dlbcl and double hit lymphoma: diagnosis and treatment
TRANSCRIPT
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Burhan Ferhanoglu M.D.
Professor of Hematology
Koç University Medical School
İzmir, April 7th,2019
DLBCL and Double Hit Lymphoma: Diagnosis and Treatment
(First Line and Relapsed Disease)
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Disclosures for Burhan Ferhanoğlu
Participated in an advisory board: Roche / Janssen and Janssen / Takeda Pharmaceutical / ABBVIE
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• Evaluate de-novo DLBCL patients; determine their risk scores and management.
• Select patients to administer CNS prophylaxis
• Manage the treatment of relapsed DLBCL patients
• Diagnose and evaluate patients with DHL and DEL and their management
Learning Objectives
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ObjectivesIntroduction
What should be emphasized in the pathology
report?
Treatment of earlystage DLBCL
Treatment of advanced stage
disease
Double Hit , Double Expressor
Lymphoma
Treatment of extranodal DLBCL
CNS prophylaxisstrategy
Treatment of relapsed/refractor
y DLBCL
Trials & New approaches
Introduction
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Introduction
DLBCL is the most common lymphoid malignancy in
adults
Almost 35% to 40% of lymphomas in Western countries
32% of lymphomas in Turkey
The estimated incidence is 7 to 8 cases per
100,000/year
The peak incidence of DLBCL is in the sixth decade.
Sant et al. Blood 2010
Fisher et al. Oncogene 2004
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DLBCL, NOS and other Large B-cell
Disorders: WHO 2008DLBCL is a heterogenous group of disorders with varied natural
history, genetic abnormalities, and response to therapy
Diffuse large B-cell lymphoma (DLBCL), NOS 30%
Primary mediastinal large B-cell lymphoma 3%
Variants: ~5%
✓T-cell/histiocyte rich large B-cell lymphoma
✓Primary cutaneous DLBCL, leg type
✓EBV positive DLBCL
✓DLBCL associated with chronic inflammation
✓Lymphomatoid granulomatosis (EBV)
✓Intravascular large B-cell lymphoma
✓ALK positive large B-cell lymphoma
✓Primary CNS large B cell lymphoma
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Diffuse large B-cell lymphoma (DLBCL), not otherwise
specified (NOS)Germinal-centre B-cell-like (GCB)
Activated B-cell-like (ABC)
DLBCL subtypesT-cell/histiocyte-rich large B-cell lymphoma
Primary DLBCL of the CNS
Primary cutaneous DLBCL, leg type
Epstein-Barr virus–positive DLBCL, NOS of the elderly
EBV+ mucocutaneous ulcer
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
DLBCL associated with chronic inflammation
Lymphomatoid granulomatosis
ALK-positive DLBCL
Plasmablastic lymphoma
Primary effusion lymphoma
HHV8-positive, DLBCL, NOS
B-cell lymphoma, with features intermediate between DLBCL and
classical Hodgkin Lym.
B-cell lymphoma, with features intermediate between DLBCL and Burkitt
lymphomaHigh grade B-cell lymphoma, with MYC and BCL2 and/or BCL6
rearrangements, NOS
DLBCL WHO Classification (2008) –
Update 2016
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Integrative Genetic and Clinical Analysis
through Whole Exome Sequencing in 1001
Diffuse Large B Cell Lymphoma (DLBCL)
Patients Reveals Novel Disease Drivers
and Risk Groups
Anupama Reddy & Jenny Zhang et al Cell 2017
Large B cells
lymphoma : a long
road before a
revolution …
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Moffitt and Dave JCO 2017
Genomic Lanscape of DLBCL
A better understanding of the genomic
markers, associated with a response, will
directly allow the development of patients-
selection strategies that only treat patients
who are most likely to respond
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ObjectivesIntroduction
What should be emphasized in the pathology
report?
Treatment of earlystage DLBCL
Treatment of advanced stage
disease
Double Hit , Double Expressor
Lymphoma
Treatment of extranodal DLBCL
CNS prophylaxisstrategy
Treatment of relapsed/refractor
y DLBCL
Trials & New approaches
What should be emphasized in
the pathology report?
