understanding and treating lymphomas: the challenges of a
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María José Terol Casterá
Department of Hematology
Hospital Clínico Universitario
Valencia
Understanding and treating lymphomas: the challenges of a
curative disease
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Declaration Of Interests
Advisory:
Roche, Abbvie, Janssen, Astra-Zeneca
Research Grants:
Janssen, Glead
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Normal lymph node anatomy
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Lymphomas
Hodgkin lymphoma
(20%)
Non-Hodgkin Lymphoma
(80%)
B origin
(85-90%)
T origin
(10-15%)
Cure: 75-85%
Cure: 65% Cure: 20%
Reed-Sternberg cell
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Diffuse Large
B-cell lymphoma
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Background
❑ B and T-cell neoplasms are clonal tumours of mature B/T/NK cells at
various stages of differentiation
❑ Highly heterogeneous : clinical features, morphology, immunophenotype
and genetics (WHO classification)
❑ Incidence: 3-15 cases/100.000 hab/year.
❑ Pathogenesis : predisposing factors
❖ primary immunodeficiency: ataxia-telangiectasia, Wiskott-Aldrich
❖ adquired immunodeficiency: : AIDS
❖ Autoimmune diseases: SEL, Sjögren
❖ Virus: Burkitt (Epstein-Barr), HTLV-1(Leucemia/linfoma), VHC, HHV-8,
HIV
❖ bacteria: gastric MALT lymphoma helycobacter p, cutaneous MALT
lymphoma- borrelia
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WHO Classification Principles
Morphology
Phenotype
Genetic
Molecular alterations
Epidemiology
Etiology
Pathogenesis
Clinical presentation
Evolution
Prognostic parameters
Therapy
Malignant Lymphomas as Disease Entities• Non-overlapping (mutually exclusive)• Stratified according to cell lineage
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Classification
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tissue biopsy
paraffin embeddedFresh tissue?
Blood sample?
morphology
flow citometry
Immunohistochemistry
Diagnosis
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CLONALITY: rearrengement of BCR (IgH) or TCR
FISHtranslocations
GENE EXPRESSIONPROFILING
Diagnosis
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Staging
• Patient evaluation: clinical history (fever, sweats, weight loss, others,), physical
examination (LN, Waldeyer ring, size of the liver, spleen, testes and skin)
• Excisional biopsy (lymph node or others) with a detailed study of morphology,
immunophenotype and genetic studies
• Blood test: blood count, blood film chemistry (LDH, 2microglobulina, uric acid),
ESR, electrophoresis
• Serology: B-hepatitis, C-hepatitis, HIV
• PET/CT scan of the neck, chest and abdomen: to detect occult nodal and
extranodal disease
• Bone marrow biopsy: detect lymphoma invasión (only in NHL)
• Lumbar puncture: burkitt lymphoma, DLBCL, lymphoblastic lymphoma
• Other: endoscopy and endoscopic ultrasound for MALT and other
GI, magnetic resonance for primary CNS lymphoma
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limited advanced
Ann-Arbor classification (Costwolds modification)
Non-Hodgkin lymphomas
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Staging: PET/CT
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Tumor board for lymphomas:
multidisciplinary approach
lymphoma
Biopsy
Morphology
IHQ
Molecular techniques
Flow citometry
FISH
StagingResponse evaluation
Treatment
Tumour board
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oMost frequent type (30-35%)
oMedian age: 60-65 y
oClinical presentation (60% nodal/40%
extranodal)
oHistology: diffuse proliferation of
atypical, irregular, large B-cells with
nucleoli and basophilic cytoplasm
oAggressive behavior: untreated drives
to death in days/months
Diffuse large B-cell Lymphoma (DLBCL)
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❑ most frequent (30% of all lymphomas)
❑Histopathology: diffuse proliferation of atypical, irregular, large B-
cells with vessicular nuclei prominent nucleoli and basophilic
cytoplasm
❑Inmunohistochemistry: pan-B cell markers: CD19 +, CD20+, CD79a +,
CD22 +, bcl-6, bcl-2, CD10 MUM-1
❑ Cytogenetics: several trasnlocations involving chromosome 3(bcl-6).
