modern management of dlbcl - oncologypro€¦ · dlbcl prognosis 1989–20071 2005–20102 overall...

MODERN MANAGEMENT OF DLBCL

Ruth Pettengell

St George’s University of London

NHL OVERVIEW

Main B-cell lymphomas distribution

MALT 9%

NHL ≈ 15%

T

≈ 85%

B

DLBCL:

The commonest subtype

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)

Presentation

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

Incidence in Europe

3.8/100 000/year2

Increases with age3

Median age at diagnosis 64 years

Risk factors4

Family history

Autoimmune disease

HIV+

Hepatitis C Virus+

DLBCL

1. Raut LS, et al., South Asian J Cancer 2014

2. Sant M, et al., Blood 2010

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)

1.63.7

5.7

12.7

21.0

24.321.5

9.4

0

5

10

15

20

25

30

New

cas

es (

%)

Age

Percent of New Cases by Age Group: NHL

SEER 18 2009-2013, All Races, Both Sexes5

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 antibody-based therapies

2016 REVISION OF THE WHO

CLASSIFICATION

1. Swerdlow SH, et al., Blood 2016 127:2375-2390

OS

1.0

0.8

0.6

0.4

0.2

0

0 2 4 6 8 10

DLBCL

subgroup

5-Yr OS,

%

PMBL 64

GCB DLBCL 59

ABC DLBCL 30

IMPORTANCE OF CELL-OF-ORIGIN

MOLECULAR SUBTYPES

From NEJM 2002, Rosenwald A, et al., The Use of Molecular Profiling to Predict Survival after Chemotherapy for Diffuse Large-B-Cell Lymphoma; 346: 1937-47.

Copyright © (2002) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society;

Rosenwald A, et al., J. Exp Med 2003 198,851-862. copyright 2003, with permission from the Rockefeller University Press;

Hans CP, et al., Blood 2004;103:275-282

Hans classification

CD10

Bcl-6

GCB

+

– +

–

MUM1

Non-GCB

+

–GCB

Non-GCB

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

PET/CT more accurate especially in CRu or PR and extranodal disease1

Plan for minimum of 3 weeks preferably 6-8 weeks post chemo2, 3 months post-

radiotherapy3

LUGANO CLASSIFICATION

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

1989–20071 2005–20102

Overall Survival according to age and time period

Events occur early….

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

0 2 4 6 8 10

Time since diagnosis (years)

0

0.2

0.4

0.6

0.8

1.0

Net

sur

viva

l

15:4545:5555:6565:7575:++

0 1 2 3 4 5

Time since diagnosis (years)

0

0.2

0.4

0.6

0.8

1.0

Net

sur

viva

l15:4545:5555:6565:7575:++

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

PROGNOSTIC SCORES

NCCN-IPI1 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

IPI2 Score

Age > 60 y ?

LDH > 1x normal ?

Stage III-IV 1

> 1 extranodal lesion 1

Performance status ≥2 1

IPI Score

L (0,1)

LI (2)

HI (3)

H (4)

Overall survival2

25

0

75

100

50

0 4 62 8 10

Pat

ient

s (%

)

L (0,1)

LI (2,3)

HI (4,5)

H (>6)0.25

0

0.75

1.00

0.50

0 2 31 4 5

Sur

viva

l (%

)

NCCN-IPI

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

http://www.bloodjournal.org/content/123/6/837#fn-4

TREATMENT ALGORITHM

FOR DLBCL

n=200

n=100

n=50 n=50

n=25 n=25

n=10 n=15

n=25 n=50

n=90

Adapted from: Friedberg JW. Hematology Am Soc Hematol Educ Program. 2011;2011:498–505.

First-line treatment

Cure First Relapse

Transplant Eligible Transplant Ineligible

Response to salvage

therapy

Proceed to ASCT

No Response to

salvage therapy

Cure Not Cured Relapsed/RefractoryRelapsed/Refractory

≥ 3rd line salvage

Aggressive non-Hodgkin Lymphoma

First Line

Second Line

Third Line

ASCT=Autologous Stem cell transplantation

LIMITED STAGE DISEASE

R-CHOP (3 cycles) plus RT prolonged follow-up

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

PFS

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 bulkIPI low risk (aaIPI = 0) with bulk or

IPI low-intermediate risk (aaIPI = 1)

IPI intermediate-high risk or IPI high risk (aaIPI =

2, 3)

R-CHOP21 × 6

R-ACVBP and consolidation

or

R-CHOP21 × 6 + IF-RT on bulk

R-CHOP21 × 6–8

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

Elderly > 60 years

Fit, 60–80 years >80 years without cardiac dysfunction Unfit or frail or >60 years with cardiac dysfunction