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What should be emphasized in the
pathology report?Excisional biopsy remains the optimal method for diagnosis
Immunohistochemical panel should be planned to confirm
B-cell lineage and, must be comprehensive enough to
highlight possible variant forms such as:
✓Immunoblastic lymphoma
✓PMLBCL
✓EBV positive DLBCL
✓T cell/ histiocyte rich B cell lymphoma
✓Primary cutaneous DLBCL, leg type
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Diagnosis accordingto the currentWHO 2016th classification
should be reported
Valera A. Mod Pathol.2016
Determining thecell of origin by at least IHC and Ki67 proliferation indexis also important
The presence of myc, bcl-2, andbcl-6 should be
reported and if it is positive should be confirmed by FISH
analysis
All cases of DLBCL should be tested
for Mycrearrangment by
FISH
The correlation between MYC rearrangement and MYC protein expression in DLBCL is less clear as
approximately one-third of rearranged cases shownegative or low expression by immunhistochemistry
further testing forBCL2 and Bcl6
rearrangements
What should be emphasized in the
pathology report?
NEW APPROACH
Kluk MJ et al. Am J Surg Path 2016
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Prognostic parameters
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Moleculer subtypes of DLBCLHigh
Level of gene
expression
Low
Gen
es
Rosenwald A et al. N Engl J Med. 2002;346:1937-1947
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Hans Algorithm
Hans et al. Blood 2004
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Clinical predictors of outcome
Bachy a
nd S
alle
s. S
em
inars
in H
em
ato
logy, 2
01
5
IPI R-IPI NCCN-IPI
Age
>40 to ≤60
>60 to ≤75
>75
1 1
1
2
3
LDH normalized
>1 to ≤3
>3
1 1 1
2
Ann Arbor stage III-IV 1 1 1
Extranodal disease
>1 site
Any if BM, CNS, liver/GI tract or lung
1 1
1
Performance status ≥2 1 1 1
Score
Low
Low-intermediate
High-intermediate
High
0-1
2
3
4-5
0
1-2
≥3
0-1
2-3
4-5
≥6
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Outcome of DLBCL with R-CHOP
55%
Sehn et al. Blood 2007 Coiffier et al. Blood 2010
Age +16
Newly diagnosed DLBCL
Treated with R-CHOP
Age 60-80
Newly diagnosed DLBCL
Treated with CHOP vs R-CHOP
LowRisk
HighRisk
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IPI vs NCCN-IPI in High Risk DLBCL
64%
29%
Ozturk & Ferhanoğlu. Leukemia&Lymphoma 2015
67 %
44%
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ObjectivesIntroduction
What should be emphasized in the pathology
report?
Treatment of earlystage DLBCL
Treatment of advanced stage
disease
Double Hit , Double Expressor
Lymphoma
Treatment of extranodal DLBCL
CNS prophylaxisstrategy
Treatment of relapsed/refractor
y DLBCL
Trials & New approaches
Treatment of earlystage DLBCL
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Treatment of early stage disease
Early stage disease is commonly defined
as stage I or non-bulky stage II disease.
Miller TP.NEJM,1998
Shenkier TN.JCO,2002
Bonnet C.JCO,2007
Patients with non-bulky stage 1A disease (IPI=0)
presenting at sitesassociated with low
morbidity for RT (i.e. Axilla, neck,
groin)
Patients who do not tolerate full course
CT due tocomorbidities oradvanced age
3 R-CHOP & RT to initial site of presentation
(30 Gy)
6 R-CHOP is an alternativeto combined
therapy
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Treatment of limited stage Diffuse
Large B Cell Lymphoma
Kumar et al. Curr Treat Options in Oncol 2016
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Stephens et al. JCO 2016
SWOG S8736 PFS and OS
Final & Long-Term Analysis
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ObjectivesIntroduction
What should be emphasized in the pathology
report?
