PD Dr Anastasios Stathis, MDHead-New Drugs Development Unit

Chair-Clinical ResearchOncology Institute of Southern Switzerland

Bellinzona, Switzerland

Advances in the management of non-Hodgkin’s Lymphomas

6th ESO-ESMO Eastern Europe and Balkan RegionMasterclass in Medical Oncology

12/04/2019 - 17/04/2019, Sibenik, Croatia

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Outline

• The different lymphoma subtypes• Diagnosis and staging• Principles of lymphoma therapy• Management of DLBCL: how to tailor

treatment based on clinical and biologicalfactors

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90 entities !!!

The 2016 revision of the 2008 WHO classification

(Swerdlow et al, Blood 2016)

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Incidence and mortality lymphomas

Siegel et al, CA Cancer J Clin. 2019ESO-E

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Lymphoma Database (Bellinzona and Novara), 2803 patients and 10 yrs follow-up

The most frequent subtypes

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• „Rapidly growing but curable“ (diffuse large B-cell)

• „Rapidly growing and uncurable“ (mantle cell)

• „Cumulative and uncurable“ (follicular)

• „Inflammatory and curable“ (Hodgkin)

To simplify…. a lymphoma can be

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Centroblasts Centrocytes

Memory B-cells

Plasma cells

Naive B-cells

ABC-DLBCL

FL, BL, LPHL

GCB-DLBCL

MZL

MCL

MMPEL, LPL

Marginal zone

Plasmablast

CLLHCL

cHL

Low Ag affinity

High Ag affinity

Germinal Center

Mantle zone

Low Ag affinity

clonal expansio

n

Novak U, et al. CANCER:

Principles & Practice of Oncology

Anatomy of the follicle

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Cb/Cc

Follicular

Diffuse

Images courtesy of Stefano A Pileri, MD

Basic microscopy

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Histologic subtype

CD5 CD23 CD10 BCL6BCL2 Cyclin D1 CD20

CD19

Mantle cell Lymphoma + – – – + +

Follicular Lymphoma – –/+ +/– + – +

Small Lymphocytic Lymphoma/CLL + + – – – +

LymphoplasmacyticLymphoma – – – – – +

Splenic Marginal Zone Lymphoma – – – – – +

Extranodal Marginal Zone Lymphoma (MALT type) – –/+ – – – +

Surface markers of B-cell lymphomas

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Hystological type Translocation Genes involved

MCL t(11;14) BCL1 IgH

FL>DLBCL t(14;18) BCL2 IgH

CLL/SLL t(14;19) BCL3 IgH

DLBCL>FL t(3;14) BCL6 IgH

ALCL t(2,5) NPM ALK

LPL t(9;14) PAX5 IgH

Genetic abnormalities

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Diagnostic work-up

•Medical history •B-symptoms (fever, weight loss, night sweats)•PS and comorbidities •complete physical exam (superficial lymphnodes, Waldeyer ring, liver spleen)•CBC, chemistry, electrophoresis, ESR, LDH, b2-microglobulin, HBV, HCV, HIV

•PET-CT•Bone marrow aspirate and biopsy•Lumbar puncture in high risk aggressive•Cardiac ultrasound when planned to use anthracyclines

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Ann Arbor staging

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Dia

gnos

is Therapy

SurveillanceRelapse

PET PET PET PET

staging early restaging late restaging( interim ) (end therapy)

PET-CT in lymphoma

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FDG avidity according to lymphoma type

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Bone marrow evaluation

•DLBCL–Biopsy if PET is negative and identifying a discordant histology is important for patient management

•Other subtypes–2 cm unilateral bone marrow biopsy is recommended, along with immunohistochemistry and flow cytometry at screening/baseline

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Response assessment(5-point scale: Deauville criteria)

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FDG-PET evaluation

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Principles of therapy:Chemotherapy

Drug Class DrugsCorticosteroids Prednisone, methylprednisolone, etc.Alkylating agents Chlorambucil, cyclophosphamide,

Ifosfamide, melphalan, DTIC, procarbazine, thiotepa, Carmustine

Anthracyclines Doxorubicin, EpirubicinCytotoxic antibiotics BleomycinVinca alkaloids Vincristine, vinorelbine, etc.Platin derivatives Cisplatin, carboplatin, oxaliplatinAntimetabolites Methotrexate, cytarabine,

gemcitabine, fludarabineTopoisomerase inhibitor Etoposide

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Principles of therapy:Anti-CD20 moAb Rituximab

Coiffier B, et al. NEJM 2002

OS (N = 399)

Surv

ival

Pro

babi

lity

Yrs

0

0.2

0.4

0.6

0.8

1

0 1 3 5 7 82 4 6

CHOPR-CHOP

P = .0004

Fisher RI, et al. J Clin Oncol. 2005.

