María José Terol Casterá

Department of Hematology

Hospital Clínico Universitario

Valencia

Understanding and treating lymphomas: the challenges of a

curative disease

Declaration Of Interests

Advisory:

Roche, Abbvie, Janssen, Astra-Zeneca

Research Grants:

Janssen, Glead

Normal lymph node anatomy

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

Diffuse Large

B-cell lymphoma

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

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

Classification

tissue biopsy

paraffin embeddedFresh tissue?

Blood sample?

morphology

flow citometry

Immunohistochemistry

Diagnosis

CLONALITY: rearrengement of BCR (IgH) or TCR

FISHtranslocations

GENE EXPRESSIONPROFILING

Diagnosis

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

limited advanced

Ann-Arbor classification (Costwolds modification)

Non-Hodgkin lymphomas

Staging: PET/CT

Tumor board for lymphomas:

multidisciplinary approach

lymphoma

Biopsy

Morphology

IHQ

Molecular techniques

Flow citometry

FISH

StagingResponse evaluation

Treatment

Tumour board

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)

❑ 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)

Rosenwald et al,

NEJM 2002

DLBCL: different behaviour based on

Cell of origin

High grade B-cell lymphoma

Double expressor

Double hit

❑ 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

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

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

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

B-cell receptor

IbrutinibONO

IdelalisibDuvelisib

X Puente et al. Nature 2015;526: 519-524

Lessons from NGS

Rituximab : clear Benefit for all B-cell NHL

RITUXIMAB

LLC CGD

Folicular

FC-rituximab

FC

CHOP-rituximab

CHOP

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

Schulz H, et al. Blood 2005;106:106a

(Abstract 351)

Impact of immunochemotherapy on survival in

indolent lymphomas

B-cell receptor

IbrutinibONO

IdelalisibDuvelisib

• 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

Relapsed/refractory CLL: Phase III PCYC-1112 /

RESONATE

Phase III RESONATE: PFS and OS

Pagel et al. iwCLL 2015; 146

(Poster Presentation)

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)

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

❑ 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

A new era in the treatment of CLL

Nivolumab for Hodgkin’s lymphoma

Nivolumab for Hodgkin’s lymphoma

NGS in treatment

monitoring

De Rossi D, Blood 2017

De Rossi D, Blood 2017

NGS en the treatment monitoring:

liquid biopsy

NGS en the treatment monitoring:

liquid biopsy

Responders

Non

Responders

De Rossi D, Blood 2017

Rushton et al, Lugano 2019

Rushton et al, Lugano 2019

Rushton et al, Lugano 2019

Rushton et al, Lugano 2019

Rushton et al, Lugano 2019

Rushton et al, Lugano 2019

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

Crump M, Blood 2017; 130: 1800-1808

Refractory DLBCL: very adverse outcome

Crump M, Blood 2017; 130: 1800-1808

SG: 6 meses

◆ 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

©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

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

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

❑ 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