Treatment of earlystage DLBCL
Treatment of advanced stage
disease
Double Hit , Double Expressor
Lymphoma
Treatment of extranodal DLBCL
CNS prophylaxisstrategy
Treatment of relapsed/refractor
y DLBCL
Trials & New approaches
Treatment of advanced stage
disease
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DLBCL
Age 60–80 years
No prior treatment
PS 0–2
Stage II–IV
R
A
N
D
O
M
I
Z
A
T
I
O
N
LNH 98.5 study: Design
CHOP
q3wk x 8
Rituximab
+
CHOP
q3wk x 8
Coiffier B, et al. NEJM 2002
Rituximab: 375 mg/m2 on day 1
Cyclophosphamide: 750 mg/m2 on day 1
Doxorubicin: 50 mg/m2 on day 1
Vincristine: 1.4 mg/m2 (up to 2 mg/m2) on day 1
Prednisolone: 40 mg/m2/d days 1–5
NHL in elderly: Rituximab era
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OS
CHOP
R-CHOP
Treatment of advanced stage diseaseR-CHOP is the standart treatment for patients with advanced stage DLBCL based on GELA (LNH98-5)
study.
Coiffier B.Blood.2010
Held G.JCO.2014
Wilson WH:Haematologica 2012
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1) Pfreundschuh et al. Lancet Oncol 2006
2) Sehn et al. JCO 2005
3) Habermann et al. JCO 2006
4) Pfreundschuh et al. Lancet Oncol 2008
R-CHOP: a consistent clinical benefit
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Even in Rituximab era, more than one
third of DLBCL are not cured …
Sehn & Gascogne Blood 2015 Gisselbrecht et al JCO 2010
N= 187
N=1660
Salvage Regimens With AutologousTransplantation for Relapsed Large B-Cell
Lymphoma in the Rituximab Era
Outcome for all patients with DLBCL treated with R-CHOP in British
Columbia between 2001 and 2013
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Intensification overR-CHOP-21?
R-CHOP-14 vs 21 UK and France (LYSA) no difference
DA-R-EPOCH Rand vs R-CHOP / Alliance P
No difference ASH 2016
Nb cycles: 6 enough(RICOVER trial)
R-ACVBP > R-CHOP (in subsets of pts:aaIPI 1; ABC ++ )
Pfreundschuh, Lancet Oncol, Feb 2008
Delarue, Lancet Oncol May 2013
Cunningham, Lancet May 2013
Wilson, Haematologica, May 2012 ASH 2016
Molina, JCO Dec 2014
Smith, NEJM, Oct 2013
DL
BC
L:
Str
ate
gie
sto
impro
ve
beyond
R-C
HO
P-2
1
Optimization of the use of Anti CD 20Rituximab /Obinutuzumab
HOVON R2 CHOP no difference
DA-R-EPOCH Rand vs R-CHOP / Alliance P
No difference ASH 2016
R-ACVBP > R-CHOP (in subsets of pts:aaIPI 1; ABC ++ )
Optimization of the use of Anti CD 20Rituximab /Obinutuzumab
HOVON R2 CHOP no difference
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Intensification ofR-CHOP-21?
Take into considerationbiological diversity of DLBCLFocus on: GCB / non GCB
Better predict /evaluatequality of response?
DLBCL: Strategies to improve beyond
R-CHOP-21
Intensification ofR-CHOP-21?
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Prospectives Study of First Line
Consolidation HDT in the Rituximab EraStudy Therapy Patients n PFS HDT vs
StdOS HDT vs
Std
SWOG9704*
CHOP (+/-)R+/- HDT
aaIPI 2,3> PR toInduction
253 2 yrs69% vs 55%
2 yrs OS 74%vs 71%
DSHNHL2002-1**
R-CHOEP vsR-MegaCHOEP
aaIPI 2,3 275 3 yrs70% vs 74%
3 yrs77% vs 85%
GOELAMS075***
RCHOP 14 vsRCHOP 14, MTX + AraC, HDT
I-II + BulkIII, IV(58% IPI 2,3)
286 3 yrs92% vs 80%
3 yrs80% vs 88%
DLCL04****
RCHOP14/MegaCHOP14+/- HDT
aaIPI 2,3 399 3 yrs70% v 59%
3 yrs81% vs 78%
*Stiff et al. NEJM 2013
**Schmitz et al. Lancel Oncol 2012
***LeGouille et al. JCO 2011
****Chiappella et al. Lancet Oncol 2017
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Take into considerationbiological diversity of DLBCLFocus on: GCB / non GCB
Better predict /evaluatequality of response?