R-CHOP21 × 6–8 (6 for IPI low risk)

or


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

YOUNG PATIENTS (<60 YEARS)

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, 1013–22, copyright 2010 with permission from Elsevier

EFS PFS OS

Months

48 9624 72 1200 48 9624 72 1200 48 9624 72 1200

R-CHOP14 vs. 21: no

difference in outcome

No subgroup identifies

with better outcome

DOSE DENSE CHEMOTHERAPY

IN DLBCL

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 ArmEFS 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

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)

R-CHOP 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%

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)

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.

Risk of CNS relapse according to the CNS IPI2

If we can get the biomarkers right we

can identify patients that may benefit

from intensification or specific

targeted therapies

CAPITALISING ON

BIOLOGIC INSIGHTSCell 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

R-CHOP TREATED PATIENTS

IN LUNENBURG

Overall survival in Lunenburg analysis

Salles G, et al., Blood 2011;117:7070-7078

0.25Pro

babi

lity

0.00

0.75

1.00

1

0.50

0 3 4 5

BCL 2

2

No staining (0–5%) 5–25% 26–50%51–75% >75%

6 7 8

0.25Pro

babi

lity

0.00

0.75

1.00

Years since treatment initiation

1

0.50

0 3 4 5

CD 5

2

No staining 1–75% >75%

6 7 8

0.25

0.00

0.75

1.00

1

0.50

0 3 4 5

BCL 6

2

No staining Weak / Variable weakStrong / Variable strong

6 7 8

0.25

0.00

0.75

1.00

Years since treatment initiation

1

0.50

0 3 4 5

Ki 67

2

1–25% 26–50% >75%51–75%

6 7 8

No difference according to cell of origin

No dose dependant response

R-CHOP PLUS IBRUTINIB

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 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.


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

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

Blastoid BL DLBCL/BL DLBCL

DLBCL, NOS

Morphology

Phenotype and

cytogenetics

Diagnosis B-LBL HGBL, NOS BL HGBL, with MYC and

BCL2 and/or BCL6R

TdT+ TdT-, cyclin D1-

MYC AND DUAL TRANSLOCATION

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; 30:3452-3459. Reprinted with permission.

© 2012 American Society of Clinical Oncology. All rights reserved.

MYC+- IG loci+MYC+- BCL2+

Republished with permission of The American Society of

Hematology, from Blood, Copie-Bergman C, et al., 126(22):2466–

74, © 2015; permission conveyed through Copyright Clearance

Center, Inc

MYC+- IG loci+ predicts poor PFS

(p=0.005) & OS (P=0.0006)

independent from IPI or Hans Classifier

Only MYC+- BCL2+ protein expression

predicts inferior PFS and OS (p<0.001)

IMPACT OF MYC STATUS IN DLBCL

DHL represents

an unmet

medical need

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

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

Variable Risk factor p value

Age ≥60 0.003

ECOG PS 2-4 0.001

WBC ≥103 <0.001

Albumin <4 0.001

LDH >3x ULN 0.011

B symptoms Present 0.019

Extranodal disease >1 site 0.014

Ann Arbor Stage 3-4 0.001

Bone marrow involvement Positive <0.001

CNS involvement Present <0.001

Multivariate analysis

WBC ≥103 0.05

LDH >3x ULN 0.05

Ann Arbor Stage 3-4 0.014

CNS involvement Present 0.011

40

PF

S (

prob

abili

ty)

20

0

80

100

Time from diagnosis (months)

25

60

0 75 100 125

Log rank p=0.0016

50

R-CHOP (N=63)

R-Hyper CVAD (N=38)

DA-EPOCH-R (N=57)

R-CODOX-M/IVAC (N=41)

Other/multiple (N=24)

R-CHOP (N=100)

R-Hyper CVAD (N=65)

DA-EPOCH-R (N=64)

R-CODOX-M/IVAC (N=42)

Other/multiple (N=24)

40

OS

(pr

obab

ility

)

20

0

80

100

Time from diagnosis (months)

25

60

0 75 100 125

Log rank p=0.119

50

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

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


CLASSIFICATION

1. Swerdlow SH, et al., Blood 2016 127:2375-2390



STRATEGIES IN DLBCL

Tilly H, et al., Annals of Oncology 2015

First line treatment: R-CHOP (-like)

Patients ≤ 60 years

IPI low risk (aaIPI = 0) and no bulkIPI low risk (aaIPI = 0) with bulk or

IPI low-intermediate risk (aaIPI = 1)

