10 20 30 40 50 60 70 80 Duration of treatment (weeks) *Ongoing patients. Walter HS, et al., Blood 2016;127:411–9 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 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 THANK YOU!