DLBCL: Strategies to improve beyond
R-CHOP-21
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Primary end point is EFS
Local
ass
ess
ment
Centr
alre
vie
w
Mamot et al JCO 2015
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Enrolled = 162 Excluded = 11did not fulfill I/E criteria
Failed to reach iPET = 8PD = 1 Toxicity = 5 (bowel perforation = 2
hepatic failure = 1, cardiac = 2) Dose-delays = 2iPET status = 143
iPET-neg = 101 iPET-pos = 42
R-ICE x 3 + Z-BEAM: n = 32PD = 6; consent w/drawn = 3; 2nd cancer = 1
R-CHOP x 2 + R x 2: n= 96PD = 3; toxicity = 1; R x 1 omitted=1
Eligible = 151
29% M H
ertz
berg
et a
l. Haem
ato
logic
a2017
DLBCL: IPI = L-I to H, L + bulk (≥ 7.5 cm) Age ≤ 70 yrs; fit for HDT
R-CHOP-14 x 4
*1. Delay #5 R-CHOP-14 x 7 days: iPET d17-20 of cycle #4. 2. Central PET consensus reporting by 2 PET physicians: IHP criteria
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PFS is equivalent: iPET- vs iPET+n=143: Median follow up = 35 m
M Hertzberg et al. Haematologica 2017
iPET- 74% 2-yr
iPET+ 67% 2-yr
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M Hertzberg et al. Haematologica 2017
IPI 3-5: PFS and OS are equivalentPFS:
iPET- vs. iPET+
P = 0.79
OS: iPET- vs. iPET+
P = 0.98
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M Hertzberg et al. Haematologica 2017
PFS OS
iPET-positive
Deauville Score 4 vs. 5
P = 0.0002
Score 5 33% 2-yr
Score 4 88% 2-yr
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Intensification ofR-CHOP-21?
Take into considerationbiological diversity of DLBCLFocus on: GCB / non GCB
Better predict /evaluatequality of response?
DLBCL: Strategies to improve beyond
R-CHOP-21
Take into considerationbiological diversity of DLBCLFocus on: GCB / non GCB
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NF-ƙB pathway
Gonzalez-Barca et al. ASH 2015 Abstract#1514
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ObjectivesIntroduction
What should be emphasized in the pathology
report?
Treatment of earlystage DLBCL
Treatment of advanced stage
disease
Double Hit , Double Expressor
Lymphoma
Treatment of extranodal DLBCL
CNS prophylaxisstrategy
Treatment of relapsed/refractor
y DLBCL
Trials & New approaches
Double Hit , DoubleExpressor Lymphoma
High grade B cell lymphoma with MYC and
BCL2 and/or BCL6 rearrangements, NOS
(WHO 2016)
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Double Hit and Double Expressor
Lymphomas
Double Hit Lymphoma is defined as rearrangement of
MYC with BCL2 or BCL6
It constitutes 10% of GCB-like DLBCL
DLBCL with high MYC >40% , plus BCL2 (50-70%)
protein expression by IHC without genetic
rearrangements is called DEL
Majority of DHL = GCB like
Majority of DEL = ABC like
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Data from the Mitelman database of chromosomal alterations in cancer;
• 62% of these newly categorized mycrearranged lymphomas involve bcl-2 translocations,
• 18% involve bcl-6 translocations,
• and the remaining cases are triple-hit lymphomas
Aukemia et al 2011
Oliveria et al.2017
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Friedberg JW:Blood 2017
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Scott et all. Blood.2018
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Characteristics of
DHL at presentation:
•Median age: 7th
decade
•Stage III/IV
•HI/H IPI
•LDH> nl
•Extranodal sites (incl.
CNS)
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Overview: OS in DHL and DEL (DLBCL)
Cheah et al. BJH 2014
DELDHL
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MYC-R DLBCL: Inferior Outcome with
CHOP/R-CHOPAuthors N Treatment MYC-R
%
DHL %
(BCL-2-
R)
Outcome
Klapper et al. 177 CHOP or
CHOEP
8% ND OS in MYC-R worse
Barrans et al. 303 R-CHOP 14% 11% 2 yr OS 35% (MYC-R)
vs
61% (MYC-N
Savage et al. 135 R-CHOP 9% 2% 5 yr OS 33% (MYC-R)
vs
72% (MYC-N)
Cunningham et
al.