❑ Molecular studies: rearrangement of BCL-6, 30% of cases, also
BCL-2 (t(14;18)
❑ Gene expression profiling: germinal-center B-cell lymphoma (GCB)
and non-GCB, activated B-cell sybtype.
❑ IHQ algorithm (Hans): not reproducible
❑ Nanostring
Diffuse large B-cell Lymphoma (DLBCL)
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Rosenwald et al,
NEJM 2002
DLBCL: different behaviour based on
Cell of origin
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High grade B-cell lymphoma
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Double expressor
Double hit
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❑ Proliferation/accumulation of monomorphic small, roud to slightly irregular
lymphocytes in the peripheral blood (PB), bone marrow (BM) spleen and
lymph nodes
❑ Most common leukaemia in Western Countries (30-40%)
❑ Incidence rate: 2-5 cases/105 /year but:
❖ Increases with age: 3/105 cases/105 /year (younger than 65)
19,7/105 cases/105 /year (over 65)
❑ Median age: 70 years. (10-15%younger than 50)
❑ slight male predominance (1,5:1)
❑ Remarkable heterogeneous clinical course
❑ Most patients diagnosed at early stage (85%)
❑ Genetic predisposition (5-10%:: 2-7fold risk in first degree relatives)
❑ uncurable
Chronic Lymphocytic Leukemia (CLL)
0,00 24,00 48,00 72,00 96,00 120,00 144,00 168,00
meses
0,0
0,2
0,4
0,6
0,8
1,0
Time to first treatment
P<0.001UM IgVH
M IgVH
Hospital Clinico de Valencia
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Cell of origin: mutational status of IgVH
Low BCR
signaling:
“good” prognosis
No IgVHm
Mutación IgVH
CD5
CD38
CFD
Germinal center
CD5
IgM
CD69
CD62
CD71
T-cell independent
antigen stimulation
Un-mutatedmutated
BCR
Ag
AgT helper
T-cell
dependent
antigen
response
High BCR
signaling
VH
VLJH
JL
“bad “
prognosis
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CLL: clinical impact of IgVH Status
❑ Molecular studies:
❖ 40-50: unmutated IgVH genes
❖ 50-60: somatic hypermutation
VH
VLJH
JL
unmutated (98% homology)
• male predominance
• aggresive course
• CD38 And ZAP70 expression
• high risk genetics: 17p del, 11q del
• Shortened survival
mutated
• typical morphology
• indolent clinical course
• CD38 and ZAP-70 negativity
• low risk genetics: 13q del
• long survival
0,00 24,00 48,00 72,00 96,00 120,00 144,00 168,00
meses
0,0
0,2
0,4
0,6
0,8
1,0
Time to first treatment
P<0.001UM IgVH
M IgVH
Hospital Clinico de Valencia
Damle RN et al. Blood 1999; 94: 1840-1847, Hamblin TJ et al Blood 1999; 94: 1848-1854
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PI3K
CLL cell
Stroma
Nurse cells
+
Anti-apoptótic
proliferation
CXCR4
CXCR5
CXCR3
CCR7CXCL12
CXCL13
VCAM
FN
CD49d
(VLA-4)
G
zap70
CD38
BAFF APRIL
CD31
BCMA,
BAFF-R
CXCL12
CCL3
CCL4
CCL22
CD40
CD40L Ag
BCR
CD95
CD95L
IL-4
citotoxicidad
Tumoral
SCA
B-CLL: PATHOGENESIS
Close influence of the microenvironment: prolonged survival
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B-cell receptor
IbrutinibONO
IdelalisibDuvelisib
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X Puente et al. Nature 2015;526: 519-524
Lessons from NGS
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Rituximab : clear Benefit for all B-cell NHL
RITUXIMAB
LLC CGD
Folicular
FC-rituximab
FC
CHOP-rituximab
CHOP
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Addition of rituximab to standard chemotherapy improved the (A) overall and (B) event-
free survival of patients with diffuse large B-cell lymphoma.