IPI intermediate-high risk or IPI high risk (aaIPI =

2, 3)

R-CHOP21 × 6

R-ACVBP and consolidation

or

R-CHOP21 × 6 + IF-RT on bulk

R-CHOP21 × 6–8

or


Consider more intensive regimens in selected

patients:

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

R-CHOP21 × 6–8 (6 for IPI low risk)

or


Attenuated regimens:

R-miniCHOP21 × 6

Doxorubicin substitution with gemcitabine,

etoposide or liposomal doxorubicin or others:

R-C(X)OP21 × 6

or

palliative care

DLBCL IN THE OLDER PATIENT

RICOVER 60

N=1222 aged 61-81

But

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

1=6x CHOP14

2=8x CHOP14

3=6x R-CHOP14 – the WINNER

4=8x RCHOP14

EFS

PFS

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), 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

Symptom control

Measurable quality of life

Single agent chemotherapy

Pulsed steroids

Involvement of the multidisciplinary team early

FRAIL PATIENT

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

OVERVIEW OF FIRST LINE DLBCL

MANAGEMENT

RELAPSED DLBCL

Rituximab-CHOP

widely accepted

1st line regimen1

DLBCL

R-CHOP

Cured Relapse Refractory≈ 60% ≈ 30% ≈ 10%

RR-DLBCL 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 months3

DLBCL PFS2

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

0.4

Tim

e to

pro

gres

sion

0.2

0.0

0.8

1.0

Time (years)2

0.6

0 4 6 8 10

Advanced stage

Limited stage

All

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

n=200

n=100

n=50 n=50

n=25 n=25

n=10 n=15

n=25 n=50

n=90



Cure First Relapse


Response to salvage

therapy

Proceed to ASCT

No Response to

salvage therapy




First Line

Second Line

Third Line


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)


GUIDELINES: RECOMMENDED

TREATMENT STRATEGIES IN DLBCL

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

consolidation

Consider allogeneic transplantation in patients relapsed after R-

HDCT with ASCT

or in patients with poor-risk factors at relapse

Platinum- and/or gemcitabine-

based regimens

Clinical trials with novel drugs


First relapse/progress

R, rituximab; HDCT, high-dose chemotherapy; ASCT, autologous stem-cell transplantation; DHAP, cisplatin, cytarabine, dexamethasone;

ICE, ifosfamide, carboplatin, etoposide; GDP, cisplatin, gemcitabine, dexamethasone

RR-DLBCL: ELIGIBLE FOR

HDCT-ASCT

CORAL

Event-free survival by duration of response and prior rituximab

50% 3-yr EFS 30%

Maintenance no

benefit

no ∆

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

Standard salvage regimen

does not overcome poor

prognosis of early relapse

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

Cuccuini W, et al., Blood 2012;119(20):4619–24

MYC positive 17%

R-DHAP/R-ICE no difference

Time (months)

18%

42%

p=0.0322

0.2

0.4

0.6

0.8

1.0

0.0120 24 36 48 60 72

MYC+

MYC-

Progression free survival Overall survival

29%

62%

p=0.0113

Time (months)

0.2

0.4

0.6

0.8

1.0

0.0120 24 36 48 60 72

MYC+

MYC-

CORAL: PREDICTIVE VALUE OF

PET-CT PRE TRANSPLANT

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

FDG-PET - FDG-PET+ P-value

N=123 61 62

BEAM 50 26

ORR (CR) 60 (53) 30(5)

RR CT 98%

(CI 91-100%)

50%

(CI 37-63%)

EFS @ 3y 40% 16% <0.0001

PFS @ 3y 43% 28%

OS @ 3y 66% 49% <0.007

Trneny M, et al., Blood 2009 114: Abstract 881

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?

WHO SHOULD BE CONSIDERED

FOR AN ALLO-SCT

Clinical studies required

to assess efficacy of

alloSCT in this setting

TREATMENT ALGORITHM

FOR DLBCL

n=200

n=100

n=50 n=50

n=25 n=25

n=10 n=15

n=25 n=50

n=90



Cure First Relapse


Response to salvage

therapy

Proceed to ASCT

No Response to

salvage therapy




First Line

Second Line

Third Line


Which assessment criteria?1,2

RR-DLBCL PATIENTS INELIGIBLE

FOR ASCT

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%

1. Majhail NS, et al., Biol Blood Marrow Transplant 2015

2. Rodriguez J, et al., Ann Oncol 2004

* Low cardiac ejection fraction

** Forced expiratory volume



STRATEGIES IN DLBCL

First relapse/progress


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

or in patients with poor-risk factors at relapse

Platinum- and/or gemcitabine-

based regimens


R, rituximab; HDCT, high-dose chemotherapy; ASCT, autologous stem-cell transplantation; DHAP, cisplatin, cytarabine, dexamethasone;