1080 R-CHOP-14
or R-CHOP-
21
6% 3% 2 yr OS not inferior in
MYC-R
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Double-hit Lymphoma Results•IPI score
•0-1: 13%
•2-3: 61%
•4-5: 26%
•DLBCL or BCLU: 92%
•Translocations
•MYC: 81%
•BCL2: 84%
•BCL6: 12%
•MYC & BCL2: 72%
•Triple hit: 11%
•GCB by IHC: >90%
Oki et al. BJH 2014
3 y PFS 29% & OS 38%
•129 patients
•Median age 62 (17-84)
•65% are male
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EFS improved following intensive
therapy
P=0.004
P=0.057
Oki et al., BJH 2014
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High IPI: Worse EFS – N=129
Oki et al. BJH 2014
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Translocation Partner does not influence EFS
Oki et al. BJH 2014
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OS is better in patients receivingDA-EPOCH-R
R-CHOP: 57 (44%)
R-EPOCH: 28 (22%)
R-HCVAD/MA: 34 (26%)
Diğer 10 (7%)
P=0.057
Oki et al. BJH 2014
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CNS nvolvement / relapse risk is high in DHL
Oki et al. BJH 2014
%13
CNS relapse risk at 3 years
decreased from 15% to 5% with
IT prophylaxis (p=0.017)
Bone marrow involvement
ECOG ≥2
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No improvement in EFS & OS in patients with ASCT in frst CR
Oki et al. BJH 2014
P=0.17 P=0.56
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Petrich A.M. et al. Blood 2014
•311 patients
•Median age 60 (19-87)
•61% are male
•Stage III or IV: 81%
•>2 extranodal site: 28%
•DLBCL or BCLU ratio; 98%
•Partner translocations
•BCL2: 87%
•BCL6: 5%
•Triple hit: 8%
• GCB ratio with IHC >%87
2 y PFS:40%
OS 49%
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Multi-center study– DHL results,
Petrich AM. et al. Blood 2014
There is a small number of DHL patients whose clinical and
laboratory parameters point us a better outcome
• DHL prognostic
score
• Leucocytosis
• Stage 3-4
• LDH>3x ULN
• CNS inv
%7
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CR rates are higher with DA-EPOCH-R
Petrich AM.. Blood 2014
R-CHOP: 33%
R-Hyper CVAD: 21%
DA-EPOCH-R: 21%
R-CODOX-M/IVAC: 15%
Other: 10%
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PFS improved after intensive therapy
Petrich AM. et al. Blood 2014
•>60 yo patients received
mostly R-CHOP or DA-
EPOCH-R
•No OS advantage of SCT
performed in CR
•CNS prophylaxis: OS 14
vs 45 months (p=0.06)
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Median follow-up for survivors: 46 months
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Herrera et al. Biol Blood Marrow Transplant 2018
30%
39%
31%
49%
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Herrera et al. Biol Blood Marrow Transplant 2018
34%
40%
38%
50%
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ObjectivesIntroduction
What should be emphasized in the pathology
report?
Treatment of earlystage DLBCL
Treatment of advanced stage
disease
Double Hit , Double Expressor
Lymphoma
Treatment of extranodal DLBCL
CNS prophylaxisstrategy
Treatment of relapsed/refractor
y DLBCL
Trials & New approaches
Treatment of extranodal DLBCL
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I administerCNS
prohylaxis
ESMO Extranodal DLBCL Guideline
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ObjectivesIntroduction
What should be emphasized in the pathology
report?
Treatment of earlystage DLBCL
Treatment of advanced stage
disease
Double Hit , Double Expressor
Lymphoma
Treatment of extranodal DLBCL
CNS prophylaxisstrategy
Treatment of relapsed/refractor
y DLBCL
Trials & New approaches
CNS prophylaxisstrategy
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CNS-IPI includes
➢age>60➢LDH>UNL➢stage:III or IV➢ECOG>1➢Extranodal inv. >1➢renal or adrenal involvement
NCCN Guideline Version 2.2016
Low (0,1): <%1
Intermediate: (2,3) : %2-10
High: (4-6): %17; perform LP!
