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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)?
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