DLBCL FL

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Rituximab: mechanism of action

D.G. Maloney. N Engl J Med 2012

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Definite treatment–FL stage I–MALT lymphoma stage I

After chemotherapy –DLBCL

Palliative

Principles of therapy:Radiotherapy

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High dose chemotherapy(autologous transplant)

•Mantle cell lymphoma (1st line)•DLBCL (relapse)

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Chakraverty & MacKinnon, JCO 2011 Khouri et al Blood 2012

Curative potential through graft-versus lymphoma effect• Remission desirable• Reduced-intensity conditioning• Donor lymphocyte infusions

Accepted indications:• MCL >1st relapse/progression• FL >2nd relapse/progression• CLL/SLL >1st relapse/progression after FC-R; • >2nd relapse/progression• DLBCL, PTCL investigational

Allogeneic hematopoietic stem celltransplantation in lymphoma

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CAR-T cells therapy(chimeric antigen receptor)

Kochenderfer and Rosenberg, Nat Rev Clin Oncol, 2013ESO-E

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CAR Design

S.S. Neelapu. et al, NEJM 2017

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Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma: ZUMA-1

S.S. Neelapu. et al, NEJM 2017

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Watch and wait strategy in FL (and criteria for treatment start)

Overall survival

Ardeshna K M et al., The Lancet, August 2003

W+W vs. ProMACE-MOPP89 ptsYoung, 1988

W+W vs. Prednimustine130 ptsBrice, 1997

W+W vs. Chlorambucil309 ptsArdeshna, 2003

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1st line management of DLBCL

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Diffuse large B-cell lymphoma

•the commonest type (30%-55% of NHL)•4 new cases per 100’000/year in the EU

•incidence increases with age

• <40 yro: 0.3 per 100 000/year

• >80 yro 26.6 per 100 000/year

•aggressive histology(highly atypical, large and irregular cells with vescicular nuclei and prominent nucleoli)

•aggressive behavior(untreated, kill patients)ESO-E

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Diffuse large B-cell lymphomaR-CHOP-21 Standard treatment today

Coiffier et al Blood 2010

Pfreundschuhet al. Lancet Oncol 2011

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How can we tailor treatment in DLBCL?

CLINICAL FACTORS

Age, comorbidityStage (eg short course

chemo + RT)Extranodal sites (eg CNS

prophylaxis for some sites; different treatment for PCNSL)

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A Predictive Model for Aggressive Non-Hodgkin's LymphomaThe International Non-Hodgkin's Lymphoma Prognostic Factors Project

International Prognostic Index (IPI)

Adverse risk factors:• age ≥60 yr• PS ≥ 2• LDH > normal• Ann Arbor stage III-IV• extranodal sites ≥ 2

1993;329:987-994ESO-E

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1993;329:987-994

Age-adjusted IPI (aaIPI)

aa IPI

1.Stage > II2. ECOG > 13. LDH > UNV

patients ≤ 60 years

Low 0Low-intermediate 1High-intermediate 2High 3ESO-E

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Risk of CNS relapseage > 60 y, LDH > N, stage 3 or 4, extranodal sites > 1,

kidney/adrenal gland involvement

Savage KJ et al. (Abs) Blood. 2014ESO-E

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Treatment based on clinical features

Characteristic TreatmentaaIPI=0 non bulky disease 4x RCHOP +2RaaIPI≥1 and/or bulky disease 6x RCHOP (+RT?)aaIPI=3 6xRCHOP (+auto SCT?)Older and fit patients 6x RCHOP with pre-phaseOlder not-fit 6x R-miniCHOP, or R-CEOP, or

R-Bendamustine

Testis involvement, multiple extranodal sites, close to SNC, ≥4 risk factors of the IPI score

SNC prophylaxis with HD-MTX

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Can we improve over R-CHOP21?

• Shorter treatment intervals • Maintenance rituximab • Intensive 1st line regimen • Front-line autotransplant• Infusional regimens • Replace rituximab with other MoAb

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Can we improve over R-CHOP21?

• Shorter treatment intervals NO• Maintenance rituximab NO• Intensive 1st line regimen YES but..• Front-line autotransplant In selected pts• Infusional regimens NO• Replace rituximab with other MoAb NO

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How can we tailor treatment in DLBCL?

CLINICAL FACTORS

Age, comorbidityStage (eg short course

chemo + RT)Extranodal sites (eg CNS

prophylaxis for some sites; different treatment for PCNSL)

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How can we tailor treatment in DLBCL?

CLINICAL FACTORS

Age, comorbidityStage (eg short course

chemo + RT)Extranodal sites (eg CNS

prophylaxis for some sites; different treatment for PCNSL)

BIOLOGICAL FACTORS??