CNS prophylaxis strategy
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CNS prophylaxis shouldbe performed for;
➢Double Hit lymphoma,➢HIV lymphoma➢Testicular lymphoma,➢Breast involvement
NCCN Guideline Version 2.2016
At least 2 IT MTX for elderly patients on D15th of first and second cycle of CT
At least 2 High dose MTX for young highrisk patients
CNS prophylaxis strategy
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ObjectivesIntroduction
What should be emphasized in the pathology
report?
Treatment of earlystage DLBCL
Treatment of advanced stage
disease
Double Hit , Double Expressor
Lymphoma
Treatment of extranodal DLBCL
CNS prophylaxisstrategy
Treatment of relapsed/refractor
y DLBCL
Trials & New approaches
Treatment of relapsed/refractory
DLBCL
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Treatment of relapsed-
refractory patientsConfirm relapse by biopsy
Re-stage the patient
Follow renal
function closely
especially for R-
DHAP!
Intensive salvage
chemoimmunotherapy
with non-cross resistant
regimen
But Cell of origin?
GCB
Is patient transplant
eligible?
Non-GCB R-ICE
R-DHAP
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CORAL study: Autologous Stem
Cell Transplantation for DLBCL in
Rituximab Era
•Which salvage regimen is better?
Gisselbrecht C et al. JCO 2010;28:4184-
4190
CORAL study:
Autologous
Stem Cell
Transplantation
for DLBCL in
R/R disease
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Gisselbrecht C et al. JCO 2010;28:4184-4190
Response After Induction Treatment
(including death) for All Patients
R-ICE R-DHAP
N 197 % N 191 %
Response (including death)
Complete response 48 24 53 28
Unconfirmed complete response 24 12 22 12
Partial response 53 27 45 24
Stable disease 23 12 22 12
Progressive disease 38 19 35 18
Death 6 3 10 5
Premature withdrawal, not evaluated4 2 4 2
Total 197 100 191 100
63 .5 % 62.8 %
Treatment arm n
Mobilization
adjusted
response MARR (%)
R-ICE 197 103 52.3
R-DHAP 191 104 54.5
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PFS EFS OS
Prior rituximab administration 0.003 0.0007 0.01
Relapse < 12 ay < 0.0001 <0.0001 <0.0001
sIPI > 1 < 0.0001 <0.0004 <0.0001
Treatment arm 0.1 0.3 0.07
➢Relapses are more severe following rituximab administration.
➢Early relapse and treatment failure are poor prognostic factors.
Multivariate Analysis to Evaluate Survival
- p values
Gisselbrecht C et al. JCO 2010;28:4184-4190
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R-DHAP
R-DHAP
R-ICE
R-ICE
Thieblemont et al. JCO 2011;29:4079-4087
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Median follow-up : 53 months
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Crump et al. JCO 2014
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Second line
treatment
Third line
treatment
n ORR
R-ICE DHAP-like 26 42,3%
R-DHAP ICE-like 23 43,5%
E Van Den Neste et al. Bone Marrow Transplantation 2016
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Transplant
ation
Median
OS
Performed 11.1
months
Not
performed
3.2
months
E Van Den Neste et al. Bone Marrow Transplantation 2016
Tertiary IPI
score
Median OS
0-2 10.3 months
(HR=3.2)
>2 3.2 months
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• The results of studies from GEL-TAMO group and ABMTR suggestedthat HDT/ASCR should be considered for patients who do not experience CR but who have chemosensitive disease
• About a third of patients achieving PR also experince long term DFS with ASCT
Treatment of relapsed-refractory patients
Derenzini E.cancer 2008Vose JM. JCO.2001Rodriguez J. Annals of Oncol.2004
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Treatment of relapsed-refractory patientsPretransplant PET scans have been
identified as predictive factorsfollowing HDT/ASCR
Derenzini E.cancer 2008
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100 Relapsed or Refractory DLBCL
50 Transplant Ineligible
Potential Deaths from Lymphoma
50 Transplant Eligible
25 Respond to
Salvage Therapy and ASCT
10 Patients Cured
*Estimates based on Gisselbrecht et al. J Clin Onc 2010 28:27, 4184-4190.*Assumes all patients received rituximab as part of primary therapy W
ha
t d
oe
s A
uto
SC
Tachie
ve
as s
eco
nd
lin
e t
he
rapy in
th
e
ritu
xim
ab e
ra* ?