Kai Fu et al. JCO 2008;26:4587-4594
©2008 by American Society of Clinical Oncology
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Schulz H, et al. Blood 2005;106:106a
(Abstract 351)
Impact of immunochemotherapy on survival in
indolent lymphomas
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B-cell receptor
IbrutinibONO
IdelalisibDuvelisib
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• Co-developed by Janssen y
Pharmacyclics
• Small molecule which inhibits BTK
• Specified and covalent union
• Highly strong BTK inhibition
• Oral administration
• 24-h inhibitory effect:
• Inhibits growth and triggers apoptosis in
neoplastic B-cells
• Blocks migration and adhesion
• No cytotoxic effect on T and NK cells
BTK: a key smolecule in BCR signalling pathway
Ibrutinib: first BTK inhibitor
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Relapsed/refractory CLL: Phase III PCYC-1112 /
RESONATE
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Phase III RESONATE: PFS and OS
Pagel et al. iwCLL 2015; 146
(Poster Presentation)
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Progression-Free Survival Overall Survival
*Only 2 patients in the TN group showed PD or death. Subgroup analyses, therefore, focused on the R/R population.
Median OS 5-year OS
Del17p (n=34) 57 mo 32%
Del11q (n=28) NR 61%
Trisomy 12 (n=5) NR 80%
Del13q (n=13) NR 91%
No abnormality** (n=16) NR 83%
Median PFS 5-year PFS
Del17p (n=34) 26 mo 19%
Del11q (n=28) 55 mo 33%
Trisomy 12 (n=5) NR 80%
Del13q (n=13) NR 91%
No abnormality** (n=16) NR 66%
Impact of high risk cytogenetics
O’Brien S et al. ASH 2016: Abstract 233 (Oral Presentation)
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OS
(%
)
Time (months)
HR: 0.34 (95% CI=0.19, 0.6)
p<0.0001
100
80
60
40
20
0
0 2 4 6 8 10 12 14 2616 18 20 22 24
Placebo + Ra
Median OS: 20.8 months
New BCR inhibitors: Idelalisib
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❑ Venetoclax (ABT-199) :potent oral
inhibitor of bcl-2
❑ Blocks the union BAX/BCL-2 and
triggers cell death
❑ Induces 80% de responsess in
relapsed/refractory CLL
❑ Sinergistic effecr “in vitro” with
rituximab
Bcl-2 inhibitors: ABT-199 (VenetoclaxR)
Roberts A.W., N Eng J Med 2016; 374: 311-322
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A new era in the treatment of CLL
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Nivolumab for Hodgkin’s lymphoma
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Nivolumab for Hodgkin’s lymphoma
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NGS in treatment
monitoring
De Rossi D, Blood 2017
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De Rossi D, Blood 2017
NGS en the treatment monitoring:
liquid biopsy
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NGS en the treatment monitoring:
liquid biopsy
Responders
Non
Responders
De Rossi D, Blood 2017
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Rushton et al, Lugano 2019
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Rushton et al, Lugano 2019
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Rushton et al, Lugano 2019
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Rushton et al, Lugano 2019
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Rushton et al, Lugano 2019
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Rushton et al, Lugano 2019
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NGS infividual tumor profile
¿does it have a target?
