LNH du manteau

et son traitement

PREMIERE LIGNE

Présentation clinique

• Age > 50 ans• Maladie de l’homme (3/1)• Adénopathies diffuses, splénomégalie• Stade III, IV > I, II• BM envahie (>80%) and phase Leucémique• Atteinte digestive(40%)• Atteinte SNC?• PS conservé (0-1 >2-3)

Multicenter Evaluation of MCLAnnency Criteria fulfilled

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

years

0

0,25

0,5

0,75

1

p

single agent

comb. no anthra.

comb. with anthra.

event free interval after chemotherapy in stages III + IV

Efficacy of conventional chemotherapy

Comment améliorer

le pronostic des

lymphomes du manteau ?

Stratégie habituelle en hématologie

Induction Consolidation

maintenance

SCT

=> éradication?=> Réduction tumorale

Association chimiothérapie + Rituximab

Sujets jeunes

Induction Consolidation

SCT

=> éradication?=> Réduction tumorale

Association chimiothérapie + Rituximab

European MCL Network

ASCT vs. IFN

PR, CR

Interferon-a

maintenance

Cyclo 120mg/kg

+ TBI

autologous PBSCT

RELAPSE

DexaBEAM(stem cell harvest)

6x CHOP-like chemotherapy

2 cycles

consolidation

Dreyling, Blood 2005 (updated)

Mantle cell lymphoma

High dose consolidation

Progression-free survival: il faut obtenir une CR

CR PR

HR 0.30 (95% CI 0.14 – 0.66) HR 0.60 (95% CI 0.37 – 0.96)

Dreyling ASH 2008

Quelles drogues?

Induction ?

SCT

=> tumor reduction

Augmenter le taux de RC avant autogreffe?

• HDT améliore le pronostic mais n’est pas curateur si l’on utilise le CHOP et l’endoxan lors de la greffe.

• Avons nous mieux que le CHOP ?

• Adjonction du Rituximab ? -Induction

- In vivo purge

- Maintenance

CHOP vs. R-CHOP: MCL

Time to treatment failure

Hoster, ASH 2008

Quelle chimiothérapie

en première ligne?

Le R-CHOPUn standard?

High dose Ara-C in MCL

Lefrere et al., 2002 : CHOP-DHAP (n=28)

CR OR

4x CHOP 7% 57%

4x DHAP 84% 92%

Delarue et al., 2012 :R CHOP-R DHAP (n=60)

CR OR

4x RCHOP 12% 93%

4x RDHAP 61% 95%

GELA

European MCL Network Study

Hermine O, et al. lancet 2016

PR, CR4 x R-CHOP

2 x R-CHOP

Cyclo 120 mg/kg +TBI 12 Gray

PBSCT

PR, CR

(2+1) x R-CHOP/R-DHAP

alternatingstem cell

mobilization after course 6

TBI 10 Gray +Ara-C 4 x 1.5 g/m2 +

Melphalan 140 mg/m2

PBSCT

DexaBEAM(stem cell mobilization)

Correlation between Cyclin D1 and GST-p mRNA

expression in MCL. GST-p protein is highly

expressed in MCL in 100% of cases (CCR in press)

Role of GST-p in MCL resistance to

chemotherapy

GST-p

IKK

JNK

NFKB

MAPK

Yin et al Cancer res 2000

p38

Erk

Apoptosis

Survival

And

Proliferation

Alkylating

Agents

Anthracyclins

ROS

sujets jeunes (< 65 ans): survie globale

Hermine O, et al. lancet 2016

A) Time to treatment failure

in primary analysis

(B) overall survival HR=hazard ratio

Étude de phase III LyMa

Schéma de l’étude

Le Gouill S et al : N Engl J Med 2017; 377:1250-1260

TBRP : très bonne réponse partielle.R-

DHAP

R-

DHAP

R-

DHAP

R-

DHAP

R-

BEAM

Observation

Rituximabtous les 2 mois durant 3 ansR-CHOP

S1 S4 S7 S10

Si < TBRP Si > TBRP

R-DHAP : rituximab 375 mg/m² ; cytarabine 2 g/m² i.v. 3 h d’injection à 12 h d’intervalle ;

dexaméthasone 40 mg J1 à 4 ; cisplatine 100 mg/m² J1 (ou oxaliplatine ou carboplatine)

R-BEAM : rituximab 500 mg/m² J-8 ; BCNU 300 mg/m² J-7 ; étoposide 400 mg/m²/j de J-6 à J-3 ;

cytarabine 400 mg/m²/j de J-6 à J-3, melphalan 140 mg/m² J-2

Le Gouill S et al : N Engl J Med 2017;