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Allo-transplantation for patients
relapsing following ASCT
• There is no clearly defined group where allo-SCT is
preferable to ASCT, but it may be an option for some
younger patients (age <40-50 years) with high-risk
disease.
• The prognosis of the patients relapsing after ASCT is
poor.
• Patients who respond to salvage therapy can be
considered for alloSCT. Freytes CO.Biol of Blood and Marrow Trans.2012
Bacher U.Blood,120,2012
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IBMTR data between 2008-
2013
N=987 pts
254 DLBCL pts
HLA-Matched SiblingDonorN=807
189 DLBCL pts
Haploidentical relateddonorN=180
65 DLBCL pts
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Ghosh et al. JCO 2016
PFS Haplo HLA-
matched
p
1 yr 59% 61% 0,55
2 yrs 51% 52% 0,78
3 yrs 48% 48% 0,96
OS Haplo HLA-
matched
p
1 yr 77% 78% 0,64
2 yrs 65% 68% 0,39
3 yrs 61% 62% 0,82
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Follow-up
• Patients who achieve a CR following treatment
should be followed up on a 3-4 monthly basis for up
to 2 years . The risk of relapse beyond 2 years is
<10% .
• Outside a clinical trial, there is no role for routine
surveillance scans during post-treatment follow-up
and patients should be assessed clinically.
Vose JM.BJH.2010El-Galaly TC.JCO.2015
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ObjectivesIntroduction
What should be emphasized in the pathology
report?
Treatment of earlystage DLBCL
Treatment of advanced stage
disease
Double Hit , Double Expressor
Lymphoma
Treatment of extranodal DLBCL
CNS prophylaxisstrategy
Treatment of relapsed/refractor
y DLBCL
Trials & New approaches
Trials & New approaches
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Yescarta Kymriah
CD19 Directed CAR-T Cells
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Summary of Pivotal CAR-T Trials in R/R DLBCL
Borchmann et al. EHA 2018 Abstracts S799Abramson et al. ASCO 2018 Abstract 7505
Locke et al. ASCO 2018 Abstract 3003Locke et al. ASCO 2018 Abstract 3039
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Locke et al. Lancet Oncol. 2018
update 2 yearsfollow up
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Victor A. Chow et al. Blood 2018
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New Treatment-Targeted ModalitiesTargets of Signaling Pathways
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Agent Target Status Overall
Response
Subtype
DLBCL
References
Ibrutinib BTK Phase I/ II 37% ABC (Wilson et al ; 2015)
Fostamatinib SYK Phase II 3%
22%
DLBCL (Flinn et al, 2016)
(Friedberg et al, 2010)
Lenalidomide immunomodulato
r
Phase II 42%
52%
DLBCL
ABC
(Zinzani et al, 2015
(Hernandez-Ilizaliturri et
al, 2011)
Bortezomid +
chemo
NF kB Phase II 83% ABC (Dunleavy et al, 2009)
Tazemetostat EZH2 Phase II 60% DLBCL (Italiano et al, 2018)
Everolimus m TOR Phase II 30% GCB (Witzig et al, 2011)
Temsirolimus mTOR Phase II 28% DLBCL (Smith et al, 2010)
CUDC 907 PI3K delta +HDAC Phase II 37% GCB/Myc (Oki et al, 2017)
obinutuzumab CD20 Phase II 32% DLBCL (Morschhauser et al, 2013)
MOR00208 CD 19 Phase II 29% DLBCL (Jurczak et al, 2016)
Blinatumumab B specific
CD19/CD3
Phase II 43% DLBCL (Viadrot et al, 2016)
Polatuzumab
vedotin
CD79b Phase I 25% DLBCL (Palanca et al, 2015)
Nivolumab Anti PD1 Phase I 36% DLBCL (Lesokhin et al, 2016)
Selinexor
Ublituximab +
1202+ benda
Exportin XPO1
CD20
Phase I/IIb
Phase II/III
32% DLBCL
DLBCL
(Kuruvilla et al, 2017)
(Lunning et al, 2017)
Are
Th
ey C
an
did
ate
s f
or
Tre
atm
ent
Wilson, WH, et al. Nat Med. 2015;2(198):922-926. Flinn IW, et al. Eur J Cancer. 2016;5411-5417. Friedberg JW, et al. Blood. 2010;115(13):2578-2585. Zinzani PL, et al. Cancer.