Yes
Quality of response:
Responders
Not responders
New therapeutic strategy
based on NGS tumor profile
Relapse or progression
New NGS study
(clonal evolution)
New treatment
strategyNGD minimal residual disease technique
Personalized targeted therapy
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Crump M, Blood 2017; 130: 1800-1808
Refractory DLBCL: very adverse outcome
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Crump M, Blood 2017; 130: 1800-1808
SG: 6 meses
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◆ Joint Meeting Spanish Society of Hematology and Hemotherapy &
Moffitt Cancer Center
◆ Frederick L. Locke, MD◆ Vice Chair and Associate Member
◆ Department of Blood and Marrow Transplant and Cellular Immunotherapy
◆ Co-Leader, Immunology Research Program
◆ Moffitt Cancer Center
CAR T cell therapy for Lymphoma
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©M
ed
scap
e, L
LC
Anti-CD19 CAR T cell Constructs in Pivotal Trials for ALL and NHL
◆ van der Stegen SJ, et al. Nat Rev Drug Discov. 2015;14:499-508.
Gene transfer
Kite/GileadKTE-C19
Axicabtagene ciloleucel
NovartisCTL-019
Tisagenlecleucel
Juno/CelgeneJCAR017
lisocabtagene maraleucelCD4:CD8 = 1.1
Signal 1
Signal 2
Transmembrane
CD19 Ab
Hinge
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Pivotal trials testing CD19 CAR T cell constructs for DLBCL & variants: Direct comparison of efficacy is difficult
TRANSCEND
FULL
TRANSCEND CORE
Product JCAR017 (Liso-cel) JCAR017 (Liso-cel)
# pheresed 134 NR
# treated 114 NR
# evaluable 102 73
# never treated 20/134 (15%) NR
Bridging tx (%) NR NR
ORR (%) 75 80
CR (%) 55 59
6m ORR (%) n/a 47
6m CR (%) n/a 41
ZUMA-1 (NEJM
2017;377:2531)
JULIET (Schuster, ASH
2017)
KTE-C19 (axi-cel) CTL-019 (T-cel)
111 147
101 99
101 81
9/111 (8%) 43/147 (30%)
0 89
82 53
54 40
41 37
36 30
JULIET Label Package
CTL-019 (T-cel)
160
106
68*
49/160 (30%)
90
50
32
NR
NR
Adapted from Caron Jacobson, ASCO 2018
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Pivotal trials testing CD19 CAR T cell constructs for DLBCL & variants: Toxicity comparison complicated by grading and design differences
Adapted from Caron Jacobson, ASCO 2018
TRANSCEND
FULL
TRANSCEND CORE
# pheresed 134 NR
# treated 114 NR
# evaluable 102 73
# never treated 20/134 (15%) NR
Bridging tx (%) NR NR
CRS (%) 39 37
Gr 3+ CRS (%) 1 3
NT (%) 23 25
Gr 3+ NT (%) 13 15
ZUMA-1 (NEJM
2017;377:2531)
JULIET (Schuster, ASH
2017)
111 147
101 99
101 81
9/111 (8%) 43/147 (30%)
0 89
93 58
13 23
64 21
28 12
JULIET Label Package
Insert
160
106
106*
49/160 (30%)
90
74
23
58
18
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❑ B-cell lymphomas are highly heterogeneous diseases that reproduce the
neoplastic counterpart behaviour (WHO classification)
❑ Diagnosis is based in a good excisional biopsy to perform an accurate
morphology, immunohistoquemistry and molecular techiniques
❑ Nowadays, B-cell lymphoma treatment is based on rituximab-containing
chemotherapy schedules as Rituximab has improved disease free and
overall survival
❑ BCR signalling pathways plays a central role in CLL progression
❑ Several BCR signaling targeted therapies have been recently introduced in
clinical practice with good clinical results (DFS and OS) and manageable
toxicity
❑ In Hodgkin’s lymphoma, Check-point inhibitors are able to restore
immunesurveillance and thus, rescue a group of refractory patients
❑ NGS technology is a crucial technology both for tailoing and monitring
treatment
❑ CAR T-cell is an immunological, targeted aprrpoach which is able to cure
refractory DLBCL and lymphoastic leukemia patients
Take-home messatges
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