377:1250-1260

Expert Recommendations for Patient Case Examplefrom www.clinicaloptions.com/MCLTool

Age: < 65 years

Fitness: Fit

Del17p: No

LDH: Above ULN

Ki-67: Unknown

Expert Treatment Recommendation Additional Treatment Planned

Expert 1 Bendamustine + rituximab Maintenance rituximab

Expert 2 Alternating R-CHOP/R-DHAP ASCT followed by maintenance rituximab

Expert 3 Bendamustine + rituximab ASCT followed by maintenance rituximab

Expert 4 R-HyperCVAD ASCT followed by maintenance rituximab

Expert 5 Alternating R-HyperCVAD/R-MA Maintenance rituximab

Second-lineTreatment

Options

Current Treatment Landscape in MCL

Aggressive ChemotherapyR-CHOP/R-DHAPR-DHAPNORDIC (maxi-CHOP/R+HD cytarabine)R-HyperCVAD

Less Aggressive ChemotherapyBRVR-CAPR-CHOPLenalidomide + R

MaintenanceHDT + ASCT → R maint for 3 yrs

MaintenanceAfter R-CHOP: R maint until PDNo maint after BR

IbrutinibAcalabrutinibLenalidomide + R

Bortezomib ±RRepeat chemo (if prolonged response)

First-lineTreatment

Options

Slide credit: clinicaloptions.com

Maintenance ?

maintenance

+/-SCT

Induction

Traitement chez les sujets ne pouvant pas recevoir d‘intensification?

European MCL Consortium Phase III Study: R-CHOP vs FCR

• Randomized phase III study: R-CHOP vs FCR in untreated patients older than 60 yrs of age (planned N = 570)

– 2nd randomization to maintenance rituximab or IFN

• DSMB stopped study early

– Significant improvement with maintenance rituximab in R-CHOP patients

Kluin-Nelemans HC, et al. 2011 International Conference on Malignant Lymphoma. Abstract 16.

Survie globale : supériorité du R-CHOP Durée rémission: supériorité du rituximab

Quand?Quelle technique?Quel tissu liquide?

Améliorer 2 séquences du traitement

• Maintenance: R2 (lenalidomide approuvé par la

FDA pour les MCL)

• Induction: rôle de l’aracytine chez les sujets âgés.

26

First-line Lenalidomide + Rituximab in MCL 5-Yr

Follow-up: Study Design

▪ 5-yr follow-up of open-label, single-group, multicenter phase II trial

Ruan J, et al. ASH 2017. Abstract 154. ClinicalTrials.gov. NCT01472562. Slide credit: clinicaloptions.com

Pts with untreated

MCL,* tumor mass ≥ 1.5

cm, MIPI low to

intermediate risk (high

risk allowed if ineligible

for or declined CT),

adequate organ

function, able to take

ASA as DVT

prophylaxis

(N = 38)

Rituximab 375 mg/m2 Q1W

for cycle 1 then Q2M

starting cycle 4 +

Lenalidomide 20-25 mg

Days 1-21 of 28-day cycle

Cycle

12Induction

Rituximab 375 mg/m2 Q2M

starting cycle 14 +

Lenalidomide 15 mg

Days 1-21 of 28-day cycle

Maintenance

▪ Primary endpoint: ORR per IWG 2007 criteria

▪ Secondary endpoints: survival, QoL, safety

*With disease that is CD20+, CD5+, CD23-, and cyclin D1+.

Response assessed every 3 mos for first 2 yrs, then every 6 mos during Yr 3+.

Unti

l PD

First-line Lenalidomide + Rituximab in MCL 5-Yr

Follow-up: Baseline Pt Characteristics

CharacteristicPts

(N = 38)

Median age, yrs (range) 65 (42-86)

Male, n (%) 27 (71)

ECOG PS 0-1/> 1, n (%) 37 (97)/1 (3)

Stage III-IV MCL, n (%) 38 (100)

Elevated LDH, n (%) 14 (37)

Bone marrow involvement, n (%) 34 (89)

MIPI risk, n (%)

▪ Low (score < 5.7)

▪ Intermediate (score ≥ 5.7 to < 6.2)

▪ High (score ≥ 6.2)

13 (34)

13 (34)

12 (32)

Ki67 < 30%/≥ 30%, n (%) 26 (68)/8 (21)

Ruan J, et al. ASH 2017. Abstract 154. Slide credit: clinicaloptions.com

First-line Lenalidomide + Rituximab in MCL 5-Yr

Follow-up: Other Efficacy Results

▪ Median follow-up: 61 mos (range: 21-74)

