MODERN MANAGEMENT OF DLBCL - OncologyPRO€¦ · DLBCL PROGNOSIS 1989–20071 2005–20102 Overall...
Transcript of 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
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
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
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.
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
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
2016 REVISION OF THE WHO
CLASSIFICATION
1. Swerdlow SH, et al., Blood 2016 127:2375-2390
ESMO CLINICAL PRACTICE
GUIDELINES: RECOMMENDED TREATMENT
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
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
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
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
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
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
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
Tilly H, et al., Annals of Oncology 2015
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
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
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
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
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
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
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
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
ESMO CLINICAL PRACTICE
GUIDELINES: RECOMMENDED
TREATMENT STRATEGIES IN DLBCL
Eligible for transplant Not eligible for transplant
Allogeneic transplantation
Clinical trials with novel drugs
Clinical trials with novel drugs
Palliative care
> 2nd relapse/progress
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)
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!