2015;56(6):1671-1676. Hernandez-Ilizaliturri FJ, et al. Cancer. 2011;117(22):5058-5066. Dunleavy K, et al. Blood. 2009;113(24):6069-6076. Italiano A, et al. Lancet Oncol.
2018;19(5):649-659. Witzig TE, et al. Leukemia. 2011;25(2):341-347. Smith SM, et al. J Clin Oncol. 2010;28(31):4740-4746. Oki Y, et al. Haematologica. 2017;102(11):1923-1930.
Morschhauser FA, et al. J Clin Oncol. 2013;31(23):2912-2919. Jurczak W, et al. J Med Case Rep. 2016;10(1):123. Viadrot A, et al. Blood. 2016;127(11):1410-1416. Palanca MA, et
al. Lancet. 2015;16(6):706-715. Lesokhin AM, et al. J Clin Oncol. 2016;34(23):2698-2704. Kuruvilla J, et al. Blood. 2017;129(24):3175-3183.
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Polatuzumab + BR
[n = 40]) BR [n = 40]
OR 70.0% 32.5%
CR 57.5% 20.0%
OS 11.8 months 4.7HR = 0.31 (0.19–
0.67); P<.0008
PFS 6.7 months 2.0 monthsHR = .31; (0.18–
0.55); P<.0001
DOR 8.8 months 3.7 months
Bendamustine + Rituximab
Bendamustine + Rituximab
+
Polatuzumab vedotin
Heavily pretreated DLBCL
(n = 80)
• Patients could have had prior autoSCT, but not alloSCT
• Transplant-eligible patients were excluded
DOR, duration of response Sehn L, et al. Blood. 2017;130: Abstract 2821.
Po
latu
zum
ab
Anti-C
D79b
Imm
uno
co
nju
gate
+ B
R:
Results
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Sehn et al. ASH 2018 Abstract1683
GO29365: Updates Phase II Trial Resultsof Polatuzumab Vedotin in Combination
with BR for R/R DLBCL or FL
•CR rate for pola+BR and BR were 45% and 18%, respectively
•Updated follow-up suggests that durable responses could be possible; responses of >20 months have been observed with pola + BR or pola + BD
•Updated safety results are similar to those previously described with no new safetysignals identified.
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Auto
logo
usTr
ansp
lantAlg
orith
mDiffuse Large B Cell Lymphoma
Chemotherapy ± R
PR+ with: InductionFailure
CR: all others
➢Primary CNS DLBCL➢Aggressive B in PR➢High Risk B-cell
➢C-myc +➢Doubleprotein/hit➢High IPI
Autotransplant
Salvage Relapse(s)
Chemosensitive Refractory
Clinical trialand/or
Allograft
Landsburg et al. JCO 2017
CAR-T
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Conclusions
Outcome in DLBCL has improved dramatically over the
last decade with the addition of rituximab to CHOP,
which remained the current standart of care.
However, patients who fail R-CHOP continue to have a
poor outcome, highligthing the limits of standart
chemotherapy in the setting of chemoresistant disease.
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Conclusions
Currently, patients with double hit-lymphoma, as well
as DEL, represent poor risk subsets in which
alternative strategies should be explored.
To optimize future management , it is necessary to
know the molecular heterogeneity of DLBCL and to
investigate novel targeted agents within biological
subsets that will most likely benefit.
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Burhan Ferhanoglu M.D.
Professor of Hematology
Koç University Medical School
İzmir, April 7th,2019
DLBCL and Double Hit Lymphoma: Diagnosis and Treatment
(First Line and Relapsed Disease)