▪ Differences in survival outcomes between low/intermediate-risk and high-risk MIPI subgroups:

– Not significantly different for PFS (log-rank P = .68)

– Significantly different for OS (log-rank P = .02)

– 4-yr OS rate: 91.4% vs 65.6%

Ruan J, et al. ASH 2017. Abstract 154. Slide credit: clinicaloptions.com

Efficacy

Endpoint, %

(95% CI)

36 Mos 48 Mos

PFS rate 80.3

(63.0-90.1)

70.6

(52.0-83.1)

OS rate 91.9

(76.9-93.7)

83.0

(65.9-92.0)

STUDY DESIGN

633 patientsResponse assessment

according to Cheson 1999 criteria

30

STUDY DESIGN

443 patientsAfter induction treatmentPatients CR, Cru or PR

Direct randomization allowed

during 6 months for patients

treated by 8 R-CHOP21

STUDY DESIGN

32

Expert Recommendations for Patient Case Examplefrom www.clinicaloptions.com/MCLTool

Age: > 75 years old

Fitness: Unfit

Del17p: No

LDH: Above ULN

Ki-67: 30-50%

Expert Treatment Recommendation

Expert 1 Bendamustine + rituximab

Expert 2 Lenalidomide + rituximab

Expert 3 Bendamustine + rituximab

Expert 4 Bendamustine + rituximab

Expert 5 Bendamustine + rituximab

Do we need a molecular

selection of the patients?

Étude PHILEMON : LCM en rechute/réfractaire

SSP selon le statut TP53

ASH 2016 - D’après Jerkeman M et al., abstr. 148, actualisé

NORDIC MCL2/3NORDIC MCL6 PHILEMON

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20

p = 0,43

Mois

(%)TP53 mut absent (n = 38)

TP53 mut présent (n = 11)

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16

TP53 mut absent (n = 136)

TP53 mut présent (n = 15)(%)

p < 0,0001

Années

Ibrutinib 560 mg/j

Semaines

Rituximab

Lénalidomide

WES in 29 cases and 6 MCL cell lines.

Beà S et al. PNAS 2013;110:18250-18255

NGS new data concerning MCL

Zhang J et al. Blood 2014;123:2988-2996

Exome sequencing in MCL reveals recurrently mutated genes.

Patterns of exonic mutations across lymphomas

show similarly and differentially mutated genes.

Zhang J et al. Blood 2014;123:2988-2996

Subclonal architecture in MCL. Representation of four informative

MCL patients with two tumor samples analyzed.

Beà S et al. PNAS 2013;110:18250-18255

Targeting the BCR

Targeting BTK

Outcomes in 370 patients with mantle cell lymphoma treated

with ibrutinib: a pooled analysis from three open‐label studies

British Journal of Haematology, Volume: 179, Issue: 3, Pages: 430-438, First

published: 18 August 2017, DOI: (10.1111/bjh.14870)

Lymph node response.

Brad S. Kahl et al. Blood 2014;123:3398-3405

©2014 by American Society of Hematology

Apoptosis

New Bcl2-inhibitors

IAP inhibitors

(BIRC3 mutated in MCL)

ABT-199: active in phase I

ORR 3/3, 2CR and 1PR

IAP?

MCL1 inhibitors?

Apoptosis

Monothérapie

Combinaison avec

ibrutinib

DNA repair.

ATM deficiency one of the most frequent oncogenic event in MCL

PARP

-Veliparib, Bendamustine, and Rituximab

-E7449

ChK1

-GDC-0575

BER

-TRC102 (Tracon)

ATR

-AZ and others

2 new therapy areas

Immunotherapy

epigenetics

GUSTAVE ROUSSY NOM DU DOCUMENT / Date

PD-1 Role in T Cell Activation

Combinations ongoing

Which anti PD-1 / PD-L1

Other targets?

2 new therapy areas

Immunotherapy

epigenetics

WES in 29 cases and 6 MCL cell lines.

Beà S et al. PNAS 2013;110:18250-18255

NGS new data concerning MCL

Zhang J et al. Blood 2014;123:2988-2996

Exome sequencing in MCL reveals recurrently mutated genes.

Epigenetics

Zhang J et al. Blood 2014;123:2988-2996

HDAC-Inhibitors

S78545 (Ribrag) 1/6 PR

Vorinostat (Krishbaum) ORR 0%

BET inhibitors

OTX015

GSK525762

CPI-0610

EZH2 (overexpression SUZ12)?