ICE, ifosfamide, carboplatin, etoposide; GDP, cisplatin, gemcitabine, dexamethasone


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

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

R-GEMOX IN RR DLBCL PATIENTS

OS and PFS in patients treated

with R-GemOx

Mounier N, et al., Haematologica 2013

0.4

%0.2

0.0

0.8

1.0

Months

12

0.6

0 24 36 48 60 72 84

OS

PFS

TREATMENT ALGORITHM

FOR DLBCL

n=200

n=100

n=50 n=50

n=25 n=25

n=10 n=15

n=25 n=50

n=90



Cure First Relapse


Response to salvage

therapy

Proceed to ASCT

No Response to

salvage therapy




First Line

Second Line

Third Line



GUIDELINES: RECOMMENDED

TREATMENT STRATEGIES IN DLBCL


Allogeneic transplantation



Palliative care

> 2nd relapse/progress


>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)

Pro

babi

lity

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

patients

No. of previous

lines chemo

PFS (months)TTP*, EFS**, median time

from last treatment†, FFS‡

CR/CRu

(%)

OR

(%)

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

R-GEMHigh grade B-NHL

(64-78 years)7 71%/29%

Median PFS and OS,

10 and 11 months,Wenger et al. 2005

R-GEMOX Aggressive NH 46 74%/72%2-year EFS 43%,

2-year OS 66%El Gnaoui et al. 2007

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 +

BendamustineDLBCL 34 20%/12% PFS 0-3 months Rigacci et al. 2012

R + E DLBCL 1547%/33%

(CR/CRu)

Median PFS 6 monthsStrauss et al. 2006

R-CMDDLBCL

(65–79 years)30

74%/57%

(CR/CRu)

2-year OS 45%,

PFS 37%Niitsu et al. 2006

R-TTP Aggressive NHL71 (32 primary

refractory)

70%25%

primaryMedian DR 21 months Younes et al. 2005

R-TTP B-cell lymphoma 10 60%/30% Canales et al. 2005

R-ADOXDLBCL

(heavily pre-treated)20 70%/25% Median OS 11 months Woehrer et al. 2005

CMD: irinotecan, mitoxantrone, dexamethasone; TTP: paclitaxel, topotecan; E: epratuzumab

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)

PD1/PD-L1 IN DLBCL

Kiyasu J, et al., Blood. 2015 Nov 5; 126(19): 2193–2201

Lesokhin AM, et al., J Clin Oncol 2016;34:2698

ONO/GS-4509 in 17 DLBCL pts

(A) Waterfall plot by dose

(B) by CT imaging

BTK INHIBITION IN DLBCL

*Ongoing patients.Walter HS, et al., Blood 2016;127:411–9

80 mg 160 mg 320 mg

480 mg 600 mg 240 mg bid

-20

Cha

nge

in tu

mou

r S

PD

(%

)

-40

-60

-80

20

40

102-

140

GC

B10

1-10

8

202-

169

AB

C

Pla

sma-

blas

tic

201-

148

AB

C10

1-16

7 A

BC

201-

168

AB

C20

1-12

2 A

BC

101-

123

AB

C20

2-14

6 A

BC

101-

144

AB

C10

3-11

9 A

BC

101-

159

AB

C20

1-12

0 A

BC

103-

132

AB

C20

2-12

4 A

BC

203-

113

AB

C20

1-17

1 A

BC

Subject #, DLBCL subtype

101108101123101130 MLBCL101144 ABC101152 ABC101157 GCB101159 ABC101167 ABC102140 GCB102145 ABC103119 ABC103132 ABC103134 ABC103149 ABC103153 ABC103155 ABC201120 ABC201121 ABC201122 ABC201131 ABC201146 ABC201147 ABC201148 ABC201151 ABC201168 ABC201171 ABC202124 ABC202135 ABC202137 ABC202150 ABC202158 ABC202169 ABC203113 ABC203133 ABC203143 ABC

0 10

Sub

ject

#, D

LBC

L su

btyp

e

Duration of treatment (weeks)

Plasma-blastic

0 20 30 40 50 60 70 80

**

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

OVERVIEW REL/REF DLBCL

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

CONCLUSIONS

THANK YOU!

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