COO (ABC vs GCB)Myc , BCL2, BCL6

translocationsMYC/BCL2 IHC double

expression (DE)

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Myc, Bcl-2 and Bcl-6

Rosenthal and Younes, Blood Reviews 2016

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Myc, Bcl-2 and Bcl-6

• MYC is a transcription factor which regulates the expression of several target genes involved in the cell cycle, DNA damage repair, metabolism, protein synthesis, and response to stress– MYC translocation can be detected in approximately 10% of DLBCL

(range 4% to 14%)

• BCL2 normally serves an anti-apoptotic function– BCL2 translocations are found in 20–30% of de novo DLBCL and the

vast majority of cases are observed in the GCB subtype

• BCL6 is expressed in normal mature germinal center B-cells and acts as a transcription repressor

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Adverse impact on survival of MYC translocations

Rosenthal and Younes, Blood Reviews 2016

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Swerdlow et al, Blood 2016

MYC+MYC+

DH+

DH+

DH+ DH+

Aggressive B-cell lymphomas in the new classification

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Landsburg DJ. Et al, J Clin Oncol, 2017

MYC +/- BCL2 +/- BCL6 rearrangements(role of intensive 1st line R-chemo)

RFS OS

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MYC +/- BCL2 +/- BCL6 rearrangements(role of auto-SCT in 1st line)

Landsburg DJ. Et al, J Clin Oncol, 2017

RFS OS

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Double-expressor lymphoma

19-34% of cases

IHC expression(40% MYC)(50% BCL2)

Rosenthal and Younes, Blood Reviews 2016

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Coexpression of MYC and BCL2 considered new prognostic marker (double-expressor lymphoma)

Hu et al, Blood 2013ESO-E

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DLBCL heterogeneityGene expression profiling results

Alizadeh AA et al., Nature 2000;403:503-11

GC B like

Activated B like

Different cell of origin

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DLBCL heterogeneityGene expression profiling results

Rosenwald et al, NEJM, 2002ESO-E

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Immunohistochemistry as a surrogate

Hans CP et al., Blood 2004;103:275-82

Discordances with cDNA: 20%

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Biological differences between GCB and ABC

GCB ABCBCR/NFkB signalling

Histone modification

Blocks to terminal differentiation

Cell cycle

Signalling cascade

EZH2 mutations

BCL6 expression

MYC and BCL2 translocations

PTEN del/loss(PI3k/AKT/mTORactivation)

CD79A, CARD11, MYD88mutationsTNFAIP3 (A20) deletions

PRDM1 loss/mutations

MYC and BCL2 proteinoverexpression

JAK-STAT pathway activationSehn and Gascoyne, Blood 2015

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Drugable genetic alterationsGCB ABC

BCR/NFkB signalling

Histone modification

Blocks to terminal differentiation

Cell cycle

Signalling cascade

EZH2 mutations

BCL6 expression

MYC and BCL2 translocations

PTEN del/loss(PI3k/AKT/mTORactivation)

CD79A, CARD11, MYD88mutationsTNFAIP3 (A20) deletions

PRDM1 loss/mutations

MYC and BCL2 proteinoverexpression

JAK-STAT pathway activationSehn and Gascoyne, Blood 2015

Inhibitors of the signalling

cascade

BCL6 inhibitors

EZH2 inhibitors

BCL2 inhibitors

Inhibitors of BCR/NFkBsignalling

JAK inhibitors

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Phase III studies based on COO

• Phase III studies in ABC (non-GCB)– R-CHOP +/- bortezomib– R-CHOP +/- ibrutinib– R-CHOP +/- lenalidomide

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Phase III studies based on COO

• Phase III studies in ABC (non-GCB)– R-CHOP +/- bortezomib NEGATIVE– R-CHOP +/- ibrutinib NEGATIVE– R-CHOP +/- lenalidomide NO RESULTS YET

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Phase III studies with new drugs in 1st line DLBCL

Iacoboni G et al, Ann Oncol, 2018

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Recurrent mutations by whole exome sequencing

Schmitz et al NEJM 2018

• 574 tumour samples

• Identification of 4 DLBCL genetic subtypes

• Different prognosis and possible targets for treatment

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Recurrent mutations by whole exome sequencing

Chapuy et al Nature Medicine 2018

• 304 tumour samples• 5 newly proposed DLBCL clustersESO-E

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How I treat DLBCL

• R-CHOP remains the standard of care• Consolidation with ASCT in selected young high IPI• R-CHOP + CNS prophylaxis based on CNS risk factors• No data to support MTAs added to R-CHOP based on

COO• Intensified treatment and CNS prophylaxis in HGBL

with MYC +/- BCL2 +/- BCL6 rearrangements

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In conclusion

• Treatment outcomes improved for many different lymphomas

• In DLBCL RCHOP remains the standard of care• All phase III trials have failed to imrpove treatment

outcomes in 1st line• CARTs have shown great activity in r/r DLBCL patients

(problem of costs!!!)• Need to direct treatment to specific genetic

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Thank you for your attention

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